CN100591773C - 在含油酵母中生产多不饱和脂肪酸 - Google Patents
在含油酵母中生产多不饱和脂肪酸 Download PDFInfo
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- CN100591773C CN100591773C CN200480019580A CN200480019580A CN100591773C CN 100591773 C CN100591773 C CN 100591773C CN 200480019580 A CN200480019580 A CN 200480019580A CN 200480019580 A CN200480019580 A CN 200480019580A CN 100591773 C CN100591773 C CN 100591773C
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Abstract
本发明涉及在含油酵母中生产ω-3和/或ω-6脂肪酸的方法。因此,将能够催化亚油酸(LA)转化成γ-亚麻酸(GLA);α-亚油酸(ALA)转化成十八碳四烯酸(STA);GLA转化成二高-γ-亚油酸(DGLA);STA转化成二十碳四烯酸(ETA);DGLA转化成花生四烯酸(ARA);ETA转化成二十碳五烯酸(EPA);DGLA转化成ETA;EPA转化成二十二碳五烯酸(DPA);以及将ARA转化成EPA的去饱和酶和延伸酶导入了耶氏酵母属中,用于合成ARA和EPA。
Description
本申请要求申请日为2003年5月7日的美国临时申请号60/468677的权益。
发明领域
本发明属于生物技术领域。更具体地讲,本发明涉及编码可用于在含油酵母中生产长链多不饱和脂肪酸(PUFAs)的酶的核酸片段的合成。
发明背景
很久以来就已经认识到,某些多不饱和脂肪酸,或PUFAs,是健康细胞的重要的生物学成分。例如,这样的PUFAs被认为是:
·″必需″脂肪酸,它不能够在哺乳动物体内从头合成,相反,必须从饮食中获得或者通过亚油酸(LA)或α-亚麻酸(ALA)的进一步去饱和及延伸产生;
·细胞质膜的成分,其中,它们能够以诸如磷脂或甘油三酯的形式存在;
·为正常发育所必需,特别是为婴儿脑发育和组织形成和修复所必需;和,
·在哺乳动物体内起着重要作用的若干种生物学活性类二十烷酸的前体,包括前列环素,类二十烷酸,白三烯和前列腺素。
在二十世纪70年代,发现格陵兰岛爱斯基摩人的心脏病的低发病率和大量摄入长链ω-3PUFAs相关(Dyerberg,J.等,Amer.J.Clin Nutr.28:958-966(1975);Dyerberg,J.等,Lancet 2(8081):117-119(July 15,1978))。更近一些的研究业已证实了ω-3PUFAs的心血管保护作用(Shimokawa,H.,World Rev Nutr Diet,88:100-108(2001);von Schacky,C.,和Dyerberg,J.,World Rev Nutr Diet,88:90-99(2001))。另外,业已发现,某些病症对用ω-3脂肪酸治疗有反应,如在血管成形术之后的再狭窄率,炎症症状和类风湿性关节炎,哮喘,牛皮癣和湿疹。业已证实γ-亚麻酸(GLA,一种ω-6PUFA)能降低与应激相关的血压升高,并且改善算术测验的表现。业已证实GLA和二高-γ-亚麻酸(DGLA,另一种ω-6PUFA)能抑制血小板聚集,导致血管舒张,降低胆固醇含量,并且抑制血管壁平滑肌和纤维组织的增殖(Brenner等,Adv.Exp.Med.Viol.83:85-101(1976))。施用单独的或者与二十碳五烯酸(EPA,ω-3PUFA)组合的GLA或DGLA,业已表现出能减轻或防止胃肠出血,和由非甾体类抗炎药物导致的其他副作用(U.S.4,666,701)。另外,业已证实GLA和DGLA能预防或治疗子宫内膜异位和经前综合征(U.S.4,758,592),并且治疗肌痛性脑脊髓炎和在病毒感染之后的慢性疲劳(U.S.5,116,871)。其他证据表明,PUFAs可能与钙代谢的调控有关,表明了它们可用于治疗或预防骨质疏松症和肾或尿道结石。最后,PUFAs可用于治疗癌症和糖尿病(U.S.4,826,877;Horrobin等,Am.J.Clin.Nutr.57(Suppl.):732S-737S(1993))。
PUFAs通常被划分成两种主要类型(由ω-6和ω-3脂肪酸组成),它们是分别通过必需脂肪酸,LA和ALA的去饱和和延伸产生的。尽管具有从“必需”脂肪酸的这种常见的衍生,越来越明确饮食中ω-6与ω-3的比例对维持良好的健康状态很重要。由于人类饮食习惯的改变,目前ω-6与ω-3的比例是大约10∶1,而优选的比例是2∶1(Kris-Etherton,P.M.et al.,Am.J.Olin.Nutr.71(1SuppI.):179S-88S(2000);Simopoulos,A.P.et al.,Ann.Nutr.Metab.43:127-130(1999);Krauss,R.M.et al.AHA Circulation 102:2284-2299(2000)).
ω-6脂肪酸的主要来源是含有大量LA的植物油(如玉米油、大豆油)。GLA存在于许多植物的种子,包括月见草(Oenothera biennis),,琉璃苣(Borago officinalis)和黑醋栗(Ribes nigrum)。被孢霉属(丝状真菌)的微生物、Entomophthora、腐酶属和Porphyridium(红藻)可以用于ω-6脂肪酸花生四烯酸(ARA)的商业生产。例如,用一种真菌高山被孢霉生产含ARA的油,而U.S.5,658,767(Martek Corporation)教导了生产含ARA的油的方法,包括在含有碳和氮源的培养基中培养Pythium insidiuosum。
重要的ω-3PUFAs包括EPA和二十二碳六烯酸(DHA),两者都存在于不同类型的鱼油和海洋浮游生物中。U.S.5,244,921(MartekCorporation)描述了用于生产含EPA的可食用油的方法,包括在发酵罐中培养异养硅藻,具体是Cyclotella sp.和Nitzschia sp。DHA可以获自冷水海洋鱼类、蛋黄部分,以及通过培养Dinophyceae纲的某些异养微藻类,具体是Crypthecodinium sp.,如C.cohnii(U.S.5,492,938和U.S.5,407,957)。十八碳四烯酸(STA),即EPA和DHA的一种前体,可以存在于海洋油类和植物种子中;其商业来源包括在Trichodesma和Echium属中的生产。ω-3酸的其它来源存在于亚麻籽油和胡桃油,它们均含有占绝对优势的ALA。
尽管PUFAs的多种商业来源来自于天然来源,但是存在与所述生产方法相关的若干缺陷。首先,诸如鱼和植物的天然来源倾向于具有高度的不一致的油类组成。因此,从这些来源获得的油,可能需要高度纯化,以便分离或者富集一种或多种需要的PUFAs。鱼油通常具有不佳的味道和气味,这可能不能与需要的产物经济地分开,并且可导致所述产物不能被接受为食物补充物。不佳的味道和气味可以导致基于摄入高剂量的医学方案不被接受,并且可能降低患者的依从性。此外,鱼类可能积累环境污染物,并且摄入鱼油胶囊作为饮食补充物可能导致摄入不良的污染物。天然来源同样会出现可利用性的无法控制的波动(例如,由于天气,疾病,或者对于鱼类资源来说的过度捕捞);和产生PUFAs的作物通常在经济上无法与为了食物生产而培育的杂交作物竞争。能天然产生PUFAs的某些生物(例如,Porphyridium,被孢霉)的大规模发酵同样可能是昂贵的,和/或难以以商业化规模培养。
上述限制的结果是,为了达到以下目的必须进行大量的研究:1.)开发便于商业化生产的PUFAs的重组资源;和2.)修饰脂肪酸生物合成途径,以便能够生产需要的PUFAs。
在过去若干年中在从各种生物中分离,克隆并且操作脂肪酸去饱和酶和延伸酶基因方面取得了进展。对这些基因序列的了解,提供了在不能天然产生PUFAs的新的宿主生物中生产需要的脂肪酸和/或脂肪酸组合物的前景。以下文献披露了在酿酒酵母中的多种例子,如:
1.Domergue,F.,et al.(Eur.J.Biochem.269:4105-4113(2002)),其中海洋硅藻三角褐指藻来源的两种去饱和酶被克隆进酿酒酵母内,导致生成了EPA;
2.Beaudoin F.,et al.(Proc.Natl.Acad.Sci.U.S.A.97(12):6421-6426(2000)),其中利用了秀丽新杆线虫来源的基因在酿酒酵母内重构了ω-3和ω-6PUFA生物合成途径;
3.Dyer,J.M.et al.(Appl.Eniv.Microbiol.,59:224-230(2002)),其中在酿酒酵母内表达了植物脂肪酸去饱和酶(FAD2和FAD3),导致生成了ALA;以及
4.U.S.6,136,574(Knutzon et al.,Abbott Laboratories),其中将甘蓝型油菜来源的一种去饱和酶和真菌高山被孢霉来源的两种去饱和酶克隆进酿酒酵母内,导致生成了LA、GLA、ALA和STA。
不过,仍然需要合适的微生物系统,其中,上述类型的基因可以表达,以便提供商业化数量的一种或多种PUFAs的经济生产。另外,需要富集了特殊PUFAs,特别是EPA和DHA的油。
许多微生物(包括藻类、细菌、霉菌和真菌)能够在细胞代谢的普通过程中合成油类。因此,油生产包括在合适的培养基中培养微生物以合成油,然后从发酵培养基分离微生物,并且进行处理以回收细胞内的油。已经进行了多种尝试以便通过发酵手段优化脂肪酸的生产,所述手段包括改变如使用的微生物、允许油生产的培养基和条件等参数。但是,已经证明这些努力在改进油产率或控制产生的油组合物的特征方面非常不成功。
以前尚未作为PUFAs的生产平台检验的一种类型的微生物是含油酵母。这种微生物能够积累最多占它们的干细胞重量80%的油类。业已完善了用于生长具有高油含量的含油酵母的技术(例如,参见EP 0005 277 B1;Ratledge,C.,Prog.Ind.Microbiol.16:119-206(1982)),并且可以提供与生产ω-3或ω-6PUFAs的商业化微藻发酵相比的成本优势。完整的酵母细胞可能还体现了对ω-3或ω-6PUFA-富集的油进行包囊以便用于功能性食品和动物饲料添加剂的方便途径。
尽管具有上述优点,含油酵母天然上是ω-6和ω-3PUFAs缺陷型的,因为在这种微生物中天然产生的PUFAs局限于18∶2脂肪酸(以及更不常见的是18∶3脂肪酸)。因此,要解决的问题是,开发能积累富含ω-3和/或ω-6脂肪酸的油类的含油酵母。为此,必须导入去饱和酶和延伸酶,这两种酶能够在含油酵母中合成和积累ω-3和/或ω-6脂肪酸。尽管在基因工程领域已经有了进展,但是这类技术没有被开发用于含油酵母。因此,必须克服与将这些特定宿主生物用于生产PUFAs相关的问题。
申请人通过导入异源ω-3和/或ω-6生物合成途径,证明了宿主解脂耶氏酵母(Yarrowia Lipolytica)中PUFAs的生产,从而解决了上述问题。具体地,在此生产了ARA(代表ω-6脂肪酸)和EPA(代表ω-3脂肪酸),以例证本发明的技术。
发明概述
本发明提供了在含油酵母宿主中表达包括ω-3/ω-6脂肪酸生物合成途径的酶,以便生产ω-3和/或ω-6脂肪酸的方法。因此,本发明提供了生产ω-3和/或ω-6脂肪酸的方法,包括:
a)提供包括功能性ω-3/ω-6脂肪酸生物合成途径的含油酵母;
b)在可发酵碳源的存在下生长步骤(a)的酵母,从而生产ω-3或ω-6脂肪酸;并且
c)任选回收ω-3或ω-6脂肪酸。
在一种具体实施方案中,本发明提供生产亚油酸的方法,包括:
a)提供包括以下成分的含油酵母:
(i)编码Δ12去饱和酶多肽的基因;和
(ii)油酸的内源来源;
b)在合适的可发酵碳源的存在下生长步骤(a)的酵母,其中表达编码Δ12去饱和酶多肽的基因并且将油酸转化为亚油酸;并且
c)任选回收步骤(b)的亚油酸。
在具体实施方案中,本发明提供了通过从头生物合成或从合适的前体进行单步骤酶促反应而生产特殊ω-6脂肪酸,如亚油酸(LA),γ-亚麻酸(GLA),二高-γ-亚油酸(DGLA),和花生四烯酸(ARA)的方法。类似地,本发明提供了通过单步骤酶促反应从合适的前体生产特殊ω-3脂肪酸,如α-亚油酸(ALA),十八碳四烯酸(STA),二十碳四烯酸(ETA),二十碳五烯酸(EPA),二十二碳五烯酸(DPA)和二十二碳六烯酸的方法。
附图和序列描述的简要说明
图1表示含油酵母内脂质积累生化机制的示意图。
图2表示ω-3/ω-6脂肪酸生物合成途径。
图3表示用于在解脂耶氏酵母中进行基因表达的质粒载体pY5的构建。
图4表示用于在解脂耶氏酵母中进行基因表达的质粒载体pY5-4和pY5-13的构建。
图5表示中间载体pYZM5CHPPA的构建示意图。
图6表示异丝水霉Δ17去饱和酶基因和密码子优化以便在解脂耶氏酵母中表达的合成基因的DNA序列的比较。
图7表示在解脂耶氏酵母中位于翻译起始密码子′ATG′周围的优选的共有序列。
图8表示体外合成密码子优化的Δ17去饱和酶基因的方案。
图9表示用于在解脂耶氏酵母内表达合成的密码子优化的Δ17去饱和酶基因和野生型Δ17去饱和酶基因的质粒。
图10A和10B所示为对在分别经过野生型Δ17去饱和酶基因和合成的密码子优化的Δ17去饱和酶基因转化的解脂耶氏酵母内生成的脂肪酸进行气相色谱分析的结果。
图11所示为中间载体pY24-4的构建示意图。
图12所示为中间载体pYZV16的构建示意图。
图13所示为整合载体pYZM5EL6的构建示意图。
图14所示为整合载体pYZV5EL6和pYZV5EL6/17的构建示意图。
图15是说明由工程改造的解脂耶氏酵母生产ARA的色谱图。
图16是说明由工程改造的解脂耶氏酵母生产EPA的色谱图。
通过以下的详细说明和所附的序列说明能够更全面地理解本发明,这些内容构成了本发明的一部分。
下列序列遵循37C.F.R.§1.821-1.825(“对含有核苷酸序列和/或氨基酸序列公开内容的专利申请的要求---序列规则”),并符合世界知识产权组织(WIPO)标准ST.25(1998)以及EPO和PCT的序列列表要求(管理细则的规则5.2和49.5(a-bis),以及第208节和附录C)。应用于核苷酸和氨基酸序列信息的符号和格式遵循37C.F.R.§1.822所述规则。
SEQ ID NO:1表示高山被孢霉Δ6去饱和酶基因的DNA序列,而SEQ ID NO:2表示高山被孢霉Δ6去饱和酶的氨基酸序列。
SEQ ID NO:3表示高山被孢霉Δ5去饱和酶基因的DNA序列,而SEQ ID NO:4表示高山被孢霉Δ5去饱和酶的相应的氨基酸序列。
SEQ ID NO:5表示异丝水霉Δ17去饱和酶基因的DNA序列,而SEQ ID NO:6表示异丝水霉Δ17去饱和酶的相应的氨基酸序列。
SEQ ID NO:7表示高山被孢霉高亲和力延伸酶基因的DNA序列,而SEQ ID NO:8表示高山被孢霉高亲和力延伸酶的氨基酸序列。
SEQ ID NO:9表示密码子优化以便在解脂耶氏酵母中表达的合成的Δ17去饱和酶基因的DNA序列。
SEQ ID NOs:10-31相当于11对寡核苷酸,它们共同组成了异丝水霉Δ17去饱和酶基因的完整的密码子优化的编码区(例如,分别为D17-1A,D17-1B,D17-2A,D17-2B,D17-3A,D17-3B,D17-4A,D17-4B,D17-5A,D17-5B,D17-6A,D17-6B,D17-7A,D17-7B,D17-8A,D17-8B,D17-9A,D17-9B,D17-10A,D17-10B,D17-11A和D17-11B)。
SEQ ID NOs:32-37分别相当于引物D17-1,D17-4R,D17-5,D17-8D,D17-8U和D17-11,用于在合成密码子优化的Δ17去饱和酶基因期间进行PCR扩增。
SEQ ID NOs:38和39分别相当于用于分离TEF启动子的引物TEF5′和TEF3′。
SEQ ID NOs:40和41分别相当于用于分离XPR2转录终止子的引物XPR5′和XPR3′。
SEQ ID NOs:42和43相当于引物YL21A和YL22,用于从质粒pRSP19扩增异丝水霉的野生型Δ17去饱和酶基因。
SEQ ID NOs:44和45分别相当于引物YL53和YL54,用于定点诱变,以便产生pYSD17M。
SEQ ID NO:46和47分别对应于引物KU5和KU3,被用于扩增含有耶氏酵母URA3基因的1.7kB DNA片段(SEQ ID NO:48;氨基酸序列如SEQ ID NO:49所示)。
SEQ ID NO:50和51分别对应于引物KI5和KI3,被用于扩增含有Impatient balsama的接合酶基因的1.1kB DNA片段(SEQ IDNO:52;氨基酸序列如SEQ ID NO:53所示)。
SEQ ID NO:54和55分别对应于引物KTI5和KTI3,被用于扩增含有TEF::接合酶::XPR嵌合基因的1.7kB DNA片段(SEQ ID NO:56;氨基酸序列如SEQ ID NO:57所示)。
SEQ ID NO:58和59分别对应于引物KH5和KH3,被用于扩增含有大肠杆菌潮霉素抗性基因的1kB DNA片段(SEQ ID NO:60;氨基酸序列如SEQ ID NO:61所示)。
SEQ ID NO:62和63分别对应于引物KTH5和KTH3,被用于扩增含有TEF::HPT::XPR融合基因的1.6kB DNA片段(SEQ ID NO:64;氨基酸序列如SEQ ID NO:65所示)。
SEQ ID NO:66和67分别对应于解脂耶氏酵母URA3基因中401bp的5’-序列和568bp的3’-序列,被用于将表达盒直接整合进耶氏酵母基因组的Ura位点。
SEQ ID NO:68-71分别对应于引物YL63、YL64、YL65和YL66,被用于定点诱变,以生成pY24-4。
SEQ ID NO:72和73分别对应于引物YL11和YL12,被用于扩增高山被孢霉Δ5去饱和酶。
SEQ ID NO:74-77分别对应于引物YL81、YL82、YL83和YL84,被用于定点诱变,以生成pYZM5CH。
SEQ ID NO:78和79分别对应于引物YL105和YL106,被用于定点诱变,以生成pYZM5CHPP。
SEQ ID NO:80和81分别对应于引物YL119和YL120,被用于定点诱变,以生成pYZM5CHPPA。
SEQ ID NO:82和83分别对应于引物YL121和YL122,被用于扩增解脂耶氏酵母URA3基因上游440bp的5’-非编码DNA序列(SEQ IDNO:84)。
SEQ ID NO:85和86分别对应于引物YL114和YL115,被用于定点诱变,以生成pYZV5和pYZV5P。
SEQ ID NO:87对应于适合在解脂耶氏酵母基因组内整合和表达Δ5去饱和酶基因的5.2kB DNA片段。
SEQ ID NO:88-91分别对应于引物YL61、YL62、YL69和YL70,被用于定点诱变,以生成pY58BH。
SEQ ID NO:92-95分别对应于引物YL77、YL78、YL79A和YL80A,被用于定点诱变,以生成pY54PC。
SEQ ID NO:96对应于适合在解脂耶氏酵母基因组内整合和同步表达Δ6去饱和酶、高山被孢霉延伸酶和高山被孢霉Δ5去饱和酶基因的8.9kB DNA片段。
SEQ ID NO:97-100分别对应于引物YL101、YL102、YL103和YL104,被用于定点诱变,以生成pYSD17SPC。
SEQ ID NO:101对应于适合在解脂耶氏酵母基因组内整合和同步表达Δ6去饱和酶、高山被孢霉延伸酶、高山被孢霉Δ5去饱和酶和密码子优化的Δ17去饱和酶基因的10.3kB DNA片段。
SEQ ID NO:102-113分别对应于引物YL1、YL2、YL3、YL4、YL5、YL6、YL7、YL8、YL9、YL10、YL23和YL24,被用于构建质粒。
SEQ ID NO:114表示异丝水霉Δ5去饱和酶基因的DNA序列,而SEQ ID NO:115表示异丝水霉Δ5去饱和酶的相应的氨基酸序列。
SEQ ID NO:116、117、120、121、124和125分别对应于引物YL13A、YL14A、YL19A、YL20、YL15和YL16B,用于克隆多种Δ5去饱和酶基因。
SEQ ID NO:118表示Isochrysis galbana Δ5去饱和酶基因的DNA序列,而SEQ ID NO:119表示Isochrysis galbana Δ5去饱和酶的相应的氨基酸序列。
SEQ ID NO:122表示Thraustochytrium aureum Δ5去饱和酶基因的DNA序列,而SEQ ID NO:119表示Thraustochytrium aureum Δ5去饱和酶的相应的氨基酸序列。
SEQ ID NO:126对应于最适合在耶氏酵母种内表达的基因的密码子优化翻译起始位点。
发明的详细说明
根据本发明,申请人提供了在含油酵母中生产ω-3和/或ω-6脂肪酸的方法。具体地,申请人提供了生产亚油酸、γ-亚麻酸、二高-γ-亚油酸、花生四烯酸、α-亚麻酸、十八碳四烯酸、二十碳四烯酸、二十碳五烯酸、二十二碳五烯酸和二十二碳六烯酸的方法。这是通过将由赋予Δ17去饱和酶、Δ6去饱和酶、Δ5去饱和酶、Δ9去饱和酶、Δ12去饱和酶、Δ15去饱和酶、Δ4去饱和酶和延伸酶活性的基因编码的功能性ω-3/ω-6脂肪酸生物合成途径导入含油宿主酵母中以便进行重组表达而实现的。因此,本公开内容证明了可以对含油酵母进行工程改造,以便能够生产任何所需的PUFA组合物。
本发明具有多种用途。通过本文所披露的方法制备的PUFAs,或它的衍生物可被用作饮食代用品,或补充物,特别是婴儿配方,用于静脉内喂饲的患者或用于预防或治疗营养不良。另外,可以将纯化的PUFAs(或它的衍生物)掺入烹饪油,脂肪,或配制的人造奶油中,以便在正常使用时,受体能接受到所需数量的饮食补充。还可将PUFAs掺入婴儿配方,营养补充物或其他食品中,并且可以用作抗炎剂或降胆固醇剂。可任选将所述组合物用于药物学用途(人或兽医)。在这种场合下,PUFAs通常是口服的,不过,可以通过能够成功地吸收它们的任何途径施用,例如,肠胃外(例如皮下,肌内或静脉内),直肠内,阴道内或局部(例如,作为皮肤油膏或洗液)。
给人或动物补充通过重组方法生产的PUFAs,可以导致水平增加的添加的PUFAs,以及它们的代谢产物。例如,用花生四烯酸(ARA)治疗,不仅能够产生水平增加的ARA,而且还能产生ARA的下游产物,如前列腺素。复杂的调控机制,可能需要组合各种PUFAs,或者添加PUFAs的不同的缀合物,以便预防,控制或克服这样的机制,以便在个体内获得理想水平的特定的PUFAs。
定义
在本说明书中,使用了多种术语和缩写。提供了以下定义。
″开放读框″被缩写为ORF。
″聚合酶链反应″被缩写为PCR。
″美国典型培养物保藏中心″被缩写为ATCC。
″多不饱和脂肪酸″被缩写为PUFA(s)。
术语″脂肪酸″表示具有各种链长的长链脂族酸(链烷酸),从大约C12-C22(不过已知可以采用更长和更短链长的酸)。主要的链长为C16至C22。脂肪酸的结构是通过简单的符号系统″X:Y″表示的,其中,X是在特定脂肪酸中的碳(C)原子的总数,而Y是双键的数量。
一般,脂肪酸被划分成饱和的或不饱和的。术语″饱和脂肪酸″表示在它们的碳主链之间没有″双键″的脂肪酸。相反,″不饱和脂肪酸″是沿它们的碳主链具有″双键″的顺式异构体。″单不饱和脂肪酸″沿碳主链只有一个″双键″(例如,对于棕榈油酸(16∶1)和油酸(18∶1)来说通常位于第9和第10个碳原子之间),而″多不饱和脂肪酸″(或″PUFAs″)沿碳主链具有至少两个双键(例如,对于亚油酸(18∶2)来说位于第9和第10和第12和第13个碳原子之间;对于α-亚麻酸(18∶3)来说位于第9和第10,第12和第13,和第15和第16个碳原子之间)。
″PUFAs″可以划分成两种主要类型(根据最靠近脂肪酸碳链的甲基末端的第一个双键的位置(n))。因此,″ω-6脂肪酸″(ω-6或n-6)的第一不饱和的双键距离该分子的ω(甲基)末端六个碳原子,并且一共还具有两个或两个以上双键,每一个随后的不饱和出现在朝向该分子羧基末端的三个额外的碳原子。相反,″ω-3脂肪酸″(ω-3或n-3)的第一不饱和的双键距离该分子的ω末端三个碳原子,并且一共还具有三个或三个以上双键,每一个随后的不饱和出现在朝向该分子羧基末端的三个额外的碳原子。
在本说明书中,将利用ω-参考系统表示碳原子的编号,双键的编号,和最接近ω碳原子的双键的位置,从ω碳原子开始计数(它是用于这种目的的第1号)。在下面的表1中示出了这种命名方法,表示在标题为″简化符号″的栏目中。该表的其余部分归纳了ω-3和ω-6脂肪酸的常用名,在说明书中将要使用的缩写,以及每一种化合物的化学名称。
表1
多不饱和脂肪酸的命名
常用名 | 缩写 | 化学名称 | 简化符号 |
亚油酸 | LA | 顺-9,12-十八碳三烯酸 | 18∶2 ω-6 |
γ-亚油酸 | GLA | 顺-6,9,12-十八碳三烯酸 | 18∶3 ω-6 |
二高-γ-亚油酸 | DGLA | 顺-8,11,14-二十碳三烯酸 | 20∶3 ω-6 |
花生四烯酸 | ARA | 顺-5,8,11,14-二十碳三烯酸 | 20∶4 ω-6 |
α-亚麻酸 | ALA | 顺-9,12,15-十八碳三烯酸 | 18∶3 ω-3 |
十八碳四烯酸 | STA | 顺-6,9,12,15-十八碳三烯酸 | 18∶4 ω-3 |
二十碳三烯酸 | ETA | 顺-8,11,14,17-二十碳三烯酸 | 20∶4 ω-3 |
二十碳五烯酸 | EPA | 顺-5,8,11,14,17-二十碳三烯酸 | 20∶5 ω-3 |
二十二碳五烯酸 | DPA | 顺-7,10,13,16,19-二十二碳五烯酸 | 22∶5 ω-3 |
二十二碳六烯酸 | DHA | 顺-4,7,10,13,16,19-二十二碳六烯酸 | 22∶6 ω-3 |
术语″必需脂肪酸″表示个体为了生存必须摄入的PUFA,因为所述个体不能从头合成所述特定必需脂肪酸。例如,哺乳动物不能合成必需脂肪酸亚油酸(18∶2,ω-6)。其他必需脂肪酸包括GLA(ω-6),DGLA(ω-6),ARA(ω-6),EPA(ω-3)和DHA(ω-3)。
术语″脂肪″表示脂类物质,它在25℃下是固体,并且通常是饱和的。
术语″油″表示在25℃下是液体并且通常是多不饱和的脂类。PUFAs存在于某些藻类,含油酵母和丝状真菌的油中。″微生物油″或″单细胞油″是由微生物在它们的生命过程中天然产生的油类。这种油类可能包括长链PUFAs。
术语″PUFA生物合成途径酶″表示与PUFA的生物合成相关的以下任何酶(以及编码所述酶的基因),包括:Δ4去饱和酶,Δ5去饱和酶,Δ6去饱和酶,Δ12去饱和酶,Δ15去饱和酶,Δ17去饱和酶,Δ9去饱和酶和/或延伸酶。
术语″ω-3/ω-6脂肪酸生物合成途径″表示一组基因,当它们在合适的条件下表达时,编码能催化ω-3和/或ω-6脂肪酸生产的酶。通常,与ω-3/ω-6脂肪酸生物合成途径相关的基因编码某些或所有以下的酶:Δ12去饱和酶,Δ6去饱和酶,延伸酶,Δ5去饱和酶,Δ17去饱和酶,Δ15去饱和酶,Δ9去饱和酶和Δ4去饱和酶。在图2中示出了典型的途径,证实了如何由普通来源生产ω-3和ω-6脂肪酸。本文所用与ω-3/ω-6脂肪酸生物合成途径相关的术语“功能性”指该途径中的所有基因或其中一部分可表达活性酶。应当理解的是,“ω-3/ω-6脂肪酸生物合成途径”或“功能性ω-3/ω-6脂肪酸生物合成途径”并不意味着该节所列的所有基因均是必需的,因为许多脂肪酸产物仅需该途径中部分基因的表达。
术语″去饱和酶″表示能够对一种或多种脂肪酸去饱和以便产生单-或多不饱和脂肪酸或感兴趣的前体的多种酶复合物的多肽成分。尽管在本说明书中ω-参考系统被用于表示特殊的脂肪酸,更常见的是,利用Δ-系统从底物的羧基末端开始计数以表示去饱和酶的活性。本发明特别感兴趣的是:1.)Δ17去饱和酶,它能使脂肪酸的位于从该分子的羧基末端开始计数的第17和第18个碳原子之间去饱和,并且,例如,催化ARA转化成EPA和/或DGLA转化成ETA;2.)Δ6去饱和酶,它能催化LA转化成GLA和/或ALA转化成STA;3.)Δ5去饱和酶,它能催化DGLA转化成ARA和/或ETA转化成EPA;4.)Δ4去饱和酶,它能催化DPA转化成DHA;5.)Δ12去饱和酶,它能催化油酸转化成LA;6.)Δ15去饱和酶,它能催化LA转化成ALA;和7.)Δ9去饱和酶,它能催化棕榈酸酯或盐转化成棕榈油酸(16∶1)和/或硬脂酸酯或盐转化成油酸(18∶1)。
术语″延伸酶″表示能够延伸脂肪酸碳链,以便产生比延伸酶作用的脂肪酸底物长2个碳原子的单或多不饱和脂肪酸的多酶复合物的多肽成分。这种延伸过程是通过与脂肪酸合成酶相关的多步骤机制发生的,其中,CoA是酰基载体(Lassner等,The Plant Cell 8:281-292(1996))。简单地讲,丙二酰-CoA与长链酰基-CoA缩合,以便产生CO2和β-酮酰基-CoA(其中,酰基部分业已延长了两个碳原子)。随后的反应包括还原成β-羟酰基-CoA,脱水形成烯酰基-CoA,并且第二次还原,以便产生延长的酰基-CoA。由延伸酶催化的反应的例子是将GLA转化成DGLA,STA转化成ETA和将EPA转化成DPA。因此,延伸酶可以具有不同的特异性(例如,C16/18延伸酶优选C16底物,C8/20延伸酶优选C18底物,而C20/22延伸酶优选C20底物)。
术语″高亲和力延伸酶″表示它的底物特异性优选GLA的延伸酶(DGLA是延伸酶反应的产物)。在WO 00/12720中披露了一种这样的延伸酶。
术语″转化效率″和″底物转化百分比″表示特定的酶(例如,去饱和酶或延伸酶)可以将底物转化成产物的效率。转化效率是按照以下公式计算的:([产物]/[底物+产物])*100,其中′产物′包括产生它的途径上的中间产物和所有产物。
术语″含油的″表示倾向于以脂类形式储存它们的能源的生物(Weete,In:Fungal Lipid Biochemistry,2nd ed.,Plenum,1980)。一般,所述微生物的细胞PUFA含量遵循S形曲线,其中,脂类的浓度增加,直到在后对数期或早期静止生长期的最大值,然后在晚期静止期和死亡期逐渐减少(Yongmanitchai and Ward,Appl.Environ,Microbiol.57:419-25(1991))。
术语″含油酵母″表示被分类为酵母的微生物,它们能够积累占干细胞重量至少25%的油。含油酵母的例子包括,但不局限于以下属:耶氏酵母属,假丝酵母属,红酵母属,红冬孢属,隐球酵母属,丝孢酵母属和油脂酵母属。
术语″可发酵的碳源″表示微生物能够代谢以便产生能量的碳源。本发明的典型的碳源包括,但不局限于:单糖,寡糖,多糖,链烷,脂肪酸,脂肪酸酯,甘油单酯,甘油二酯,甘油三酯,二氧化碳,甲醇,甲醛,甲酸盐或酯以及含碳的胺。
在本文中,″分离的核酸片段″是单链或双链RNA或DNA,它任选包括合成的,非天然的或改变了的核酸碱基。DNA聚合物形式的分离的多核酸片段可能由一个或多个cDNA,基因组DNA或合成DNA的片段组成。
氨基酸或核苷酸序列的″主要部分″是包括多肽的一定数目的氨基酸序列或基因的核苷酸序列的部分,所述数目足够通过本领域技术人员对所述序列进行的人工评估,或通过计算机自动化的序列比较,以及使用诸如BLAST的算法的鉴定(Basic Local Alignment Search Tool;Altschul,S.F.,等,J.Mol.Biol.215:403-410(1993)而推测性地鉴定该多肽或基因。一般,核苷酸序列的″主要部分″包括足够的序列(例如,20-30个连续的核苷酸),以便特异性地鉴定和/或分离包括所述序列的核酸片段。本说明书披露了编码一种或多种特定蛋白的部分或全部核苷酸序列。技术人员利用本文所提供的序列,可以将所披露序列的全部或主要部分用于本领域技术人员所公知的目的。因此,本发明包括在所附序列表中所提供的完整的序列,以及如上文所定义的这些序列的主要部分。
术语″互补的″被用于表示能够彼此杂交的核苷酸碱基之间的相互关系。例如,对于DNA来说,腺嘌呤互补于胸腺嘧啶,而胞嘧啶互补于鸟嘌呤。因此,本发明还包括分离的核酸片段,它互补于在所附序列表中提供的完整序列,以及基本上类似的核酸序列。
″密码子简并性″表示遗传密码的性质,它允许改变核苷酸序列,而又不影响所编码的多肽的氨基酸序列。技术人员在用核苷酸密码子表示特定氨基酸时充分理解由特定宿主细胞所表现出来的″密码子偏倚″。因此,在合成用于改善在宿主细胞中的表达的基因时,需要设计所述基因,以便它的密码子选择的频率接近宿主细胞的优选密码子选择的频率。
表示DNA序列的″化学合成的″表示组成核苷酸是在体外组装的。DNA的人工化学合成,可以通过使用业已建立的方法完成;或可以利用多种商业化仪器中的一种进行自动化的化学合成。″合成基因″可以由寡核苷酸基本单位组装,它们是利用本领域技术人员所公知的方法化学合成的。将这些基本单位连接在一起并且退火,以便形成基因片段,然后酶促组装,以便构建完整的基因。因此,可以对基因进行修饰,以便根据核苷酸序列的优化优化基因表达,以便体现宿主细胞的密码子偏倚。如果密码子选择偏向宿主优选的密码子,技术人员可以理解成功的基因表达的可能性。优选密码子的确定可以根据对来自宿主细胞的基因的检查,其中,可以获得序列信息。
″基因″表示能表达特定蛋白的核酸片段,包括位于编码序列前面(5′非编码序列)和后面(3′非编码序列)的调控序列。″天然基因″表示天然与它自身的调控序列一起出现的基因。″嵌合基因″表示不是天然基因的任何基因,包括不是天然一起存在的调控和编码序列。因此,嵌合基因可以包括来自不同来源的调控序列和编码序列,或来自相同的来源,但是以不同于天然存在的方式排列的调控序列和编码序列。″内源基因″表示存在于生物基因组上的天然位置上的天然基因。″外源″基因表示正常情况下不存在于宿主生物中,而是通过基因转移导入所述宿主生物的基因。外源基因可以包括插入非天然生物的天然基因,或嵌合基因。″转基因″是业已通过转化方法导入所述基因组的基因。″密码子优化的基因″是具有经过设计以便模拟宿主细胞的优选的密码子选择频率的密码子选择频率的基因。
″编码序列″表示编码特定氨基酸序列的DNA序列。″合适的调控序列″表示位于编码序列上游(5′非编码序列),序列内,或下游(3′非编码序列)的核苷酸序列,并且,它能影响相关编码序列的转录,RNA加工或稳定性,或翻译。调控序列可以包括启动子,翻译前导序列,内含子,聚腺苷酸化识别序列,RNA加工位点,效应物结合位点和茎-环结构。
″启动子″表示能够控制编码序列或功能性RNA表达的DNA序列。一般,编码序列位于启动子序列的3′侧。启动子可能完全来自天然基因,或者由来自天然存在的不同启动子的不同元件组成,或者甚至包括合成的DNA片段。本领域技术人员可以理解的是,不同的启动子能够指导基因在不同的组织或细胞类型中的表达,或者在发育的不同阶段的表达,或者对不同的环境或生理学条件作出反应的表达。能导致基因在大多数细胞类型中在大多数时间表达的启动子通常被称作″组成型启动子″。还应当理解的是,由于在大多数场合下,调控序列的确切边界未能完全确定,不同长度的DNA片段可能具有相同的启动子活性。
术语″3′非编码序列″或″转录终止子″表示位于编码序列下游的DNA序列。它包括聚腺苷酸化识别序列以及编码能够影响mRNA加工或基因表达的调控信号的其他序列。聚腺苷酸化信号通常以影响聚腺苷酸添加在mRNA前体的3′末端为特征。所述3′区能够影响相关编码序列的转录,RNA加工或稳定性,或翻译。
″RNA转录物″表示由RNA聚合酶催化的DNA序列转录而得到的产物。当RNA转录物是所述DNA序列的完整的互补拷贝时,它被称作初级转录物,或者它可以是来自初级转录物的转录后加工的RNA序列,并且被称作成熟的RNA。″信使RNA″或″mRNA″表示没有内含子,并且能够由细胞翻译成蛋白的RNA。″cDNA″表示双链DNA,它是互补于mRNA并且由mRNA衍生的。″有义″RNA表示包括mRNA,并能够由细胞翻译成蛋白的RNA转录物。″反义″RNA表示互补于靶初级转录物或mRNA的全部或部分的RNA,并且它能抑制靶基因的表达(U.S.5,107,065;WO 99/28508)。反义RNA的互补性可以是与特定基因转录物的任何部分,即,位于5′非编码序列,3′非编码序列,或编码序列互补的。″功能性RNA″表示反义RNA,核酶RNA,或不能翻译,但仍然能影响细胞加工的其他RNA。
术语″可操作地连接的″表示核酸序列缔合在一个核酸片段上,以便其中一个的功能受到另一个的影响。例如,当启动子能够影响编码序列的表达时,它就是与该编码序列可操作地连接的(即,所述编码序列受所述启动子的转录控制)。编码序列能够沿有义或反义方向可操作地与调控序列连接。
在本文中,术语″表达″表示来自本发明的核酸片段的有义(mRNA)或反义RNA的转录和稳定积累。表达还可以表示mRNA翻译成多肽。
″转化″表示将核酸分子转入宿主生物,导致了遗传学稳定的遗传性。例如,核酸分子可以是能自主复制的质粒;或者它可以整合到宿主生物的基因组中。包括转化的核酸片段的宿主生物被称作″转基因″或″重组″或″转化过的″生物。
术语″质粒″,″载体″和″盒″表示染色体外元件,它通常携带有不是细胞的中央代谢部分的基因,并且通常是环状双链DNA片段形式的。所述基因可以是自主复制的序列,基因组整合序列,噬菌体或核苷酸序列,线性或环状的单或双链DNA或RNA,可以来自任何来源,其中,多个核苷酸序列业已连接或重组成独特的结构,它能够将启动子片段和选定的基因产物的DNA序列,以及合适的3′非翻译序列导入细胞。″转化盒″表示包括外源基因,并且除了外源基因之外还具有能促进在特定宿主细胞中转化的元件的特定载体。″表达盒″表示包括外源基因,并且除了外源基因之外,还具有能够增强基因在外源宿主中表达的元件的特定载体。
术语″序列分析软件″表示可用于分析核苷酸或氨基酸序列的任何计算机算法或软件程序。″序列分析软件″可以是通过商业渠道获得的或者独立开发的。典型的序列分析软件包括,但不局限于:1.)GCG程序组(Wisconsin Package Version 9.0,Genetics Computer Group(GCG),Madison,WI);2.)BLASTP,BLASTN,BLASTX(Altschul等,J.Mol.Biol.215:403-410(1990));3.)DNASTAR(DNASTAR,Inc.,Madison,WI);和4.)采用了Smith-Waterman算法的FASTA程序(W.R.Pearson,Comput.Methods Genome Res.,[Proc.Int.Symp.](1994),Meeting Date 1992,111-20.Editor(s):Suhai,Sandor.Plenum:New York,NY)。在本申请的范围内应当理解的是,在将序列分析软件用于分析时,分析的结果是基于有关程序的″预设值″的,除非另有说明。在本文中,″预设值″表示任何组的值或参数,它是在初次初始化时最初随所述软件加载的。
本发明所使用的标准重组DNA和分子克隆技术是本领域众所周知的,并且披露于以下文献中:Sambrook,J.,Fritsch,E.F.和Maniatis,T.,Molecular Cloning:A Laboratory Manual,2nd ed.,Cold SprmgHarbor Laboratory:Cold Spring Harbor,NY(1989)(此后称作″Maniatis″);Silhavy,T.J.,Bennan,M.L.和Enquist,L.W.,Experiments with Gene Fusions,Cold Spring Harbor Laboratory:ColdSpring Harbor,NY(1984);以及Ausubel,F.M.等,Current ProtocolsinMolecular Bioloqy,由Greene Publishing Assoc.andWiley-Interscience(1987)出版。
脂肪酸的微生物生物合成
一般,在含油微生物中的脂类的积累是反应于存在于生长培养基中的总的碳与氮的比例引发的(图1)。当细胞耗尽了可利用的氮源时(例如,当碳与氮的比例超过大约40时),细胞一磷酸腺苷(AMP)的消耗,导致了线粒体中AMP-依赖型异柠檬酸脱氢酶活性的终止和柠檬酸的积累,并且将柠檬酸转移到细胞质,并且随后通过ATP-柠檬酸裂解酶裂解,产生乙酰-CoA。乙酰-CoA是脂肪酸从头合成的主要基本单位。尽管任何能够有效代谢产生乙酰-CoA的化合物都可用作脂肪酸的前体,葡萄糖是这种类型反应中的主要碳源(图1)。通过糖酵解将葡萄糖转化成丙酮酸,并且然后将丙酮酸转入线粒体,在这里,它能够通过丙酮酸脱氢酶转化成乙酰-CoA(”PD”)。由于乙酰-CoA不能直接通过线粒体膜转入细胞质,乙酰-CoA上的两个碳与草酰乙酸缩合,以便产生柠檬酸(通过柠檬酸合酶催化)。柠檬酸被直接转入细胞质,在这里,它被ATP-柠檬酸酶裂解,以便再生乙酰-CoA和草酰乙酸。草酰乙酸通过转化成苹果酸重新进入三羧酸循环。
丙二酰-CoA的合成是脂肪酸生物合成的第一个关键步骤,它是在细胞质中进行的。丙二酰-CoA是通过乙酰-CoA羧化酶催化由乙酰-CoA的羧化产生的。脂肪酸合成是通过多种酶脂肪酸合酶复合物(″FAS″)催化的,并且通过八种二碳片段(来自乙酰-CoA的乙酰基团)的缩合进行,以便形成16-碳饱和脂肪酸棕榈酸。更具体地讲,FAS催化一系列的7个反应,该系列包括以下反应(Smith,S.FASEB J,8(15):1248-59(1994)):
1.乙酰-CoA和丙二酰-CoA被转移到FAS的酰基载体肽(ACP)上。所述乙酰基团然后被转移到丙二酰基团上,形成β-酮丁酰基-ACP,并且释放CO2。
2.所述β-酮丁酰基-ACP发生还原(通过β-酮酰基还原酶)和脱水(通过β-羟酰基脱水酶),以便形成反式-单不饱和的脂肪酰基。
3.通过NADPH还原双键,产生比最初的基团长两个碳原子的饱和脂肪酰基。然后再生了丁酰基-基团与新的丙二酰基团缩合,并且重复所述延伸过程的能力。
4.当脂肪酰基变成16个碳原子长时,硫酯酶活性水解它,释放游离的棕榈酸。
棕榈酸(16∶0)是长链饱和和不饱和脂肪酸(例如,硬脂酸(18∶0),棕榈油酸(16∶1)和油酸(18∶1))的前体,通过存在于内质网膜中的延伸酶和去饱和酶的作用产生棕榈酸。通过Δ9去饱和酶的作用分别将棕榈酸和硬脂酸转化成它们的不饱和衍生物,即棕榈油酸(16∶1)和油酸(18∶1)。
三酰基甘油(脂肪酸的主要储存单位)是通过将两个分子的酰基-CoA酯化成甘油-3-磷酸产生1,2-磷酸二酰基甘油的(通常被称为磷脂酸)。然后通过磷脂酸磷酸酶除去磷酸,以便得到1,2-二酰基甘油。三酰基甘油是通过二酰基甘油-酰基转移酶的作用添加第三个脂肪酸形成的。
Ω3和Ω6脂肪酸的生物合成
简单地讲,将LA转化成GLA,DGLA和ARA(ω-6途径)和ALA转化成STA,ETA,EPA,DPA和DHA(ω-3途径)的代谢过程涉及通过添加碳原子延长碳链,和通过添加双键使分子去饱和(图2)。这需要存在于内质网膜中的一系列特殊去饱和和延伸酶。
ω-6脂肪酸
通过Δ12去饱和酶的作用将油酸转化成LA(18∶2),它是ω-6脂肪酸的第一个。按以下方法产生后续的ω-6脂肪酸:1.)通过Δ6去饱和酶的活性将LA转化成GLA;2.)通过延伸酶的作用将GLA转化成DGLA;和3.)通过Δ5去饱和酶的作用将DGLA转化成ARA。
ω-3脂肪酸
通过Δ15去饱和酶的作用将亚油酸(LA)转化成ALA,即ω-3脂肪酸的第一个。通过一系列类似于ω-6脂肪酸的步骤产生后续的ω-3脂肪酸。具体地讲:1.)通过Δ6去饱和酶的活性将ALA转化成STA;2.)通过延伸酶的活性将STA转化成ETA;和3.)通过Δ5去饱和酶的活性将ETA转化成EPA。另外,ETA和EPA可以通过Δ17去饱和酶的活性分别由DGLA和ARA产生。还可以通过延伸酶和Δ4去饱和酶的活性进一步将EPA转化成DHA。
与Ω脂肪酸生产相关的基因
很多微生物,包括藻类,细菌,霉菌和酵母都可以通过正常细胞代谢过程合成PUFAs和ω脂肪酸。进行过充分研究的是包括Schizochytrium aggregatm,破囊壶菌属的种和高山被孢菌在内的真菌。很多沟鞭藻类(Dinophyceaae)都能天然产生高浓度的PUFAs。因此,业已通过遗传学方法鉴定了与油类产生相关的多个基因,并且某些基因的DNA序列可以公开获得(非限定性例子如下面的表2所示):
表2
某些可公开获得的与PUFA生产相关的基因
GenBank登录号 | 描述 |
AY131238 | Argania spinosa Δ6去饱和酶 |
Y055118 | Echium pitardii var.pitardii Δ6去饱和酶 |
AY055117 | Echium gentianoides Δ6去饱和酶 |
AF296076 | 鲁克氏毛霉Δ6去饱和酶 |
AF007561 | Borago officinalis Δ6去饱和酶 |
L11421 | Synechocystis sp.Δ6去饱和酶 |
NM_031344 | 褐家鼠Δ6脂肪酸去饱和酶 |
AF465283,AF465281,AF110510 | 高山被孢霉Δ6脂肪酸去饱和酶 |
AF465282 | 深黄被孢霉Δ6脂肪酸去饱和酶 |
AF419296 | 畸雌腐霉Δ6脂肪酸去饱和酶 |
AB052086 | 卷枝毛霉Δ6脂肪酸去饱和酶的D6d mRNA |
AJ250735 | Ceratodon purpureus Δ6脂肪酸去饱和酶的mRNA |
AF128799 | 人Δ6脂肪酸去饱和酶 |
AF126798 | 小鼠Δ6脂肪酸去饱和酶 |
AF199596,AF226273 | 人Δ5去饱和酶 |
AF320509 | 褐家鼠肝Δ5去饱和酶 |
AB072976 | 小鼠Δ5去饱和酶的D5D mRNA |
AF489588 | 破囊壶菌种ATCC21685 Δ5脂肪酸去饱和酶 |
AJ510244 | 大雄疫霉Δ5脂肪酸去饱和酶的mRNA |
AF419297 | 畸雌腐霉Δ5脂肪酸去饱和酶 |
AF07879 | 秀丽新杆线虫Δ5脂肪酸去饱和酶 |
AF067654 | 高山被孢霉Δ5脂肪酸去饱和酶 |
AB022097 | Dictyostelium discoideum Δ5脂肪酸去饱和酶的mRNA |
AF489589.1 | 破囊壶菌种ATCC21685 Δ4脂肪酸去饱和酶 |
AY332747 | Pavlova lutheri Δ4脂肪酸去饱和酶 |
AAG36933 | Emericella nidulans油酸Δ12去饱和酶 |
AF110509,AB020033 | 高山被孢霉Δ12脂肪酸去饱和酶mRNA |
AAL13300 | 高山被孢霉Δ12脂肪酸去饱和酶 |
GenBank登录号 | 描述 |
AF417244 | 高山被孢霉ATCC16266 Δ12脂肪酸去饱和酶基因 |
AF161219 | 鲁克氏毛霉Δ12去饱和酶mRNA |
X86736 | Spiruline platensis Δ12去饱和酶 |
AF240777 | 秀丽新杆线虫Δ12去饱和酶 |
AB007640 | Chlamydomonas reinhardtii Δ12去饱和酶 |
AB075526 | 普通小球藻Δ12去饱和酶 |
AP002063 | 拟南芥微粒体Δ12去饱和酶 |
NP_441622,BAA18302,BAA02924 | Synechocystis sp.PCC 6803 Δ15去饱和酶 |
AAL36934 | Perilla frutescens Δ15去饱和酶 |
AF338466 | Acheta domesticus Δ9去饱和酶3mRNA |
AF438199 | Picea glauca去饱和酶Δ9(Des9)mRNA |
E11368 | Anabaena Δ9去饱和酶 |
E11367 | Synechocystis Δ9去饱和酶 |
D83185 | Pichia angusta Δ9脂肪酸去饱和酶的DNA |
U90417 | Synechococcus vulcanus Δ9酰基-脂类脂肪酸-去饱和酶(desC)基团 |
AF085500 | 高山被孢霉Δ9去饱和酶mRNA |
AY504633 | Emericella nidulans Δ9硬脂酸去饱和酶(sdeB)基因 |
NM_069854 | 秀丽新杆线虫必需脂肪酸去饱和酶,硬脂酰-CoA去饱和酶(39.1KD)(脂肪-6)完整mRNA |
AF230693 | Brassica oleracea cultivar Rapid Cycling硬脂酰-ACP去饱和酶(Δ9-B0-1)基因,外显子序列 |
AX464731 | 高山被孢霉延伸酶基因(也见WO 02/08401) |
NM_119617 | 拟南芥脂肪酸延伸酶1(FAE1)(At4g34520)mRNA |
NM_134255 | 小鼠ELOVL家族成员5,长链脂肪酸的延伸(酵母)(Elov15),mRNA |
NM_134383 | 褐家鼠脂肪酸延伸酶2(rEL02),mRNA |
NM_134382 | 褐家鼠脂肪酸延伸酶1(rEL01),mRNA |
NM_068396,NM_068392,NM_070713,NM_068746,NM_064685 | 秀丽新杆线虫脂肪酸延伸(elo-6),(elo-5),(elo-2),(elo-3)和(elo-9)mRNA |
另外,专利文献提供了与PUFA生产相关的很多其他基因的DNA序列(和/或与上述若干基因相关的细节以及它们的分离方法)。例如,参见:U.S.5,968,809(Δ6去饱和酶);U.S.2003/0196217 A1(Δ17去饱和酶);U.S.5,972,664和U.S.6,075,183(Δ5去饱和酶);WO 91/13972和U.S.5,057,419(Δ9去饱和酶);WO 93/11245(Δ15去饱和酶);WO 94/11516,U.S.5,443,974和WO 03/099216(Δ12去饱和酶);WO 02/090493(Δ4去饱和酶);和WO 00/12720和U.S.2002/0139974A1(延伸酶)。上述每一份专利和专利申请都以它们的全文形式收作本文参考。
正如本领域技术人员所了解的,导入用于生产特定的PUFA最终产物的宿主生物所需要的特殊功能,取决于宿主细胞(以及它的天然PUFA谱和/或去饱和酶谱),底物的可利用性和需要的最终产物。如图2中所示出的,LA,GLA,DGLA,ARA,ALA,STA,ETA,EPA,DPA和DHA都可以在含油酵母中生产,这是通过导入以下PUFA酶功能的各种组合:Δ4去饱和酶,Δ5去饱和酶,Δ6去饱和酶,Δ12去饱和酶,Δ12去饱和酶,Δ17去饱和酶,Δ9去饱和酶和/或延伸酶。根据可公开获得的文献(例如,GenBank),专利文献,以及对具有生产PUFAs的能力的微生物进行的实验分析,本领域技术人员能够鉴定编码上述每一种酶的各种候选基因。所述序列可来自任何来源,例如,从天然来源中分离(从细菌,藻类,真菌,植物,动物等中分离),通过半合成途径生产,或从头合成。在一些实施方案中,宿主内源基因的操作是优选的;对于其它目的,必须导入异源基因。
尽管导入宿主的去饱和酶和延伸酶基因的特定来源并不重要,选择具有去饱和酶或延伸酶活性的特定多肽的考虑因素包括:1.)所述多肽的底物特异性;2.)所述多肽或它的成分是否是限速酶;3.)所述去饱和酶或延伸酶是否是合成需要的PUFA所必需的;和/或4.)所述多肽所需要的辅助因子。所表达的多肽优选具有与它在宿主细胞中的部位的生物化学环境相容的参数。例如,所述多肽可能必须与宿主细胞中的其他酶竞争底物。因此,在确定特定多肽修饰PUFA在特定宿主细胞中的生产的合适性时,需要考虑KM和所述多肽比活性的分析。用于特定宿主细胞中的多肽是这样的多肽,它能在存在于预期宿主细胞中的生物化学条件下起作用,但原本可以是具有能够修饰需要的PUFA的具有去饱和酶或延伸酶活性的任何多肽。
内源PUFA基因
在某些情况下,需要用来生产PUFAs的宿主生物将具有编码某些PUFA生物合成途径酶的内源基因。例如,含油酵母一般可以生产18∶2脂肪酸(某些具有合成18∶3脂肪酸的额外能力);因此,含油酵母一般具有天然的Δ12去饱和酶活性,并且可能也具有Δ15去饱和酶活性。因此,在某些实施方案中,天然去饱和酶的表达相对于异源(或“外源”)酶是优选的,因为:1.)天然酶最适合与细胞内其它酶和蛋白相互作用;且2.)异源基因不太可能与宿主生物共有相同的密码子优先。此外,已知天然基因序列时的优势在于,易于通过定向破坏将内源基因破坏。
异源PUFA基因
在很多情况下,合适的去饱和酶和延伸酶不存在于选择用来生产需要的PUFA产物的宿主生物中。因此,必须导入异源基因。
为了此处描述的本发明的目的,需要证明将ω-3和/或ω-6生物合成途径导入含油宿主生物的例子;因此,高山被孢霉Δ5去饱和酶、高山被孢霉Δ6去饱和酶、异丝水霉Δ17去饱和酶、和高山被孢霉延伸酶被导入解脂耶氏酵母。但是,将特定的酶(和编码这些酶的基因)导入宿主生物和产生的特定PUFAs并不是对本发明进行限制。
如此处所证明的,如果需要产生EPA,本领域技术人员将明白,来源于不同来源的许多其它基因将适于将Δ5去饱和酶、Δ6去饱和酶、Δ17去饱和酶、和延伸酶活性导入优选的微生物宿主。因此,在本发明的一个实施方案中,也可以将与高山被孢霉Δ6去饱和酶、Δ5去饱和酶和高亲和力PUFA延伸酶以及异丝水霉Δ17去饱和酶基本等同的其它DNA用于在含油酵母中生产ω-6和/或ω-3脂肪酸(如EPA)。“基本等同的”是指与选定的多肽或编码氨基酸序列的核酸序列具有至少80%、90%或95%同源性的序列。对于多肽,比较序列的长度通常为至少16个氨基酸,优选至少20个氨基酸或最优选35个氨基酸。对于核酸,比较序列通常为至少50个核苷酸,优选至少60个核苷酸,更优选至少75个核苷酸,最优选110个核苷酸。
通常采用序列分析软件测量同源性,其中″序列分析软件″表示可用于分析核苷酸或氨基酸序列的任何计算机算法或软件程序。″序列分析软件″可以是通过商业渠道获得的或者独立开发的。典型的序列分析软件包括,但不局限于:1.)GCG程序组(Wisconsin Package Version9.0,Genetics Computer Group(GCG),Madison,WI);2.)BLASTP,BLASTN,BLASTX(Altschul等,J.Mol.Biol.215:403-410(1990));3.)DNASTAR(DNASTAR,Inc.,Madison,WI);和4.)采用了Smith-Waterman算法的FASTA程序(W.R.Pearson,Comput.MethodsGenome Res.,[Proc.Int.Symp.](1994),Meeting Date 1992,111-20.Editor(s):Suhai,Sandor.Plenum:New York,NY)。在本申请的范围内应当理解的是,在将序列分析软件用于分析时,分析的结果是基于有关程序的″预设值″的,除非另有说明。在本文中,″预设值″表示任何组的值或参数,它是在初次初始化时最初随所述软件加载的。概言之,所述计算机软件通过给多种取代、缺失和其它修饰分配同源性程度而匹配相似的序列。
此外,本领域技术人员应当理解,多肽可以具有氨基酸保守取代,其取代方式使得多肽的功能没有改变或受损。具有此处描述的去饱和酶和延伸酶活性并且具有所述保守取代的多肽包括在本发明的范围内。保守取代一般包括下列各组内的取代:1.)甘氨酸和丙氨酸;2.)缬氨酸、异亮氨酸和赖氨酸;3.)天冬氨酸、谷氨酸、天冬酰胺和谷氨酰胺4.)丝氨酸和苏氨酸;5.)赖氨酸和精氨酸;和6.)苯丙氨酸和酪氨酸。也可以在保守的疏水性或亲水性基础上进行取代(Kyte andDoolittle,J.Mol.Biol.157:105-132(1982)),或在假定相似多肽二级结构的能力的基础上进行取代(Chou and Fasman,Adv.Enzymol.47:45-148(1978))。
在本发明的备选实施方案中,其它尽管不基本等同于高山被孢霉Δ6去饱和酶、Δ5去饱和酶和高亲和力PUFA延伸酶以及异丝水霉Δ17去饱和酶的DNA也可以用于此处的目的(如,用于生产ω-3和/或ω-6PUFAs,如ARA和EPA)。例如,用于根据本发明的教导导入含油酵母的编码Δ6去饱和酶多肽的DNA序列可以获自具有生产GLA或STA的能力的微生物。所述微生物包括,例如,属于被孢霉属、耳霉属、腐霉属、疫霉属、青霉属、Porphyridium、Coidosporium、毛霉属、镰孢属、曲霉属、红酵母属和虫霉属的那些。在Porphyridium属内,特别感兴趣的是P.Cruentum。在被孢霉属内,特别感兴趣的是长形被孢霉、微小被孢霉、喜湿被孢霉、M.ramanniana var.angulispora和高山被孢霉。在毛霉属中,特别感兴趣的是卷枝毛霉和爪哇毛霉。
或者,不与高山被孢霉Δ6去饱和酶基本等同,但可以在脂肪酸分子的羧基末端开始的第6个碳对脂肪酸分子去饱和的相关去饱和酶也可以在本发明中用作Δ6去饱和酶,假定该去饱和酶仍然可以有效将LA转化为GLA和/或将ALA转化为STA。因此,可以通过基本与此处公开的去饱和酶和延伸酶起相同作用的能力而鉴定相关的去饱和酶和延伸酶。
总之,可以从多种来源分离适于此处目的的编码PUFA生物合成途径酶的基因。用于此处目的的去饱和酶的特征在于以下能力:1.)使脂肪酸的位于从该分子的羧基末端开始计数的第17和第18个碳原子之间去饱和,并且,催化ARA转化成EPA和DGLA转化成ETA(Δ17去饱和酶);2.)催化LA转化成GLA和/或ALA转化成STA(Δ6去饱和酶);3.)催化DGLA转化成ARA和/或ETA转化成EPA(Δ5去饱和酶);4.)催化DPA转化成DHA(Δ4去饱和酶);5.)催化油酸转化成LA(Δ12去饱和酶);6.)催化LA转化成ALA(Δ15去饱和酶);和7.)催化棕榈酸酯或盐转化成棕榈油酸和/或硬脂酸酯或盐转化成油酸。以相似的方式,用于此处目的的合适的延伸酶不限于来源于特定来源的那些;而是,用于此处目的的酶的特征在于它们具有使得脂肪酸碳链相对于延伸酶作用的底物能够延长2个碳,从而产生单或多不饱和脂肪酸的能力。
对Ω脂肪酸基因进行优化以便在特定生物中表达
尽管PUFA去饱和酶或延伸酶的特定来源在本发明中不是关键的,本领域技术人员将理解,异源基因将在备选的宿主以多种效率进行表达。因此,ω-3和/或ω-6PUFA生产可以通过选择特定去饱和酶或延伸酶而进行优化,所述去饱和酶或延伸酶在异源宿主中的表达水平相对于备选去饱和酶或延伸酶在感兴趣的宿主生物中的表达而言是优选的。此外,可能需要根据感兴趣的特定PUFA产物组成,修饰特定PUFA生物合成途径酶的表达,以达到每一种的最佳转化效力。多种基因工程技术可以用于优化特定酶的表达。两种这样的技术包括密码子优化和基因突变,如下文所描述。例如,通过这两种方法中的任意一种产生的具有去饱和酶和/或延伸酶活性的基因可以用于本发明中合成ω-3和/或ω-6脂肪酸。
密码子优化
正如本领域技术人员所理解的,通常修饰在外源宿主中表达的编码特定多肽的密码子的一部分,使得修饰的多肽使用替代的宿主优选的密码子。使用宿主优选的密码子能够显著增强编码多肽的外源基因的表达。
一般,可以在特定的感兴趣的宿主物种中确定宿主优选的密码子,包括检查蛋白中的密码子选择(优选大量表达的蛋白),并且确定哪些密码子是以最高频率使用的。然后,可以使用在所述宿主物种中优选的密码子完全或部分合成具有去饱和酶或延伸酶活性的感兴趣的多肽的编码序列。也可以合成DNA的全部(或部分),以便除去可能出现在转录的mRNA上的任何去稳定化序列或二级结构区。还可以合成所述DNA的全部(或部分),以便改变将碱基组成改变成在需要的宿主细胞中更优选形式。
对于本发明来说,需要修饰编码具有Δ17去饱和酶活性的多肽的密码子的一部分,以便增强基因在解脂耶氏酵母中的表达。修饰了天然基因(如异丝水霉Δ17去饱和酶)的核酸序列,以便使用宿主优选的密码子。技术人员了可以理解的是,该优化方法同样可应用于ω-3/ω-6脂肪酸生物合成途径中的其他基因(例如,参见共同未决的美国临时申请NO.60/468718,在此全文收作本文参考)。此外,对异丝水霉Δ17去饱和酶的调节仅仅是示例的。
基因突变
用于合成序列并且将这些序列组合在一起的方法在文献中业已完善。例如,体外诱变和选择,定点诱变,易错PCR(Melnikov等,NucleicAcids Research,27(4):1056-1062(February 15,1999)),″基因改组″或其他方法可用于获得天然存在的或密码子优化的去饱和酶或延伸酶基因的突变。这样使得能够生产去饱和酶或延伸酶多肽,它们分别具有,例如更长的半衰期或需要的PUFA在体内生产的更高速度。
如果需要,对酶促活性重要的感兴趣多肽(即去饱和酶或延伸酶)的区可以通过常规诱变,所得到的突变多肽的表达以及确定它们的活性而确定。突变体可以包括缺失,插入或点突变,或它们的组合。典型的功能性分析始于缺失诱变,以便确定功能所需要的蛋白的N-末端和C-末端限制,然后进行内部缺失,进行插入或点突变,以便进一步确定功能所需要的区。还可以使用其他技术,如盒诱变或完全合成。例如,缺失诱变是通过使用核酸外切酶依次去掉5′或3′编码区实现的。可以获得用于这种技术的试剂盒。在缺失之后,在5′或3′缺失之后通过将包括起始或终止密码子的寡核苷酸分别连接在缺失的编码区上获得所述编码区。另外,通过各种方法将编码起始或终止密码子的寡核苷酸插入所述编码区,包括定点诱变,诱变PCR或通过连接到在现有限制位点上消化过的DNA上。内部缺失同样可以通过多种方法实现,包括使用DNA上的现有限制位点,通过使用诱变引物进行定点诱变或诱变PCR。插入是通过诸如接头-扫描诱变,定点诱变或诱变PCR的方法完成的。点突变是通过诸如定点诱变或诱变PCR的技术完成的。
还可将化学诱变用于鉴定对活性重要的去饱和酶或延伸酶多肽区。表达突变的构建体,并且测定所得到的改变了的蛋白作为去饱和酶或延伸酶的能力。这种结构-功能分析,可以确定哪些区可以缺失,哪些区能够承受插入,以及哪些点突变使得突变的蛋白能够以基本上与天然的去饱和酶或天然的延伸酶相同的方式起作用。所有这样的突变蛋白及其来源于本文所述密码子优化的基因的编码核苷酸序列均属于本发明范畴。
对于本发明来说,需要修饰编码具有Δ17去饱和酶活性的多肽的密码子的一部分,以便增强基因在解脂耶氏酵母中的表达。修饰了天然基因(如异丝水霉Δ17去饱和酶)的核酸序列,以便使用宿主优选的密码子。技术人员了可以理解的是,该优化方法同样可应用于ω-3/ω-6脂肪酸生物合成途径中的其他基因(例如,参见共同未决的美国临时申请NO.60/468718,在此全文收作本文参考)。此外,对异丝水霉Δ17去饱和酶的调节仅仅是示例的。
ω-3和/或ω-6脂肪酸的微生物生产
ω-3和/或ω-6脂肪酸的微生物生产与从诸如鱼或植物的天然来源中纯化相比具有若干优点。例如:
1.)已知与高等生物相比,很多微生物具有大大简化了的油类组成,使得对需要成分的纯化更容易;
2.)微生物生产不容易出现由外部因素导致的波动,如天气和食物供应;
3.)微生物生产的油基本上不会受到环境污染物的污染;
4.)微生物能够以可能具有特殊用途的特定形式提供PUFAs;和,
5.)微生物油类生产可以通过控制培养条件操纵,特别是通过提供用于微生物表达的酶的特定底物,或通过添加化合物或通过遗传工程手段抑制不希望的生物化学途径。
除了上述优点之外,用重组微生物生产ω-3和/或ω-6脂肪酸,提供了通过在宿主中提供新的生物合成途径或通过抑制不希望的途径而改变天然存在的微生物脂肪酸特性的能力,从而提高需要的PUFAs,或它的缀合形式的水平,以及降低不需要的PUFAs的水平。例如,可以改变所生产的ω-3与ω-6脂肪酸的比例,专门生产ω-3或ω-6脂肪酸,同时消除其他ω脂肪酸的生产,或工程生产特定PUFA,而又没有其他PUFA下游或上游产物的大量积累。
表达系统,盒和载体
本发明所披露的序列的密码子优化的基因和基因产物可以在异源微生物宿主细胞中生产,特别是在含油酵母(例如,解脂耶氏酵母)的细胞中生产。在重组微生物宿主中的表达,可用于生产各种PUFA途径中间产物,或用于调控业已存在于宿主中的PUFA途径,以便利用所述宿主合成迄今为止不可能的新的产物。
包括能指导外源蛋白高水平表达的调控序列的微生物表达系统和表达载体是本领域技术人员所熟知的。它们都可用于构建嵌合基因,以便生产本发明密码子优化的序列的任何基因产物。然后可以通过转化将所述嵌合基因导入合适的微生物,以便提供所编码酶的高水平表达。
因此,预计导入受合适启动子控制的编码PUFA生物合成途径(例如,本文所披露的Δ5去饱和酶,Δ6去饱和酶,Δ17去饱和酶,和延伸酶)的嵌合基因,会导致ω-3和/或ω-6脂肪酸产量的增加。预计,可将它用于在宿主微生物中表达本发明密码子优化的基因的各种组合。预计可以用其在宿主微生物中一起表达这些PUFA去饱和酶和延伸酶基因的多种组合。本领域技术人员显而易见的是,包括在特定表达盒内的特定基因将取决于宿主细胞,其采用天然去饱和酶和延伸酶合成PUFAs的能力、底物和所需终产物的可获得性。例如,可能需要构建的表达盒包括编码下列一种或多种酶促活性的基因:Δ4去饱和酶,Δ5去饱和酶,Δ6去饱和酶,Δ12去饱和酶,Δ15去饱和酶,Δ17去饱和酶,Δ9去饱和酶和/或延伸酶这样,本发明涉及生产PUFAs的方法,包括让脂肪酸底物与本文所披露的PUFA酶接触,以便将所述底物转化成需要的脂肪酸产物。因此,可以将本文所披露的每一种PUFAs基因和相应的酶产物(如具有合适的去饱和酶或延伸酶活性的野生型、密码子优化的、合成的和/或突变的酶)直接或间接用于生产PUFAs。PUFAs的直接生产是这样进行的,将脂肪酸底物直接转化成需要的脂肪酸产物,而没有任何中间步骤或中间途径。例如,ARA生产能够在能产生或提供了DLGA的宿主细胞中进行,包括向所述细胞中添加或导入能提供Δ5去饱和酶活性的表达盒。
相反,编码PUFA生物合成途径的多个基因可以组合使用,以便发生一系列反应,以便产生需要的PUFA。例如,编码延伸酶,Δ5去饱和酶,Δ17去饱和酶和Δ4去饱和酶活性的表达盒使得宿主细胞天然产生GLA,而不是产生DHA(以便通过延伸酶将GLA转化成DGLA;然后可以通过Δ5去饱和酶将DGLA转化成ARA;然后通过Δ17去饱和酶将ARA转化成EPA,再通过延伸酶将后者转化成DPA;和通过Δ4去饱和酶将DPA转化成DHA)。在优选实施方案中,其中,宿主细胞是含油酵母,编码PUFA生物合成所必需的每一种酶的表达盒都需要导入所述生物,因为在这些生物中天然产生的PUFAs局限于18∶2脂肪酸(即,LA),并且更不常见的是18∶3脂肪酸(即,ALA)。另外,可能需要底物补给。
用于转化合适的宿主细胞的载体或DNA盒为本领域所公知。存在于所述构建体中的序列的具体选择取决于需要的表达产物(同上)、宿主细胞的性质以及推荐的分离转化细胞与未转化细胞的方式。不过,通常,所述载体或盒包括指导相关基因转录和翻译的序列,选择标记,和使得它能够自主复制或染色体整合的序列。合适的载体包括所述基因的5′区,它控制转录起始,和DNA片段的3′区,它控制转录终止。最优选的是,当两个控制区都来自转化过的宿主细胞的基因时是最优选的,不过,可以理解的是,所述控制区不一定来自被选择用作生产宿主的特定物种的天然基因。
可用于在需要的宿主细胞中驱动去饱和酶和/或延伸酶ORFs表达的起始控制区或启动子是多种多样的,并且为本领域技术人员所熟知。实际上,能够指导这些基因在选定的宿主细胞中表达的任何启动子都适合本发明。在宿主细胞中的表达能够以瞬时或稳定的方式进行。瞬时表达可以通过诱导可操作地连接在感兴趣的基因上的可调控启动子的活性而实现。稳定表达可以通过使用可操作地与感兴趣的基因连接的组成型启动子而实现。例如,当宿主细胞是酵母时,提供能够在酵母细胞中起作用的转录和翻译区,特别是来自宿主物种的那些。例如,转录起始调控区可以从以下渠道获得:1.)糖酵解途径上的基因,如醇脱氢酶,甘油醛-3-磷酸脱氢酶(参见美国专利申请号60/482263),磷酸甘油变位酶(参见美国专利申请号60/482263),果糖二磷酸醛缩酶(参见美国专利申请号60/519971),磷酸葡萄糖异构酶,磷酸甘油酸激酶等;或2.)可调控的基因,如酸性磷酸酶,乳糖酶,金属硫蛋白,葡糖淀粉酶,翻译延伸因子EF1-α(TEF)蛋白(U.S.6,265,185),核糖体蛋白S7(U.S.6,265,185)等。可以使用多种调控序列中的任意一种,这取决于是需要组成型转录还是诱导型转录,启动子在表达感兴趣的ORF方面的效率,以及构建的方便性等。
通过修饰外源基因的翻译起始密码子′ATG′周围的核苷酸序列,以便它们包括有效的酵母翻译起始序列可以在酵母中获得最佳基因表达。具体地讲,可以通过定点诱变增加低效表达的基因的表达,其中,所述低效表达的基因与内源酵母基因框内融合,优选与高表达的基因融合。另外,正如本发明中在解脂耶氏酵母中所证实的,可以确定宿主中的共有翻译起始序列,并且通过工程手段将该序列结合到异源基因上,以便它们在感兴趣的宿主中实现最佳表达。
终止区可源于所述基因的3′区,所述起始区是从该基因上获得的或者从不同的基因上获得的。大量终止区是已知的,并且能在多种宿主中发挥令人满意的作用(当在与产生它们的相同和不同的属和种中使用时)。终止区通常在更大程度上是根据方便性选择的,而不是因为任何特殊特性。优选的是,终止区源于酵母基因,特别是糖酵母属,裂殖酵母属,假丝酵母属,耶氏酵母属或克罗维酵母属。同样已知编码γ-干扰素和α-2干扰素的哺乳动物基因的3′-区在酵母中起作用。终止控制区还可以来自优选宿主天然具有的各种基因。终止位点可以任选是必需的;不过,如果具有,它是最优选的。
正如技术人员所了解的,仅仅将基因插入克隆载体,不能确保它能够在需要的水平上成功地表达。根据对高表达速度的需要,业已通过操纵多种不同的遗传因子产生了多种特化的表达载体,这些遗传因子能控制来自宿主细胞的转录,翻译,蛋白稳定性,含氧极限,以及从宿主的分泌。更具体地讲,业已对某些分子特征进行了操作,以便控制基因表达,包括:1.)相关转录启动子和终止子序列的性质;2.)克隆基因的拷贝数量以及所述基因是质粒携带的或者是整合到宿主细胞的基因组上的;3。)合成的外源蛋白的最终细胞定位;4.)宿主生物的翻译效率;和5.)克隆的基因蛋白在宿主细胞中的内在稳定性。上述每一种类型的修饰包括在本发明中,作为进一步优化密码子优化的PUFA生物合成途径酶表达的手段。
微生物宿主的转化
一旦获得了适合在含油酵母中表达的编码密码子优化的去饱和酶或延伸酶多肽的DNA,将它放入能够在宿主细胞中自主复制的质粒载体上,或者将它直接整合到宿主细胞的基因组上。表达盒的整合可以在宿主基因组中随机地进行,或者可以通过使用含有与宿主基因组具有足够同源性以靶定宿主基因座内的重组的区域的构建体靶定。当所述构建体被靶定于内源基因座时,转录和翻译调控区的全部或某些可以通过内源基因座提供。
当两个或两个以上的基因由独立的复制载体表达时,希望每一个载体具有不同的选择方式,并且应当缺少与其他构建体的同源性,以便保持稳定表达,并且防止构建体之间的元件的重新分类。对调控区,选择方式和导入的构建体的繁殖方法的明智的选择,可以通过实验确定,以便所有导入的基因在需要的水平上表达,以便提供需要产物的合成。
可以通过任何标准技术将包括感兴趣的基因的构建体导入宿主细胞。所述技术包括转化(例如,乙酸锂转化[Methods in Enzymology,194:186-187(1991)]),原生质体融合,bolistic冲击,电穿孔,显微注射,或能够将感兴趣的基因导入宿主细胞的任何其他方法。可用于含油酵母(即,解脂耶氏酵母)的更具体的技术包括美国专利号4,880,741和5,071,764和Chen,D.C.等(Appl MicrobiolBiotechnol.48(2):232-235(1997))。
为了方便起见,业已通过任何方法操作以摄入DNA序列(例如,表达盒)的宿主细胞在本文中被称作″转化过的″或″重组的″。转化过的宿主具有至少一个拷贝的表达构建体,并且可以具有两个或两个以上拷贝,这取决于所述基因是整合在所述基因组上,扩增的,或者存在于具有多个拷贝的染色体外元件上。转化过的宿主细胞可以通过选择包含在导入的构建体上的标记而鉴定。另外,可以将独立的标记构建体与需要的构建体共同转化,因为很多转化技术能将很多DNA分子导入宿主细胞。通常,选择转化过的宿主在选择性培养基上生长的能力。选择性培养基可以掺入抗生素或缺少未转化的宿主生长所需要的因子,如养分或生长因子。导入的标记基因可以产生抗生素抗性,或者编码必须的生长因子或酶,以便当它在转化过的宿主中表达时能够在选择培养基上生长。当所表达的标记蛋白可以直接或间接检测时,还可以进行转化宿主的选择。所述标记蛋白可以单独表达,或者作为与另一种蛋白的融合体形式表达。标记蛋白可以通过以下方法检测:1.)它的酶促活性(例如,β-半乳糖苷酶可以将底物X-gal[5-溴-4-氯-3-吲哚基--D-半乳吡喃糖苷]转化成有颜色的产物;荧光素酶可以将荧光素转化成发光产物);或2.)它的产生光或修饰特征(例如,Aequoreavictoria的绿色荧光蛋白在用兰色光线照射时会发出荧光)。另外,例如,可将抗生素用于检测存在于感兴趣的蛋白上的标记蛋白或分子量标记。例如,能表达标记蛋白或标记的细胞可以肉眼筛选,或者通过诸如FACS的技术或使用抗生素淘选。为了选择酵母转化体,可以使用能够在酵母中起作用的任何标记。理想的是,对卡那霉素,潮霉素和氨基糖苷G418的抗性是感兴趣的,以及在缺少尿嘧啶或亮氨酸的培养基上生产的能力。
在转化之后,将适合本发明的密码子优化的序列的基因产物(并且任选包括在宿主细胞中表达的其他PUFA酶)可以由所述宿主天然地或转基因地生产,或者它们可以外源提供。
ω-3和/或ω-6脂肪酸在微生物中的生物合成的代谢工程
对本发明基因的密码子优化的序列以及优化其他PUFA基因以便在含油酵母中表达的方法的了解,可用于操作在含油酵母中的ω-3和/或ω-6脂肪酸生物合成;特别是在解脂耶氏酵母中。这可能需要在PUFA生物合成途径上的直接的代谢工程或途径的其他操作,这些操作可以将碳贡献给PUFA生物合成途径。可用于操作生物化学途径的方法为本领域技术人员所公知。
在PUFA生物合成途径内操作的情况下,可能需要增加LA的生产,以便增加ω-3和/或ω-6脂肪酸的生产。这可以通过导入和/或扩增编码Δ9和/或Δ12去饱和酶的基因而实现。
为了使ω-6不饱和脂肪酸,如ARA的生产最大化,本领域技术人员公知,该生产在基本上不含ALA的宿主微生物中是有利的。因此,优选地,宿主是通过去除或抑制使得LA转化为ALA的Δ15或ω-3型去饱和酶活性而选择或获得的。可以通过以下方法减少或消除内源去饱和酶活性,例如:1)提供用于将反义序列转录到Δ15去饱和酶转录产物的盒;2)通过插入、取代和/或缺失全部或部分靶基因而破坏Δ15去饱和酶基因;或3)使用天然具有或经过突变而具有低Δ15去饱和酶活性或无Δ15去饱和酶基因的宿主细胞。对不需要的去饱和酶途径的抑制也可以通过使用如U.S.4,778,630中描述的特定去饱和酶抑制剂而实现。
或者,可能需要使ω-3脂肪酸的生产最大化(并且使ω-6脂肪酸的合成最小化)。因此,可以利用宿主微生物,其中利用上述任何一种方法(也参见,例如,共同未决的美国临时申请No.60/484209,在此全文引入作为参考)去除或抑制了将油酸转化为LA的Δ12去饱和酶活性。随后,可以将合适的表达盒与合适的底物(如ALA)一起导入宿主,用于转化为ALA的ω-3脂肪酸衍生物(如STA,ETA,EPA,DPA,DHA)。
除了目前的PUFA生物合成途径,预期操作导致前体脂肪酸生物合成的一些其它酶促途径,可以导致特定PUFAs的总体净生物合成。这些相关途径的鉴定和途径在将来是有用的。
上调需要的生物合成途径的技术
可以将额外拷贝的去饱和酶和延伸酶基因导入宿主,以便提高ω-3和/或ω-6脂肪酸生物合成途径的产量。去饱和酶或延伸酶基因的表达还可以通过使用较强的启动子(调控型的或组成型的)而在转录水平上加强,以便导致增强了的表达,包括从mRNA或编码的蛋白上去掉/缺失去稳定化序列,或者向mRNA增加稳定化序列(U.S.4,910,141)。正如本发明所证实的,增强去饱和酶或延伸酶基因表达的另一个途径是提高所编码的mRNAs的翻译效率,包括用能在选定的宿主中优化基因表达的密码子取代天然基因上的密码子。
下调不希望的生物合成途径的技术
相反,可以通过基因破坏消除或通过其他方式(例如,反义mRNA)下调与ω-3和/或ω-6脂肪酸生物合成途径竞争能量或碳的生物化学途径,或干扰特定PUFA最终产物产生的天然PUFA生物合成途径酶。为了进行基因破坏,将外源DNA片段(通常是选择标记基因)插入要破坏的结构基因,以便破坏它的编码序列,并因此功能性灭活所述基因。将所述破坏盒转化入宿主细胞,导致了非通过同源重组用无功能的破坏的基因替代功能性天然基因(例如,参见:Hamilton等J.Bacteriol.171:4617-4622(1989);Balbas等Gene 136:211-213(1993);Gueldener等Nucleic Acids Res.24:2519-2524(1996);和Smith等Methods Mol.Cell.Biol.5:270-277(1996))。
当靶基因的序列已知时,反义是下调基因的另一种方法。为了实现这一目的,克隆了来自所需基因的核酸片段,并且可操作地与启动子连接,以便RNA的反义链能够转录。然后将该构建体导入宿主细胞,并且生产RNA的反义链。反义RNA能通过抑制编码感兴趣的蛋白的mRNA的积累,抑制基因表达。本领域技术人员可以理解的是,特殊考虑与使用反义技术相关,以便减弱特定基因的表达。例如,反义基因的适当水平的表达可能需要使用不同的嵌合基因,其中采用本领域技术人员所公知的不同的调控元件。
尽管当序列已知时,定向基因破坏和反义技术提供了下调基因的有效方法,业已开发了不是基于序列的其他特异性更低的方法,例如,细胞可以暴露于UV辐射,然后筛选需要的表型。用化学试剂进行的诱变同样能有效产生突变体,并且通常使用的物质包括能影响非复制DNA的化学物质(例如,HNO2和NH2OH),以及能影响复制DNA的试剂(例如,吖啶染料,特别是导致移码突变)。使用辐射或化学试剂产生突变体的特定方法在现有技术有大量报导。例如,参见:Thomas D.Brock in Biotechnology:A Textbook of IndustrialMicrobiology,2nd ed.(1989)Sinauer Associates:Sunderland,MA;或Deshpande,Mukund V.,Appl.Biochem.Biotechnol.,36:227(1992)。
基因破坏的另一种非特异性方法是使用可转座元件或转座子。转座子是遗传元件,它能随机地插入DNA,但是随后可以根据序列回收,以便确定是否发生了插入。体内和体外转座转座方法是公知的。这两种方法涉及组合使用可转座元件和转座酶。当可转座元件或转座子在存在转座酶的条件下与核酸片段接触时,可转座元件能随机地插入所述核酸片段。这种技术可用于随机诱变,并且用于基因分离,因为受到破坏的基因可以根据可转座元件的序列鉴定。用于体外转座的试剂盒可以通过商业渠道获得[例如,参见:1.)The Primer IslandTransposition Kit,可以从Perkin Elmer Applied Biosystems获得,Branchburg,NJ,基于酵母Ty1元件;2.)The Genome Priming System,可以从New England Biolabs获得,Beverly,MA,基于细菌转座子Tn7;和3.)EZ:TN转座子插入系统,可以从Epicentre Technologies获得,Madison,WI,基于Tn5细菌转座因子]。
在本发明的范围内,可以通过上述另一种方法将它用于调控脂肪酸生物合成途径的表达。例如,本发明提供了将编码生物合成途径上的关键酶的基因导入含油酵母以生产ω-3和/或ω-6脂肪酸的方法。这些基因编码以下一种或多种:Δ6去饱和酶,Δ5去饱和酶,Δ12去饱和酶,Δ15去饱和酶,Δ4去饱和酶,Δ17去饱和酶,Δ9去饱和酶,和PUFA延伸酶。特别适用于在含油酵母中表达这些基因,所述酵母天然不具有ω-3和/或ω-6脂肪酸生物合成途径,并且调控这些和其他PUFA生物合成基因的表述,以便使用各种方法使优选的PUFA产物的产量最大化,用于宿主生物的代谢工程。
用于重组生产ω-3和/或ω-6脂肪酸的优选的微生物宿主
用于生产ω脂肪酸的宿主细胞可以包括包括在大范围的温度和pH值下,在多种饲料上生长的微生物宿主,所述饲料包括简单的或复杂的碳水化合物,有机酸和醇,和/或烃。
但是,优选的微生物宿主是含油酵母。这些生物可天然地进行油类合成和积累,所述油包括超过大约25%的细胞干重,更优选超过大约30%的细胞干重,最优选超过大约40%的细胞干重。通常被确定为含油酵母的属包括,但不局限于:耶氏酵母属,假丝酵母属,红酵母属,红冬孢属,隐球酵母属,丝孢酵母属和油脂酵母属。更具体地讲,典型的油类合成酵母包括:类酵母红冬孢,斯达氏油脂酵母,产油油脂酵母,拉可夫氏假丝酵母,铁红假丝酵母,热带假丝酵母,产朊假丝酵母,茁芽丝孢酵母,皮状丝孢酵母,胶粘红酵母,禾木科红酵母,和解脂耶氏酵母(以前被划分为解脂假丝酵母)。
最优选的是含油酵母解脂耶氏酵母;而在其他实施方案中,最优选的是解脂耶氏酵母菌株,被命名为ATCC #20362,ATCC #8862,ATCC #18944,ATCC #76982和/或LGAM S(7)1(Papanikolaou S.,和Aggelis G.,Bioresour.Technol.82(1):43-9(2002))。
过去,已经用解脂耶氏酵母的多种菌株制备和生产:异柠檬酸裂合酶(DD259637);脂酶(SU1454852,WO2001083773,DD279267);多羟基链烷酸(WO2001088144);柠檬酸(RU2096461,RU2090611,DD285372,DD285370,DD275480,DD227448,PL160027);赤藓糖醇(EP770683);2-氧戊二酸(DD267999);γ-癸内酯(U.S.6,451,565,FR2734843);γ-十二内酯(EP578388)和丙酮酸(JP09252790)。
PUFA生产的发酵方法
转化过的微生物宿主细胞是在能优化去饱和酶和延伸酶的活性并且产生最大的和最经济的优选PUFAs的产量的条件下生长的。一般,可以优化的培养基条件包括碳源的类型和用量,氮源的类型和用量,碳-氮的比例,氧气含量,生长温度,pH,生物量生产期的长度,油积累期的长度,以及细胞收获时间。感兴趣的微生物,如含油酵母在复杂培养基(例如,酵母提取物-蛋白胨-葡萄糖培养液(YPD))或缺少生长所必需的成分,以便强制选择需要的表达盒的特定基本培养基)(例如,Yeast Nitrogen Base(DIFCO Laboratories,Detroit,MI))中生长。
本发明的发酵培养基必须包括合适的碳源。合适的碳源包括,但不局限于:单糖(例如,葡萄糖,果糖),二糖(例如,乳糖,蔗糖),寡糖,多糖(例如,淀粉,纤维素或它们的混合物),糖醇(例如,甘油)或可更新饲料的混合物(例如,干酪乳清渗透物,玉米浆,甜菜糖浆,大麦芽)。另外,碳源可以包括链烷,脂肪酸,脂肪酸酯,甘油单酯,甘油二酯,甘油三酯,磷脂,和脂肪酸的各种商业来源,包括植物油(例如,大豆油)和动物脂肪。另外,碳源可以包括一-碳源(例如,二氧化碳,甲醇,甲醛,甲酸和含碳胺),业已证实了其转化成关键生物化学中间产物的代谢转化。因此,预计,用于本发明的碳源包括可以包括多种含碳源,并且仅仅局限于宿主生物的选择。尽管上述所有碳源及其混合物预计都适合本发明,优选的碳源是糖和/或脂肪酸。最优选的是葡萄糖和/或含有10-22个碳的脂肪酸。
氮可以由无机(例如,(NH4)2SO4)或有机来源(例如,尿素或谷氨酸)提供。除了合适的碳和氮源之外,发酵培养基必须还包括合适的矿物质,盐,辅因子,缓冲液,维生素,和本领域技术人员已知的适合微生物生长,并且促进PUFA生产所需要的酶促途径的其他成分。特别关注若干金属离子(例如,Mn+2,Co+2,Zn+2,Mg+2),它们能促进脂类和PUFAs的合成(Nakahara,T.等,Ind.Appl.Single CellOils,D.J.Kyle and R.Colin,eds.pp 61-97(1992))。
本发明的优选的生长培养基是常见的商业制备的培养基,如酵母Nitrogen Base(DIFCO Laboratories,Detroit,MI)。其他确定的或合成的生长培养基也可以使用,并且适合特定微生物生长的培养基是微生物学或发酵科学领域的技术人员所公知的。用于发酵的合适的pH范围通常为大约pH 4.0-pH 8.0,其中pH 5.5-pH 7.0是起始生长条件的优选范围。发酵可以在需氧或厌氧条件下进行,其中,微需氧条件是优选的。
通常,高水平PUFAs在含油酵母细胞中的积累,需要两个阶段的过程,因为在脂肪的生长和合成/储存之间的代谢状态必须是″平衡的″。因此,最优选的是,需要两个阶段的发酵过程在含油酵母中生产PUFAs。在该方法中,发酵的第一阶段被用于制备和积累细胞物质,并且以快速细胞生长和细胞分裂为特征。在发酵的第二阶段,优选在培养物中建立氮剥夺条件,以便促进高水平的脂类积累。这种氮剥夺的作用是降低细胞中AMP的有效浓度,以便减弱线粒体的NAD-依赖型异柠檬酸脱氢酶的活性。当出现这种情况时,将积累柠檬酸,因此在细胞质中形成了乙酰-CoA的丰富的资源,并且启动了脂肪酸合成。因此,这一阶段以细胞分裂终止,随后是脂肪酸的合成和油的积累为特征。
尽管细胞通常是在大约30℃下生长的,某些研究业已在较低温度下增加了不饱和脂肪酸的合成(Yongmanitchai和Ward,Appl.Environ.Microbiol.57:419-25(1991))。根据工艺的经济学,这种温度偏移可能在两个阶段的发酵的第一阶段之后发生,此时,业已出现了大量的微生物生长。
预计,可以采用多种发酵工艺设计,其中,使用本发明的密码子优化的基因商业化生产ω脂肪酸是理想的。例如,用重组微生物宿主商业生产PUFAs,可以通过分批发酵,补料-分批发酵活连续发酵工艺生产。
分批发酵工艺是封闭的系统,其中,培养基组成是在工艺开始时确定的,并且不再进行超出在工艺过程中维持pH和氧气含量需要的进一步补充。因此,在培养过程开始时,用需要的微生物接种所述培养基,并且可以在不向培养基中添加其他来源(即,碳和氮源)条件下具有生长或代谢活性。在分批发酵工艺中,该系统的代谢物和生物量组成经常地改变,直到培养终止。在典型的分批发酵工艺中,细胞从停滞阶段发展到高速生长的对数期,并最终达到静止期,在这里,生长速度减弱或终止。在不处理的条件下,静止阶段的细胞会最终死亡。标准的分批发酵工艺的变化是补料-分批发酵工艺,其中,在发酵过程中将碳源连续地添加到发酵罐中。补料-分批发酵工艺同样适用于本发明。当代谢物抑制倾向于抑制细胞代谢或希望在任何时间在培养基中具有有限数量的来源时,补料-分批工艺是有用的。测定补料-分批系统中的碳源是困难的,因此,可以根据可测定因子的变化估算,如pH,溶解氧和废气(例如,CO2)的分压。分批和补料-分批培养方法是本领域技术人员所公知的和熟悉的,并且其例子可以参见以下文献:Thomas D.Brock,Biotechnology:A Textbook of Industrial Microbiology.2nd ed.,(1989)Sinauer Associates:Sunderland,MA;或Deshpande,Mukund V.,Appl.Biochem.Biotechnol.,36:227(1992),在此收作本文参考。
利用本发明的密码子优化的基因商业化生产ω脂肪酸的方法还可以通过连续发酵工艺实现,其中,将确定成分的培养基连续添加到生物反应器中,同时取出等量的培养物体积,用于产物回收。连续培养通常将细胞保持在恒定细胞密度的对数生长期。连续或半连续培养方法能够调节会影响细胞生长或最终产物浓度的一种因素或多种因素中的任意一种。例如,一种方法可以限制碳源,并且允许所有其他参数适当地代谢。在其他系统中,可以连续地改变影响生长的多种因素,同时保持通过培养基浊度测定的细胞浓度恒定。连续系统试图保持稳态生长,因此,细胞生长速度必须与由于将培养基从培养物中排出而导致的细胞减少。调节连续培养工艺的营养成分和生长因子的方法,以及用于增加生产形成速度的技术为工业微生物学领域所熟知,并且上文提到的Brock详细披露了多种方法。
PUFAs的纯化
PUFAs可以作为游离脂肪酸形式出现在宿主微生物中,或者以诸如酰基甘油,磷脂,硫脂或醣脂的脂化形式出现,并且可以通过本领域所熟知的多种方法从宿主细胞中提取。酵母脂类的提取技术,品质分析和可接受性标准的一种概述是以下文献:Z.Jacobs(CriticalReviews in Biotechnology 12(5/6):463-491(1992))。有关下游加工的简单概述还可以参见A.Singh和O.Ward(Adv.Appl.Microbiol.45:271-312(1997))。
一般,纯化PUFAs的方法可以包括用有机溶剂萃取,超声波处理,超临界流体萃取(例如,使用二氧化碳),皂化和物理方法,如压力,或它们的组合。特别感兴趣的是用甲醇和氯仿在存在水的条件下萃取(E.G.,Bligh & W.J.Dyer,Can.J.Biochem.Physiol.37:911-917(1959))。如果需要,可以将含水层酸化,以便使带负电荷的部分质子化,并因此增加了想得到的产物向有机层中的分配。在萃取之后,可以通过在氮气流下蒸发除去有机溶剂。当以缀合形式分离时,可以对所述产物进行酶促或化学裂解,以便释放游离的脂肪酸或感兴趣的更低复杂性的缀合物,并且然后可以进行进一步的操作,以便生产需要的最终产物。理想的是,用氢氧化钾裂解脂肪酸的缀合形式。
如果需要进一步纯化,可以采用标准方法。所述方法可以包括萃取,用尿素处理,分级结晶化,HPLC,分级蒸馏,硅胶层析,高速离心或蒸馏,或这些技术的组合。对诸如酸或烯基的活性基团的保护,可以在任何步骤通过已知技术(例如,烷基化,离子化)完成。所使用的方法包括脂肪酸甲基化,以便产生甲酯。类似地,可以在任何步骤除去保护基团。理想的是,纯化含有GLA,STA,ARA,DHA和EPA的级份可以通过用尿素处理和/或分级蒸馏实现。
优选实施方案的说明
本发明证明了将ω-3和/或ω-6生物合成途径导入含油酵母以生产PUFAs的可行性。为此,选择ARA(代表ω-6脂肪酸)和EPA(代表ω-3脂肪酸)作为在含油酵母-解脂耶氏酵母中生产的需要的产物。因此,ARA的合成需要将编码Δ6去饱和酶、延伸酶和Δ5去饱和酶活性的基因导入耶氏酵母,而EPA的合成需要将编码Δ6去饱和酶、延伸酶、Δ5去饱和酶和Δ17去饱和酶活性的基因导入耶氏酵母。
在解脂耶氏酵母中表达来自多种生物的多种公共可获得的,具有将DGAL转化为ARA和将ETA转化为EPA的能力的Δ5去饱和酶,并且筛选其活性,以便鉴定在替代的宿主中显示最高水平活性的基因。在此基础上,选择高山被孢霉Δ5去饱和酶(SEQ ID NO:4)作为在含油酵母中表达的优选基因,这是基于其将底物补料试验中大约30%细胞内DGLA转化为ARA的能力而选择的。
进行了其它底物补料试验,以证明由以下基因编码的酶活性:
高山被孢霉Δ6去饱和酶(SEQ ID NO:2)将LA转化为GLA,并且将ALA转化为STA(其中解脂耶氏酵母中LA至GLA的底物转化百分比为约30%);
异丝水霉Δ17去饱和酶(SEQ ID NO:6)将DGLA转化为ETA,并且将ARA转化为EPA(其中解脂耶氏酵母中ARA至EPA的底物转化百分比为约23%);
高山被孢霉高亲和力PUFA延伸酶(SEQ ID NO:8)将GLA转化为DGLA,将STA转化为ETA,并且将EPA转化为DPA(其中解脂耶氏酵母中GLA至DGLA的底物转化百分比为约30%)。
根据异丝水霉Δ17去饱和酶更低的底物转化百分比(相对于Δ5和Δ6去饱和酶和延伸酶),对该特定基因进行密码子优化以便增强其在耶氏酵母属中的表达。这是通过确定解脂耶氏酵母中的密码子选择和结构基因标志,指定密码子优化的Δ17去饱和酶基因,然后体外合成该基因,并且使其在替代的宿主中的效率增加(相对于野生型基因)而实现的。
为了合成ARA或EPA(由此证明含油宿主经过工程改造以生产ω-6和ω-3脂肪酸(即ARA和EPA)的能力),随后制备了两种不同的DNA表达构建体:1)第一种含Δ6去饱和酶、Δ5去饱和酶和高亲和力PUFA延伸酶;和2)第二种构建体含Δ6去饱和酶、Δ5去饱和酶、高亲和力PUFA延伸酶和密码子优化的Δ17去饱和酶。将两种构建体分别转化到解脂耶氏酵母中,并且整合到编码乳清苷-5′-磷酸脱羧酶的染色体URA3基因中(EC 4.1.1.23)。用合适的底物补料的宿主细胞的GC分析检测到了ARA(实施例5)和EPA(实施例6)的产生。因此,这是第一次证实了含油酵母中的PUFA生物合成,从而将ω-3和/或ω-6生物合成途径导入了含油酵母中。
根据此处描述的教导和结果,预计本领域技术人员将认识到通过采用含油酵母作为合成多种ω-3和/或ω-6PUFA的生产平台而建立的可行性和商业用途。
实施例
本发明还确定了以下实施例。应当理解的是,在这些实施方案中,尽管指明了是本发明的优选实施方案,但是,是以说明形式提供的。通过上述讨论和这些实施例,本领域技术人员可以确定本发明的实质性特征,并且,在不超出本发明的构思和范围的前提下,可以对本发明进行各种改变和改进,以便适应各种用途和条件。
一般方法
用于实施例中的标准重组DNA和分子克隆技术为本领域所熟知的,并且披露于以下文献中:1.)Sambrook,J.,Fritsch,E.F.andManiatis,T.Molecular Cloning:A Laboratory Manual;Cold SpringHarbor Laboratory:Cold Spring Harbor,NY(1989)(Maniatis);2.)T.J.Silhavy,M.L.Bennan,and L.W.Enquist,Experiments withGene Fusions;Cold Spring Harbor Laboratory:Cold Spring Harbor,NY(1984);和3.)Ausubel,F.M.等,Current Protocols in MolecularBiology,published by Greene Publishing Assoc.and Wiley-interscience(1987)。
适合微生物培养物维持和生长的材料和方法为本领域所公知。适合在以下实施例中使用的技术可以参见以下文献:Manual of Methodsfor General Bacteriology(Phillipp Gerhardt,R.G.E.Murray,RalphN.Costilow,Eugene W.Nester,Willis A.Wood,Noel R.Krieg and G.Briggs Philips,Eds),American Society for Microbiology:Washington,D.C.(1994));或参见Thomas D.Brock in Biotechnology:A Textbookof Industrial Microbiology,2nd ed.,Sinauer Associates:Sunderland,MA(1989)。用于生长和保持微生物细胞的所有试剂,限制酶和材料都是从Aldrich Chemicals(Milwaukee,WI),DIFCO Laboratories(Detroit,MI),GIBCO/BRL(Gaithersburg,MD),或Sigma ChemicalCompany(St.Louis,MO)获得的,除非另有说明。
大肠杆菌(XL1-Blue)感受态细胞是从Stratagene公司(SanDiego,CA)购买的。大肠杆菌菌株通常是在37℃下在Luria Bertani(LB)平板上生长的。
按照标准方法(Sambrook等,同上)进行一般分子克隆。寡核苷酸是由Sigma-Genosys(Spring,TX)合成的。用Stratagene′sQuickChangeTM定点诱变试剂盒进行定点诱变,按照生产商的说明进行。当聚合酶链反应(PCR)或定点诱变与亚克隆相关时,对所述构建体进行测序,以便证实没有将误差导入所述序列。将PCR产物克隆到Promega′s pGEM-T-easy载体(Madison,WI)上。
DNA序列是利用染料终止技术(U.S.5,366,860;EP 272,007)和载体与插入片段特异性引物的组合在ABI自动测序仪上生成的。序列编辑在Sequencher(Gene Codes Corporation,Ann Arbor,MI)中进行。所有序列在两个方向上均表现了至少两次的覆盖。遗传序列的比较是利用DNASTAR软件(DNA Star,Inc.)实现的。或者,遗传序列的操作是使用可以从Genetics Computer Group Inc.(WisconsinPackage Version 9.0,Genetics Computer Group(GCG),Madison,WI)获得的程序组进行的。使用了所述GCG程序″Pileup″,空位形成预设值为12,空位延伸预设值为4。使用了GCG″Gap″或″Bestfit″程序,预设的空位形成罚分为50,预设的空位延伸罚分为3。除非另有说明,在所有其他场合下,都使用GCG程序的预设参数。
缩写的含义如下:″sec″表示秒,″min″表示分钟,″h″表示小时,″d″表示天,″μL″表示微升,″mL″表示毫升,″L″表示升,″μM″表示微摩尔,″mM″表示毫摩尔,″M″表示摩尔,″mmol″毫摩尔,″μmole″表示微摩尔,″g″表示克,″μg″表示微克,″ng″表示纳克,″U″表示单位,″bp″表示碱基对,而″kB″表示千碱基。
解脂耶氏酵母的培养
解脂耶氏酵母菌株ATCC#76982和ATCC#90812购自美国典型培养物保藏中心(Rockville,MD)。解脂耶氏酵母菌株通常在28℃条件下生长在YPD琼脂(1%酵母提取物、2%细菌用蛋白胨、2%葡萄糖、2%琼脂)上。为选择转化体,采用的是基本培养基(不含硫酸铵或氨基酸的0.17%酵母氮源(NIFCO Laboratories,Detroit,MI)、2%葡萄糖、0.1%脯氨酸、pH6.1)。作为补充的腺嘌呤、亮氨酸、赖氨酸和/或尿嘧啶是被适当地加入直至终浓度0.01%。
解脂耶氏酵母的脂肪酸分析
为了分析脂肪酸,先通过离心收集细胞,并如Bligh,E.G.& Dyer,W.J.(Can.J.Biochem.Physiol.37:911-917(1959))所述方法提取脂质。脂肪酸甲酯是通过下述方法制备的,即用甲氧基钠使脂质提取物转酯(Roughan,G.和Nishida I.Arch Biochem Biophys.276(1):38-46(1990)),并接着用装配有30-m X 0.25mm(内径)HP-INNOWAX(Hewlett-Packard)柱的Hewlett-Packard 6890GC对其进行分析。烘箱温度以3.5℃/分钟的速度从170℃(保持25分钟)上升至185℃。
为了直接进行碱基转酯,先收获耶氏酵母培养物(3mL),在蒸馏水中洗涤一次,并在Speed-Vac内的真空条件下干燥5-10分钟。向样品中加入甲氧基钠(100μl,1%),接着涡旋并振摇样品20分钟。加入3滴1M NaCl和400μl己烷后,涡旋并离心样品。移出上层并如上所述通过GC对其进行分析。
实施例1
构建适合在解脂耶氏酵母中表达异源基因的质粒
构建了质粒pY5,即pINA532(由Dr.Claude Gaillardin馈赠,Insitut National Agronomics,Centre de biotechnologie Agro-Industrielle,laboratoire de Genetique Moleculaire et Cellularie INRA-CNRS,F-78850 Thiverval-Grignon,France)衍生物,用于在解脂耶氏酵母中表达异源基因,如图2所示。
首先,将包括pINA532的ARS18序列和LEU2基因的部分消化的3598bp EcoRl片段亚克隆到pBluescript(Strategene,San Diego,CA)的EcoRl位点上,以便制备pY2。通过PCR扩增来自解脂耶氏酵母基因组DNA的TEF启动子(Muner S.,等,Yeast,14:1267-1283(1998)),用TEF5′(SEQ ID NO:38)和TEF3′(SEQ ID NO:39)作引物。PCR扩增是在50μl的总体积中进行的,它包括:100ng耶氏酵母属基因组DNA,含有10mM KCl的PCR缓冲液,10mM(NH4)2SO4,20mMTris-HCl(pH8.75),2mM MgSO4,0.1%Triton X-100,100μg/mL BSA(最终浓度),200μM每一种脱氧核糖核苷三磷酸,10皮摩尔每一种引物和1μl的PfuTurbo DNA聚合酶(Stratagene,San Diego,CA)。扩增是按以下方法进行的:首先在95℃下变性3分钟,然后进行35轮以下循环:95℃1分钟,56℃30秒,72℃1分钟。在72℃下进行了10分钟的最终延伸,然后在4℃下终止反应。将418的PCR产物连接到pCR-Blunt上,以便制备pIP-tef。将pIP-tef的BamHI/EcoRV片段亚克隆到pY2的BamHI/Smal位点上,以便制备pY4。
使用pINA532作模板,用XPR5′(SEQ ID NO:40)和XPR3′(SEQID NO:41)作引物,通过PCR扩增XPR2转录终止子。PCR扩增是在50μl的总体积中进行的,使用上述成分和条件。用SacII消化179bp的PCR产物,然后连接到pY4的SacH位点上,以便制备pY5。因此,pY5(参见图3和4)可用作耶氏酵母属-大肠杆菌穿梭质粒,它包括:
1.)耶氏酵母属自主复制序列(ARS18);
2.)ColE1质粒复制起点;
3.)氨苄青霉素-抗性基因(AmpR),用于在大肠杆菌中选择;
4.)耶氏酵母属LEU2基因(E.C.4.2.1.33,编码异丙基苹果酸异构酶,用于在耶氏酵母属中选择);
5.)翻译延伸启动子(TEFP),用于在耶氏酵母属中表达异源基因;和
6.)细胞外蛋白酶基因终止子(XPR2),用于在耶氏酵母属中表达的异源基因的转录终止。
作为pY5的衍生物构建了pY5-13(图4),以便促进在解脂耶氏酵母中的亚克隆和异源基因表达。用pY5作模板,通过6轮定点诱变构建pY5-13。通过用寡核苷酸YL5和YL6(SEQ ID NOs:106和107)进行定点诱变将SaII和ClaI位点从pY5上消除,以便制备pY5-5。通过用寡核苷酸YL9和YL10(SEQ ID NOs:110和111)进行定点诱变将SaII位点导入pY5-5的LEU2基因和TEF启动子之间,以便制备pY5-6。用寡核苷酸YL7和YL8(SEQ ID NOs:108和109)将PacI位点导入pY5-6的LEU2基因和ARS18之间,以便制备pY5-8。使用寡核苷酸YL3和YL4(SEQ ID NOs:104和105)将NcoI位点导入pY5-8的TEF启动子的翻译起始密码子周围,以便制备pY5-9。使用YL1和YL2寡核苷酸(SEQ ID NOs:102和103)将pY5-9的LEU2基因的NcoI位点消除,以便制备pY5-12。最后,用寡核苷酸YL61和YL62(SEQ ID NOs:88和89)将BsiWI位点导入pY5-12的ColEl和XPR2区之间,以便制备pY5-13。
为了促进亚克隆,构建了质粒pY5的第二种衍生物。具体地讲,用pY5作模板,通过三轮定点诱变构建了pY5-4(图4)。用寡核苷酸YL1和YL2(SEQ ID NOs:102和103)将位于Leu2报道基因上的NcoI位点位点从pY5除去,以便制备pY5-1。通过用寡核苷酸YL3和YL4(SEQ ID NOs:104和105)进行定点诱变将NcoI位点导入pY5-1的TEF启动子和XPR2转录终止子之间,以便制备pY5-2。然后使用寡核苷酸YL23和YL24(SEQ ID NOs:112和113)将PacI位点导入pY5-2的TEF启动子和XPR2转录终止子之间,以便制备pY5-4。
实施例2
对用于在解脂耶氏酵母内表这的Δ6去饱和酶、Δ5去饱和酶、Δ17
去饱和酶和高高和力PUFA延伸酶基因的选择
将编码ω-3和/或ω-6生物合成途径的特异性基因导入含有已破坏的Δ12去饱和酶的解脂耶氏酵母内之前,有必要证实在耶氏酵母属中表达的异源Δ6去饱和酶、延伸酶、Δ5去饱和酶和Δ17去饱和酶基因的功能性。这是通过测定各野生型蛋白在可选宿主内的转化效率而得以实现的。具体而言,即分别表达高山被孢霉Δ5去饱和酶、高山被孢霉Δ6去饱和酶、异丝水霉Δ17去饱和酶和高山被孢霉高亲和力PUFA延伸酶,并在底物补料试验中进行活性筛选。根据这些结果,选择高山被孢霉基因与Δ6和Δ17去饱和酶以及高亲和力PUFA延伸酶组合。
表达质粒的构建
通常是通过限制酶切消化分离野生型去饱和酶或延伸酶基因,或通过PCR扩增,并将其插入合适的载体中进行表达。各PCR扩增均在总体积为50μl并包括PCR缓冲液的反应混合物中进行,所述PCR缓冲液含有:10ng模板、10mM KCl、10mM(NH4)2SO4、20mM Tris-HCl(pH8.75)、2mM MgSO4、0.1%Triton X-100、100μg/mL BSA(终浓度)、均为200μM的各种脱氧核苷三磷酸、均为10pmole的各种引物和1μl Pfu Turbo DNA聚合酶(Stratagene,San Diego,CA)。扩增步骤如下(除非另外指明):95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1分钟、56℃30秒、72℃1分钟。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。
野生型高山被孢霉(登录号#AF465281)Δ6去饱和酶
将包括高山被孢霉Δ6去饱和酶基因(SEQ ID NO:1)的1384bp的pCGR5的NcoI/NotI片段(U.S.5,968,809)插入pY5-2的NcoI/NotI位点(实施例1)上,以便制备pY54。
野生型高山被孢霉(登录号#AF067654)Δ5去饱和酶
通过以寡核苷酸YL11和YL12(SEQ ID NOs:72和73)为引物、以质粒pCGR-4(U.S.6,075,183)为模板进行PCR扩增高山被孢霉Δ5去饱和酶基因(SEQ ID NO:3)。PCR扩增步骤如上所述,但延伸步骤延长至1.5分钟(对循环1-35而言)。用Ncol/Notl消化1357bp的PCR产物,并与Ncol/Notl消化的pY5-13(如实施例1所述)连接生成pYMA5bp(图5)。
野生型异丝水霉(ATCC #56851)Δ5去饱和酶
通过PCR,用寡核苷酸YL13A和YL14(SEQ ID NOs:116和117)作引物,用质粒pRSP3(WO02/081668)作模板,扩增异丝水霉Δ5去饱和酶基因(SEQ ID NO:114)。PCR扩增步骤如上所述,但延伸步骤延长至1.5分钟(对循环1-35而言)。用NcoI/PacI消化1.4kB的PCR产物,然后连接到NcoI/PacI-消化过的pY5-4上(图4;参见实施例1),以便制备pYSD5。
野生型Isochrysis galbana CCMP1323 Δ5去饱和酶
通过PCR,用寡核苷酸YL19A和YL20(SEQ ID NOs:120和121)作引物,用质粒pRIG-1(WO02/081668)作模板,扩增I.galbana Δ5去饱和酶基因(SEQ ID NO:118)。PCR扩增步骤如上所述,但延伸步骤延长至1.5分钟(对循环1-35而言)。用BamHI/PacII消化1.4kB的PCR产物,然后连接到BamHI/PacII-消化过的pY5-4上(图4;参见实施例1),以便制备pYIG5。
野生型Thraustochytrium aureum(ATCC#34304)Δ5去饱和酶
通过PCR,用寡核苷酸YL15和YL16B(SEQ ID NOs:124和125)作引物,用质粒pRTA4(WO02/081668)作模板,扩增T.aureum Δ5去饱和酶基因(SEQ ID NO:122).PCR扩增步骤如上所述,但延伸步骤延长至1.5分钟(对循环1-35而言)。用NcoI/NcoI消化1.4kB的PCR产物,然后连接到NcoI/NcoI-消化过的pY5-2上(图4;参见实施例1),以便制备pYTA5。
野生型异丝水霉(ATCC#56851)Δ17去饱和酶
通过PCR,用寡核苷酸YL21A(SEQ ID NO:42)和YL22(SEQID NO:43)作引物,由质粒pRSP19(US2003/0196217A1)扩增异丝水霉的野生型Δ17去饱和酶基因。用NcoI/PacI消化PCR产物,然后连接到NcoI/PacI-消化过的pY5-4上(图4;参见实施例1),以便制备pYSD17。
野生型高山被孢霉(登录号#AX464731)高亲和力延伸酶
将包括高山被孢霉高亲和力PUFA延伸酶基因的编码区(SEQ IDNO:7)的pRPB2的973bp的NotI片段(WO00/12720)插入pY5的NotI位点(实施例1;图3和4),以便制备pY58。
解脂耶氏酵母的转化
按照Chen,D.C.等(Appl Microbiol Biotechnol.48(2):232-235-(1997))的方法将质粒pY54,pYMA5pb,pYSD5,pYIG5,PYTA5,pYSD17和pY58分别转化到解脂耶氏酵母ATCC #76982中。
简单地讲,将耶氏酵母属的亮氨酸营养缺陷型在YPD平板上划线,并且在30℃下生长大约18小时。将几个大环的细胞从平板上刮下来,并且重新悬浮在1mL的转化缓冲液中,该缓冲液包括:
·2.25mL的50%PEG,平均分子量3350;
·0.125mL的2M乙酸锂,pH6.0;
·0.125mL的2M DTT;和
·50μg的剪切的鲑鱼精子DNA。
在100μl的重新悬浮的细胞中温育大约500ng的质粒DNA,并且在39℃下保持1小时,以15分钟的间隔进行涡旋混合。将细胞铺平板到缺少亮氨酸的基本培养基平板上,并且在30℃下保持2-3天。
底物转化百分比的测定
含有pY54,pYMA5pb,pYSD5,PYIG5,PYTA5,pYSD17或pY58的转化解脂耶氏酵母的单个菌落分别在3mL基本培养基(20g/L葡萄糖,1.7g/L酵母氮基质,不含氨基酸,1g/L L-脯氨酸,0.1g/L L-腺嘌呤,0.1g/L L-赖氨酸,pH 6.1)中,在30℃下生长到OD600大约为1.0。为了进行底物补料,将100μl的细胞放在含有10μg底物的3mL基本培养基中在30℃下继代培养大约24小时。然后通过离心收集细胞,并提取脂类。脂肪酸甲酯是通过转酯制备的,随后进行GC分析(如一般方法中的描述)。底物转化百分比按以下公式测定:([产物]/[底物+产物])*100)。
野生型高山被孢霉Δ6去饱和酶的底物转化百分比
高山被孢霉Δ6去饱和酶能将LA转化成GLA和/或将ALA转化成STA。含有pY54的解脂耶氏酵母菌株按上述方法生长(不需要补充底物),并且分析脂类。结果表明,具有pY54的耶氏酵母属菌株能将大约30%LA转化成GLA。
高山被孢霉、异丝水霉、I.galbana和T.aureum Δ5去饱和酶的底
物转化百分比
高山被孢霉、异丝水霉、I.galbana和T.aureum的Δ5去饱和酶都将DGLA转化为ARA,并且将ETA转化为EPA。分别从单个菌落生长含pYMA5pb,pYSD5,pYIG5或pYTA5的解脂耶氏酵母菌株,在含有10μg的ARA的基本培养基中继代培养,并且按上述方法进行脂类分析。含有pYMA5pb(高山被孢霉)的耶氏酵母菌株将大约30%的细胞内DGLA转化为ARA,含有pYSD5(异丝水霉)的耶氏酵母菌转化大约12%,含有pYIG5(I.galbana)的耶氏酵母菌转化大约7%,含有pYTA5(T.Aureum)耶氏酵母菌转化大约23%的细胞内DGLA转化为ARA。
野生型异丝水霉Δ17去饱和酶的底物转化百分比
异丝水霉Δ17去饱和酶能将ARA转化成EPA和/或将DGLA转化成ETA。含有pYSD17的解脂耶氏酵母菌株是从单菌落生长的,在含有10μg的ARA的基本培养基中继代培养,并且按上述方法进行脂类分析。ARA补料实验的结果表明具有pYSD17的耶氏酵母属菌株能将大约23%的细胞内ARA转化成EPA。
野生型高山被孢霉高亲和力延伸酶的底物转化百分比
高山被孢霉高亲和力PUFA延伸酶能将GLA转化成DGLA,将STA转化成ETA和/或将EPA转化成DPA。包括pY58的解脂耶氏酵母菌株是从单菌落生长的,在含有10μg的GLA基本培养基中继代培养,并且按上述方法进行脂类分析。GLA补料实验的结果表明,具有pY58的耶氏酵母属菌株能将大约30%的细胞内GLA转化成DGLA。
实施例3
密码子优化Δ17去饱和酶基因在解脂耶氏酵母内的合成和表达
基于实施例2的结果,可利用的基因是编码Δ6去饱和酶、延伸酶和Δ5去饱和酶活性的基因,因为这些基因在解脂耶氏酵母内均能够实现约30%的底物转化百分率。但异丝水霉来源的Δ17去饱和酶的最大转化效率仅为23%。因此,根据耶氏酵母属的密码子选择模式、ATG翻译起始密码子周围的共有序列和RNA稳定性的普遍规律,并基于异丝水霉DNA序列(SEQ ID NO:5)设计了密码子优化Δ17去饱和酶基因(Guhaniyogi,G.和J.Brewer,Gene265(1-2):11-23(2001))。
除了对翻译起始位点的修饰外,还对1077bp编码区中的127bp片段(包括了117个密码子)进行了密码子优化。该密码子优化DNA序列(SEQ ID NO:9)与异丝水霉Δ17去饱和酶基因DNA序列(SEQ IDNO:5)之间的比较如图6所示,其中粗体所示核苷酸对应于密码子优化基因中被改动的核苷酸。该密码子优化基因中的所有变更均未改变编码蛋白的氨基酸序列(SEQ ID NO:6)。
在解脂耶氏酵母中测定优选的密码子选择
在National Center for Biotechnology Information公共数据库中发现了大约100个解脂耶氏酵母的基因。通过DNAStar的Editseq程序将包括121,167bp的这些基因的编码区翻译成相应的40,389个氨基酸,并且制成表格,以便确定由表4所示的解脂耶氏酵母密码子选择谱。标题为″No.″的栏表示编码特定氨基酸的特定密码子在40,389个氨基酸的样品中出现的次数。标题为″%″的栏表示编码特定氨基酸的特定氨基酸的频率。用粗体字符表示的代码表示解脂耶氏酵母中优选的密码子。
表3
解脂耶氏酵母的密码子选择
为了进一步优化在解脂耶氏酵母中的基因表达,检查了79个基因的′ATG′起始密码子周围的共有序列。在图7中,加下划线的ATG翻译起始密码子的第一个′A′被设为+1。分析过的基因的77%在-3号位置上出现″A″,表明了″A″在该位置上的强烈偏好。还存在′A′或′C′在-4,-2和-1号位置上的偏好,′A′,′C′或′T′在+5号位置上的偏好,以及′G′或′C′在+6号位置上的偏好。因此,用于基因在解脂耶氏酵母中优化表达的密码子优化的翻译起始位点的优选的共有序列是′MAMMATGNHS′(SEQ ID NO:126),其中使用了如下的核酸简并性密码:M=A/C;S=C/G;H=A/C/T;和N=A/C/G/T。
密码子优化基因的体外合成
被用于合成密码子优化Δ17去饱和酶基因的方法如图8所示。首先,设计11对寡核苷酸,以延伸异丝水霉Δ17去饱和酶基因的密码子优化编码区的全长(例如D17-1A、D17-1B、D17-2A、D17-2B、D17-3A、D17-3B、D17-4A、D17-4B、D17-5A、D17-5B、D17-6A、D17-6B、D17-7A、D17-7B、D17-8A、D17-8B、D17-9A、D17-9B、D17-10A、D17-10B、D17-11A和D17-11B,对应于SEQ ID NOs:10-31)。每一对有义(A)和反义(B)寡核苷酸除5’-末端具有4bp突出端外,其它部分均互补。此外,引物D17-1A、D17-4B、D17-5A、D17-8A和D17-8B还分别导入了用于后续亚克隆的Ncol、Bglll和Sall限制位点。
于37℃、体积为20μl并含有50mM Tris-HCl(pH7.5)、10mMMgCl2、10mM DTT、0.5mM亚精胺、0.5mM ATP和10U T4多核苷酸激酶的混合液中,使均为100ng的各种寡核苷酸磷酸化。将各有义和反义寡核苷酸对混合,并在采用下列参数的热循环仪中退火:95℃(2分钟)、85℃(2分钟)、65℃(15分钟)、37℃(15分钟)、24℃(15分钟)和4℃(15分钟)。因此,D17-1A(SEQ ID NO:10)退火至D17-1B(SEQ ID NO:11)可生成双链产物“D17-1AB”。同样,D17-2A(SEQ ID NO:12)退火至D17-2B(SEQ ID NO:13)可生成双链产物“D17-2AB”,依次类推。
接着将退火双链寡核苷酸分别混合所获得的三个集合连接在一起,如下所示:
●集合1:包括D17-1AB、D17-2AB、D17-3AB和D17-4AB;
●集合2:包括D17-5AB、D17-6AB、D17-7AB和D17-8AB;和
●集合3:包括D17-9AB、D17-10AB和D17-11AB。
将各退火寡核苷酸集合混合在体积为20μl并含有10U T4 DNA连接酶的混合物中,并于16℃温育过夜。
接着通过PCR扩增各连接反应的产物。具体而言,是通过以连接的“集合1”混合物(即D17-1AB、D17-2AB、D17-3AB和D17-4AB)为模板,以寡核苷酸D17-1(SEQ ID NO:32)和D17-4R(SEQ IDNO:33)为引物进行PCR,扩增密码子优化Δ17去饱和酶基因的第一个部分。该PCR扩增是在总体积为50μl并包括PCR缓冲液的混合物中进行,其中的PCR缓冲液含有10mM KCl、10mM(NH4)2SO4、20mMTris-HCl(pH8.75)、2mM MgSO4、0.1%Triton X-100、100μg/mL BSA(终浓度)、均为200μM的各种脱氧核苷三磷酸、均为10pmole的各种引物和1μl Pfu Turbo DNA聚合酶(Stratagene,San Diego,CA)。扩增步骤如下:于95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1分钟、56℃30秒、72℃40秒。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。将430bp PCR片段亚克隆进pGEM-Teasy载体(Promega)中,可生成pT17(1-4)。
同样,通过以连接的“集合2”混合物(即D17-5AB、D17-6AB、D17-7AB和D17-8AB)为模板,以寡核苷酸D17-5(SEQ ID NO:34)和D17-8D(SEQ ID NO:35)为引物进行PCR,扩增密码子优化Δ17去饱和酶基因的第二个部分,并将其克隆进pGEM-T-easy载体中,可生成pT17(5-8)。最后,同样通过以“集合3”连接混合物(即D17-9AB、D17-10AB和D17-11AB)为模板,以寡核苷酸D17-8U(SEQ ID NO:36)和D17-11(SEQ ID NO:37)为引物进行PCR,扩增密码子优化Δ17去饱和酶基因的第三个部分,并将其克隆进pGEM-T-easy载体中,可生成pT17(9-11)。
分别用pT17(1-4)、pT17(5-8)和pT17(9-11)转化大肠杆菌,并从氨苄青霉素抗性转化体中分离质粒DNA。纯化质粒DNA,并用合适的限制性内切核酸酶消化,以释放出pT17(1-4)的420bp Ncol/Bglll片段、pT17(5-8)的400bp Bglll/Sall片段和pT17(9-11)的300bpSall/Notl片段。接着将这些片段组合、连接在一起作为模板,并以D17-1(SEQ ID NO:32)和D17-11(SEQ ID NO:37)为引物扩增完整的合成密码子优化Δ17去饱和酶基因。对Δ17去饱和酶基因的每一个部分均采用上述条件,在总体积为50μl的混合物中进行PCR扩增,热循环程序如下:于95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1分钟、56℃30秒、72℃1.1分钟。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。生成1.1kB PCR产物。
含密码子优化的Δ17去饱和酶的质粒pYSD17S的构建
用Ncol/Notl消化包括完整合成Δ17去饱和酶的上述1.1kB PCR产物,并将其亚克隆进Ncol/Notl消化的pY5-13(实施例1)中,可生成pYSD17S(图9A)。
为比较野生型和合成基因在耶氏酵母属内的效率,另一个“对照”是通过以YL53(SEQ ID NO:44)和YL54(SEQ ID NO:45)为引物进行定点诱变,消除pYSD17(包括所述野生型基因;如实施例2所述)中富含AT的Pacl位点,可生成pYSD17M(图9B)。
用密码子优化的Δ17去饱和酶基因对解脂耶氏酵母的转化
根据实施例2所述方法,分别将含有野生型和密码子优化Δ17去饱和酶的质粒转化进解脂耶氏酵母ATCC#76982中。利用该技术,获得含有下述质粒的转化体:
表4
转化体耶氏酵母中的质粒一览表
质粒 | 描述 |
pYSD17 | 野生型Δ17去饱和酶 |
pYSD17M | 野生型Δ17去饱和酶,无富含AT的Pacl位点 |
pYSD17S | 密码子优化Δ17去饱和酶 |
密码子优化的Δ17去饱和酶基因的底物转化百分率
Δ17去饱和酶可将ARA转化为EPA(参见图2)。野生型和密码子优化Δ17去饱和酶基因的底物转化百分率([产物]/[底物+产物]*100)是通过利用一般方法中所述方法,在含有各可选质粒构建体的解脂耶氏酵母中测定的。
ARA补料试验结果显示具有对照质粒pYSD17或pYSD17M的耶氏酵母菌株可将大约23%的胞内ARA转化为EPA(图10A),而含有pYSD17S中的密码子优化Δ17去饱和酶基因的菌株则可将大约45%的胞内ARA转化为EPA(图10B)。因此,含有密码子优化Δ17去饱和酶的耶氏酵母可转化比含有野生型异丝水霉基因的菌株多大约2倍的ARA。
适合解脂耶氏酵母内多种ω脂肪酸生物合成基因同步表达的质粒
的构建
本实施例描述了需要合成多种表达质粒,以便构建:1)适合于被整合进解脂耶氏酵母属基因组内以表达Δ6去饱和酶、PUFA延伸酶、和Δ5去饱和酶(用于生产ARA)的DNA片段;和2)适合于被整合进解脂耶氏酵母属基因组内以表达Δ6去饱和酶、PUFA延伸酶、Δ5去饱和酶和Δ17去饱和酶(用于生产EPA)的DNA片段。
质粒pY24的构建
质粒pY24(图11)是用于构建适合被整合进解脂耶氏酵母基因组内的表达盒的亲本载体。pY24的构建方法如下:
以寡核苷酸KU5和KU3(SEQ ID NOs:46和47)为引物,以耶氏酵母基因组DNA为模板,通过PCR扩增含有耶氏酵母URA3基因的1.7kB DNA片段(SEQ ID NO:48)。该PCR扩增是在总体积为50μl的混合物中进行,该混合物包括:100ng耶氏酵母基因组DNA和含有10mM KCl、10mM(NH4)2SO4、20mM Tris-HCl(pH8.75)、2mMMgSO4、0.1%Triton X-100、100μg/mL BSA(终浓度)、均为200μM的各种脱氧核苷三磷酸、均为10pmole的各种引物和1μl Pfu TurboDNA聚合酶(Stratagene,San Diego,CA)的PCR缓冲液。扩增步骤如下:于95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1分钟、56℃30秒、72℃2分钟。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。将该PCR产物插入pGEM-T easy载体(Promega,Madison,WI)中,可生成pGYUM。
利用寡核苷酸KI5和KI3(SEQ ID NOs:50和51)进行PCR,扩增含有Impatients balsama的接合酶基因(或“imp H8”)(clone ids.pk0001.h8;E.I.du Pont de Nemours and Company,Inc.,Wilmington,DE)的1.1kB DNA片段(SEQ ID NO:52)。该PCR扩增是利用上述组成进行,但所用模板是ids.pk0001.h8的10ng质粒DNA。扩增步骤如下:于95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1.5分钟、56℃30秒、72℃1.2分钟。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。用Notl消化该PCR产物,并接着将其插入pY5(图3)的Notl位点,可生成pY9。
利用寡核苷酸KTI5和KTI3(SEQ ID NOs:54和55)进行PCR,扩增含有pY9的TEF::IMPH8::XPR嵌合基因的1.7kB DNA片段(SEQID NO:56)。如上所述进行该PCR扩增,但所用模板是pGYUM的10ng质粒DNA。扩增步骤如下:于95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1分钟、56℃30秒、72℃2分钟。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。将该PCR产物插入PCR-Script(Stratagene)中,可生成pY9R。用pGYUM的Xhol/EcoRV片段置换pY9R的1.7kB Xhol/EcoRV片段,可生成pY21。
以寡核苷酸KH5和KH3(SEQ ID NOs:58和59)为引物,以KS65的基因组DNA为模板进行PCR,扩增含有大肠杆菌潮霉素抗性基因(“HPT”;Kaster,K.R.,et al.,Nucleic Acids Res.11:6895-6911(1983))的1kB DNA片段(SEQ ID NO:60)。该PCR扩增是利用上述组分在总体积为50μl的混合物中进行,但所用模板是ids.pk0001.h8的10ng质粒DNA。扩增步骤如下:于95℃初始变性3分钟,接着进行35个循环,每个循环包括:95℃1分钟、56℃30秒、72℃1.2分钟。最终延伸循环于72℃进行10分钟,接着于4℃终止反应。用Notl消化该PCR产物,并接着将其插入pY5的Notl位点(图3),可生成pTHPT-1。
以寡核苷酸KTH5和KTH3(SEQ ID NOs:62和63)为引物,以pTHPT-1质粒DNA为模板,如上所述扩增含有TEF::HPT::XPR融合基因的1.6kB DNA片段(SEQ ID NO:64)。用Bglll消化该PCR产物,并接着将其插入pY21中,可生成pY24。
pY24-4的构建
质粒pY24(图11)被用于构建适合被整合进解脂耶氏酵母基因组的表达盒。利用pY24质粒中解脂耶氏酵母URA3基因的401bp 5’序列(SEQ ID NO:66)和568bp 3’-序列(SEQ ID NO:67)将表达盒直接整合进耶氏酵母基因组的Ura位点。通过BamHI消化,首先从pY24中移出两个嵌合基因(TEF::HPT::XPR和TEF::IMPH8::XPR),使它们自连接生成pY24-1。通过分别利用YL63和YL64(SEQ ID NOs:68和69)和YL65和YL66(SEQ ID NOs:70和71)引物对进行定点诱变,将Pacl和BsiWI位点导入pY24-1中,可生成pY24-4。
用于Δ5去饱和酶表达的整合载体的构建
将pYMA5pb的4261bp Pacl/BsiWI片段(包括高山被孢霉Δ5去饱和酶基因;如实施例2所述)连接进pY24-4(图11)的Pacl/BsiWI位点,可生成pYZM5(图5)。通过分别利用引物对YL81和YL82(SEQID NOs:74和75)和YL83和YL84(SEQ ID NOs:76和77)进行定点诱变,将Hindlll和Clal位点导入pYZM5,可生成pYZM5CH。通过以YL105和YL106(SEQ ID NO:78和79)为引物进行定点诱变,将Pmel位点导入pYZM5CH,可生成pYZM5CHPP。通过以YL119和YL120(SEQ ID NO:80和81)为引物进行定点诱变,将Ascl位点导入pYZM5CHPP,可生成pYZM5CHpPA(图5)。
为优化该整合载体,以YL121和YL122(SEQ ID NOs:82和83)为引物进行PCR,扩增解脂耶氏酵母URA3基因(SEQ ID NO:84)上游的440bp 5’非编码DNA序列。用Ascl和BsiWI消化该PCR产物,并接着用pYZM5CHPPA的Ascl/BsiWI片段置换(图5和12),可生成pYZM5UPA(图12)。通过利用寡核苷酸YL114和YL115(SEQ IDNOs:85和86)进行定点诱变,将Ascl位点导入pYZM5UPA,可生成pYZV5。为了减小pYZV5中URA3基因的3’非编码区的大小,通过利用寡核苷酸YL114和YL115(如上所述)进行的定点诱变,将第二个Pacl位点导入该区域的中部,可生成pYZV5P。通过Pacl消化切除pYZV5P的Pacl片段,再次连接后生成pYZV16(图12)。用Ascl消化pYZV16,可释放适用于Δ5去饱和酶基因(“MAD5”)在解脂耶氏酵母基因组内的整合和表达的5.2kB DNA片段(SEQ ID NO:87)。
适合高亲和力延伸酶和Δ5去饱和酶的表达的整合载体的构建
通过分别利用引物对YL61和YL62(SEQ ID NOs:88和89)和YL69和YL70(SEQ ID NOs:90和91)进行定点诱变,将BsiWI和Hindlll位点导入pY58(含有高山被孢霉高亲和力PUFA延伸酶的编码区;如实施例2所述),可生成pY58BH(图13;延伸酶基因被标记为“EL”)。将pY58BH中含有TEF::EL::XPR嵌合基因的1.7kBBsiWI/Hindlll片段连接进pYZM5CHPP(构建方法如图5所示)的BsiWI/Hindlll位点,可生成pYZM5EL(图13)。该质粒适用于高山被孢霉Δ5去饱和酶和高亲和力PUFA延伸酶基因在解脂耶氏酵母中的整合和同步表达。
适合Δ6去饱和酶、高亲和力延伸酶和Δ5去饱和酶的表达的整合
载体的构建
通过分别利用引物对YL77和YL78(SEQ ID NOs:92和93)和YL79A和YL80A(SEQ ID NOs:94和95)进行的定点诱变,将Pacl和Clal位点导入pY54(含有高山被孢霉Δ6去饱和酶;如实施例2所述),可生成pY54PC(图13;Δ6去饱和酶基因被标记为“MAD6”)。将pY54PC中含有TEF::MAD6::XPR嵌合基因的2kB Clal/Pacl DNA片段连接进pYZM5EL的Clal/Pacl位点,可生成pYZM5EL6(图13)。该质粒适用于高山被孢霉Δ6去饱和酶、Δ5去饱和酶和高亲和力PUFA延伸酶基因在解脂耶氏酵母基因组内的整合和同步表达。
适合被整合进入耶氏酵母基因组、适合Δ6去饱和酶、PUFA延伸
酶和Δ5去饱和酶表达的DNA片段的构建
采用质粒pYZV16(构建方法如图12所示)构建含有多种表达盒的质粒。
首先,将pYZV16的3.5kB BsiWI/Pacl片段与pYZM5EL6(构建方法如图13所示)的7.9kB BsiWI/Pacl片段连接,可生成pYZV5EL6(图14)。用Ascl消化pYZV5EL6,可释放适合Δ6去饱和酶、PUFA延伸酶和Δ5去饱和酶基因在解脂耶氏酵母基因组内的整合和同步表达的8.9kB DNA片段(SEQ ID NO:96)。
适合被整合进耶氏酵母基因组、适合Δ6去饱和酶、PUFA延伸酶、
Δ5去饱和酶和Δ17去饱和酶表达的DNA片段的构建
如实施例3的描述,将合成的异丝水霉Δ17去饱和酶基因插入pY5-13的Ncol/Notl位点,可生成pYSD17S(图9A)。通过分别利用引物对YL101和YL102(SEQ ID NOs:97和98)和YL103和YL104(SEQ ID NOs:99和100)进行定点诱变,将Clal和Pmel位点导入pYSD17S中,可生成pYSD17SPC(图14)。
用来源于pYSD17SPC并含有Δ17去饱和酶表达盒的1760bpClal/Pmel片段置换pYZV5EL6(图14)的347bp Clal/Pmel片段,可生成pYZV5E6/17。用Ascl消化pYZV5E6/17,可释放适合Δ6去饱和酶、PUFA延伸酶、Δ5去饱和酶和Δ17去饱和酶基因在解脂耶氏酵母基因组内的整合和同步表达的10.3kB DNA片段(SEQ ID NO:101)。
实施例5
解脂耶氏酵母转化体中ω-6脂肪酸的生物合成
用AscI限制性内切核酸酶消化pYZV5EL6(来自实施例4,含有Δ6去饱和酶、PUFA延伸酶和Δ5去饱和酶基因)并且根据实施例2中描述的方法转化到解脂耶氏酵母中。
在缺乏亮氨酸的基本培养基中选择的52种转化体中,34种不能在也缺乏尿嘧啶的培养基上生长,表明65%的转化体含有整合到靶定的解脂耶氏酵母URA3基因座中的8.9kB的多基因表达盒。将来自单个菌落的转化体接种到缺乏亮氨酸的基本培养基中,在30℃下温育最多48小时。
通过离心收集细胞,提取脂质,通过转酯制备脂肪酸甲酯,随后用Hewlett-Packard 6890GC进行分析(根据一般方法中描述的方法)。
GC分析表明在含有3种嵌合基因的转化体中存在花生四烯酸(ARA)(图15),但在野生型耶氏酵母对照菌株中不存在。工程改造解脂耶氏酵母,使其生产ARA,即一种ω-6脂肪酸。
实施例6
解脂耶氏酵母转化体中ω-3脂肪酸的生物合成
按照与实施例5相似的方式,用AscI限制性内切核酸酶消化pYZV5E6/17(来自实施例4,含有Δ6去饱和酶、PUFA延伸酶、Δ5去饱和酶和Δ17去饱和酶基因)并且转化到解脂耶氏酵母(ATCC#76982)中。在缺乏亮氨酸的基本培养基中选择的133种转化体中,89种不能在也缺乏尿嘧啶的培养基上生长,表明67%的转化体含有整合到靶定的解脂耶氏酵母URA3基因座中的10.3kB的多基因表达盒。
GC分析(根据一般方法中描述的方法)表明在含有4种嵌合基因的转化体中存在二十碳五烯酸(EPA)(图16),但在野生型耶氏酵母对照菌株中不存在。这些数据表明经过工程改造解脂耶氏酵母,生产了EPA,即一种ω-3脂肪酸。
序列表
<110>E.I.du Pont de Nemours and Company,Inc.
<120>在含油酵母中生产多不饱和脂肪酸
<130>CL2233PCT
<150>US 60/468677
<151>2003-05-07
<160>126
<170>PatentIn version 3.2
<210>1
<211>1374
<212>DNA
<213>高山被孢霉AF465281
<400>1
atggctgctg ctcccagtgt gaggacgttt actcgggccg aggttttgaa tgccgaggct 60
ctgaatgagg gcaagaagga tgccgaggca cccttcttga tgatcatcga caacaaggtg 120
tacgatgtcc gcgagttcgt ccctgatcat cccggtggaa gtgtgattct cacgcacgtt 180
ggcaaggacg gcactgacgt ctttgacact tttcaccccg aggctgcttg ggagactctt 240
gccaactttt acgttggtga tattgacgag agcgaccgcg atatcaagaa tgatgacttt 300
gcggccgagg tccgcaagct gcgtaccttg ttccagtctc ttggttacta cgattcttcc 360
aaggcatact acgccttcaa ggtctcgttc aacctctgca tctggggttt gtcgacggtc 420
attgtggcca agtggggcca gacctcgacc ctcgccaacg tgctctcggc tgcgcttttg 480
ggtctgttct ggcagcagtg cggatggttg gctcacgact ttttgcatca ccaggtcttc 540
caggaccgtt tctggggtga tcttttcggc gccttcttgg gaggtgtctg ccagggcttc 600
tcgtcctcgt ggtggaagga caagcacaac actcaccacg ccgcccccaa cgtccacggc 660
gaggatcccg acattgacac ccaccctctg ttgacctgga gtgagcatgc gttggagatg 720
ttctcggatg tcccagatga ggagctgacc cgcatgtggt cgcgtttcat ggtcctgaac 780
cagacctggt tttacttccc cattctctcg tttgcccgtc tctcctggtg cctccagtcc 840
attctctttg tgctgcctaa cggtcaggcc cacaagccct cgggcgcgcg tgtgcccatc 900
tcgttggtcg agcagctgtc gcttgcgatg cactggacct ggtacctcgc caccatgttc 960
ctgttcatca aggatcccgt caacatgctg gtgtactttt tggtgtcgca ggcggtgtgc 1020
ggaaacttgt tggcgatcgt gttctcgctc aaccacaacg gtatgcctgt gatctcgaag 1080
gaggaggcgg tcgatatgga tttcttcacg aagcagatca tcacgggtcg tgatgtccac 1140
ccgggtctat ttgccaactg gttcacgggt ggattgaact atcagatcga gcaccacttg 1200
ttcccttcga tgcctcgcca caacttttca aagatccagc ctgctgtcga gaccctgtgc 1260
aaaaagtaca atgtccgata ccacaccacc ggtatgatcg agggaactgc agaggtcttt 1320
agccgtc tga acgaggtctc caaggctacc tccaagatgg gtaaggcgca gtaa 1374
<210>2
<211>457
<212>PRT
<213>高山被孢霉AF465281
<400>2
Met Ala Ala Ala Pro Ser Val Arg Thr Phe Thr Arg Ala Glu Val Leu
1 5 10 15
Asn Ala Glu Ala Leu Asn Glu Gly Lys Lys Asp Ala Glu Ala Pro Phe
20 25 30
Leu Met Ile Ile Asp Asn Lys Val Tyr Asp Val Arg Glu Phe Val Pro
35 40 45
Asp His Pro Gly Gly Ser Val Ile Leu Thr His Val Gly Lys Asp Gly
50 55 60
Thr Asp Val Phe Asp Thr Phe His Pro Glu Ala Ala Trp Glu Thr Leu
65 70 75 80
Ala Asn Phe Tyr Val Gly Asp Ile Asp Glu Ser Asp Arg Asp Ile Lys
85 90 95
Asn Asp Asp Phe Ala Ala Glu Val Arg Lys Leu Arg Thr Leu Phe Gln
100 105 110
Ser Leu Gly Tyr Tyr Asp Ser Ser Lys Ala Tyr Tyr Ala Phe Lys Val
115 120 125
Ser Phe Asn Leu Cys Ile Trp Gly Leu Ser Thr Val Ile Val Ala Lys
130 135 140
Trp Gly Gln Thr Ser Thr Leu Ala Asn Val Leu Ser Ala Ala Leu Leu
145 150 155 160
Gly Leu Phe Trp Gln Gln Cys Gly Trp Leu Ala His Asp Phe Leu His
165 170 175
His Gln Val Phe Gln Asp Arg Phe Trp Gly Asp Leu Phe Gly Ala Phe
180 185 190
Leu Gly Gly Val Cys Gln Gly Phe Ser Ser Ser Trp Trp Lys Asp Lys
195 200 205
His Asn Thr His His Ala Ala Pro Asn Val His Gly Glu Asp Pro Asp
210 215 220
Ile Asp Thr His Pro Leu Leu Thr Trp Ser Glu His Ala Leu Glu Met
225 230 235 240
Phe Ser Asp Val Pro Asp Glu Glu Leu Thr Arg Met Trp Ser Arg Phe
245 250 255
Met Val Leu Asn Gln Thr Trp Phe Tyr Phe Pro Ile Leu Ser Phe Ala
260 265 270
Arg Leu Ser Trp Cys Leu Gln Ser Ile Leu Phe Val Leu Pro Asn Gly
275 280 285
Gln Ala His Lys Pro Ser Gly Ala Arg Val Pro Ile Ser Leu Val Glu
290 295 300
Gln Leu Ser Leu Ala Met His Trp Thr Trp Tyr Leu Ala Thr Met Phe
305 310 315 320
Leu Phe Ile Lys Asp Pro Val Asn Met Leu Val Tyr Phe Leu Val Ser
325 330 335
Gln Ala Val Cys Gly Asn Leu Leu Ala Ile Val Phe Ser Leu Asn His
340 345 350
Asn Gly Met Pro Val Ile Ser Lys Glu Glu Ala Val Asp Met Asp Phe
355 360 365
Phe Thr Lys Gln Ile Ile Thr Gly Arg Asp Val His Pro Gly Leu Phe
370 375 380
Ala Asn Trp Phe Thr Gly Gly Leu Asn Tyr Gln Ile Glu His His Leu
385 390 395 400
Phe Pro Ser Met Pro Arg His Asn Phe Ser Lys Ile Gln Pro Ala Val
405 410 415
Glu Thr Leu Cys Lys Lys Tyr Asn Val Arg Tyr His Thr Thr Gly Met
420 425 430
Ile Glu Gly Thr Ala Glu Val Phe Ser Arg Leu Asn Glu Val Ser Lys
435 440 445
Ala Thr Ser Lys Met Gly Lys Ala Gln
450 455
<210>3
<211>1341
<212>DNA
<213>高山被孢霉AF067654
<400>3
atgggaacgg accaaggaaa aaccttcacc tgggaagagc tggcggccca taacaccaag 60
gacgacctac tcttggccat ccgcggcagg gtgtacgatg tcacaaagtt cttgagccgc 120
catcctggtg gagtggacac tctcctgctc ggagctggcc gagatgttac tccggtcttt 180
gagatgtatc acgcgtttgg ggctgcagat gccattatga agaagtacta tgtcggtaca 240
ctggtctcga atgagctgcc catcttcccg gagccaacgg tgttccacaa aaccatcaag 300
acgagagtcg agggctactt tacggatcgg aacattgatc ccaagaatag accagagatc 360
tggggacgat acgctcttat ctttggatcc ttgatcgctt cctactacgc gcagctcttt 420
gtgcctttcg ttgtcgaacg cacatggctt caggtggtgt ttgcaatcat catgggattt 480
gcgtgcgcac aagtcggact caaccctctt catgatgcgt ctcacttttc agtgacccac 540
aaccccactg tctggaagat tctgggagcc acgcacgact ttttcaacgg agcatcgtac 600
ctggtgtgga tgtaccaaca tatgctcggc catcacccct acaccaacat tgctggagca 660
gatcccgacg tgtcgacgtc tgagcccgat gttcgtcgta tcaagcccaa ccaaaagtgg 720
tttgtcaacc acatcaacca gcacatgttt gttcctttcc tgtacggact gctggcgttc 780
aaggtgcgca ttcaggacat caacattttg tactttgtca agaccaatga cgctattcgt 840
gtcaatccca tctcgacatg gcacactgtg atgttctggg gcggcaaggc tttctttgtc 900
tggtatcgcc tgattgttcc cctgcagtat ctgcccctgg gcaaggtgct gctcttgttc 960
acggtcgcgg acatggtgtc gtcttactgg ctggcgctga ccttccaggc gaaccacgtt 1020
gttgaggaag ttcagtggcc gttgcctgac gagaacggga tcatccaaaa ggactgggca 1080
gctatgcagg tcgagactac gcaggattac gcacacgatt cgcacctctg gaccagcatc 1140
actggcagct tgaactacca ggctgtgcac catctgttcc ccaacgtgtc gcagcaccat 1200
tatcccgata ttctggccat catcaagaac acctgcagcg agtacaaggt tccatacctt 1260
gtcaaggata cgttttggca agcatttgct tcacatttgg agcacttgcg tgttcttgga 1320
ctccgtccca aggaagagta g 1341
<210>4
<211>446
<212>PRT
<213>高山被孢霉AF067654
<400>4
Met Gly Thr Asp Gln Gly Lys Thr Phe Thr Trp Glu Glu Leu Ala Ala
1 5 10 15
His Asn Thr Lys Asp Asp Leu Leu Leu Ala Ile Arg Gly Arg Val Tyr
20 25 30
Asp Val Thr Lys Phe Leu Ser Arg His Pro Gly Gly Val Asp Thr Leu
35 40 45
Leu Leu Gly Ala Gly Arg Asp Val Thr Pro Val Phe Glu Met Tyr His
50 55 60
Ala Phe Gly Ala Ala Asp Ala Ile Met Lys Lys Tyr Tyr Val Gly Thr
65 70 75 80
Leu Val Ser Asn Glu Leu Pro Ile Phe Pro Glu Pro Thr Val Phe His
85 90 95
Lys Thr Ile Lys Thr Arg Val Glu Gly Tyr Phe Thr Asp Arg Asn Ile
100 105 110
Asp Pro Lys Asn Arg Pro Glu Ile Trp Gly Arg Tyr Ala Leu Ile Phe
115 120 125
Gly Ser Leu Ile Ala Ser Tyr Tyr Ala Gln Leu Phe Val Pro Phe Val
130 135 140
Val Glu Arg Thr Trp Leu Gln Val Val Phe Ala Ile Ile Met Gly Phe
145 150 155 160
Ala Cys Ala Gln Val Gly Leu Asn Pro Leu His Asp Ala Ser His Phe
165 170 175
Ser Val Thr His Asn Pro Thr Val Trp Lys Ile Leu Gly Ala Thr His
180 185 190
Asp Phe Phe Asn Gly Ala Ser Tyr Leu Val Trp Met Tyr Gln His Met
195 200 205
Leu Gly His His Pro Tyr Thr Asn Ile Ala Gly Ala Asp Pro Asp Val
210 215 220
Ser Thr Ser Glu Pro Asp Val Arg Arg Ile Lys Pro Asn Gln Lys Trp
225 230 235 240
Phe Val Asn His Ile Asn Gln His Met Phe Val Pro Phe Leu Tyr Gly
245 250 255
Leu Leu Ala Phe Lys Val Arg Ile Gln Asp Ile Asn Ile Leu Tyr Phe
260 265 270
Val Lys Thr Asn Asp Ala Ile Arg Val Asn Pro Ile Ser Thr Trp His
275 280 285
Thr Val Met Phe Trp Gly Gly Lys Ala Phe Phe Val Trp Tyr Arg Leu
290 295 300
Ile Val Pro Leu Gln Tyr Leu Pro Leu Gly Lys Val Leu Leu Leu Phe
305 310 315 320
Thr Val Ala Asp Met Val Ser Ser Tyr Trp Leu Ala Leu Thr Phe Gln
325 330 335
Ala Asn His Val Val Glu Glu Val Gln Trp Pro Leu Pro Asp Glu Asn
340 345 350
Gly Ile IIe Gln Lys Asp Trp Ala Ala Met Gln Val Glu Thr Thr Gln
355 360 365
Asp Tyr Ala His Asp Ser His Leu Trp Thr Ser Ile Thr Gly Ser Leu
370 375 380
Asn Tyr Gln Ala Val His His Leu Phe Pro Asn Val Ser Gln His His
385 390 395 400
Tyr Pro Asp Ile Leu Ala Ile Ile Lys Asn Thr Cys Ser Glu Tyr Lys
405 410 415
Val Pro Tyr Leu Val Lys Asp Thr Phe Trp Gln Ala Phe Ala Ser His
420 425 430
Leu Glu His Leu Arg Val Leu Gly Leu Arg Pro Lys Glu Glu
435 440 445
<210>5
<211>1077
<212>DNA
<213>异丝水霉(ATCC #56851)
<400>5
atgactgagg ataagacgaa ggtcgagttc ccgacgctca cggagctcaa gcactcgatc 60
ccgaacgcgt gctttgagtc gaacctcggc ctctcgctct actacacggc ccgcgcgatc 120
ttcaacgcgt cggcctcggc ggcgctgctc tacgcggcgc gctcgacgcc gttcattgcc 180
gataacgttc tgctccacgc gctcgtttgc gccacctaca tctacgtgca gggcgtcatc 240
ttctggggct tcttcacggt cggccacgac tgcggccact cggccttctc gcgctaccac 300
agcgtcaact ttatcatcgg ctgcatcatg cactctgcga ttttgacgcc gttcgagagc 360
tggcgcgtga cgcaccgcca ccaccacaag aacacgggca acattgataa ggacgagatc 420
ttttacccgc accggtcggt caaggacctc caggacgtgc gccaatgggt ctacacgctc 480
ggcggtgcgt ggtttgtcta cttgaaggtc gggtatgccc cgcgcacgat gagccacttt 540
gacccgtggg acccgctcct ccttcgccgc gcgtcggccg tcatcgtgtc gctcggcgtc 600
tgggccgcct tcttcgccgc gtacgcgtac ctcacatact cgctcggctt tgccgtcatg 660
ggcctctact actatgcgcc gctctttgtc tttgcttcgt tcctcgtcat tacgaccttc 720
ttgcaccaca acgacgaagc gacgccgtgg tacggcgact cggagtggac gtacgtcaag 780
ggcaacctct cgagcgtcga ccgctcgtac ggcgcgttcg tggacaacct gagccaccac 840
attggcacgc accaggtcca ccacttgttc ccgatcattc cgcactacaa gctcaacgaa 900
gccaccaagc actttgcggc cgcgtacccg cacctcgtgc gcaggaacga cgagcccatc 960
atcacggcct tcttcaagac cgcgcacctc tttgtcaact acggcgctgt gcccgagacg 1020
gcgcagatct tcacgctcaa agagtcggcc gcggccgcca aggccaagtc ggactaa 1077
<210>6
<211>358
<212>PRT
<213>异丝水霉(ATCC #56851)
<400>6
Met Ala Glu Asp Lys Thr Lys Val Glu Phe Pro Thr Leu Thr Glu Leu
1 5 10 15
Lys His Ser Ile Pro Asn Ala Cys Phe Glu Ser Asn Leu Gly Leu Ser
20 25 30
Leu Tyr Tyr Thr Ala Arg Ala Ile Phe Asn Ala Ser Ala Ser Ala Ala
35 40 45
Leu Leu Tyr Ala Ala Arg Ser Thr Pro Phe Ile Ala Asp Asn Val Leu
50 55 60
Leu His Ala Leu Val Cys Ala Thr Tyr Ile Tyr Val Gln Gly Val Ile
65 70 75 80
Phe Trp Gly Phe Phe Thr Val Gly His Asp Cys Gly His Ser Ala Phe
85 90 95
Ser Arg Tyr His Ser Val Asn Phe Ile Ile Gly Cys Ile Met His Ser
100 105 110
Ala Ile Leu Thr Pro Phe Glu Ser Trp Arg Val Thr His Arg His His
115 120 125
His Lys Asn Thr Gly Asn Ile Asp Lys Asp Glu Ile Phe Tyr Pro His
130 135 140
Arg Ser Val Lys Asp Leu Gln Asp Val Arg Gln Trp Val Tyr Thr Leu
145 150 155 160
Gly Gly Ala Trp Phe Val Tyr Leu Lys Val Gly Tyr Ala Pro Arg Thr
165 170 175
Met Ser His Phe Asp Pro Trp Asp Pro Leu Leu Leu Arg Arg Ala Ser
180 185 190
Ala Val Ile Val Ser Leu Gly Val Trp Ala Ala Phe Phe Ala Ala Tyr
195 200 205
Ala Tyr Leu Thr Tyr Ser Leu Gly Phe Ala Val Met Gly Leu Tyr Tyr
210 215 220
Tyr Ala Pro Leu Phe Val Phe Ala Ser Phe Leu Val Ile Thr Thr Phe
225 230 235 240
Leu His His Asn Asp Glu Ala Thr Pro Trp Tyr Gly Asp Ser Glu Trp
245 250 255
Thr Tyr Val Lys Gly Asn Leu Ser Ser Val Asp Arg Ser Tyr Gly Ala
260 265 270
Phe Val Asp Asn Leu Ser His His Ile Gly Thr His Gln Val His His
275 280 285
Leu Phe Pro Ile Ile Pro His Tyr Lys Leu Asn Glu Ala Thr Lys His
290 295 300
Phe Ala Ala Ala Tyr Pro His Leu Val Arg Arg Asn Asp Glu Pro Ile
305 310 315 320
Ile Thr Ala Phe Phe Lys Thr Ala His Leu Phe Val Asn Tyr Gly Ala
325 330 335
Val Pro Glu Thr Ala Gln Ile Phe Thr Leu Lys Glu Ser Ala Ala Ala
340 345 350
Ala Lys Ala Lys Ser Asp
355
<210>7
<211>957
<212>DNA
<213>高山被孢霉AX464731
<400>7
atggagtcga ttgcgccatt cctcccatca aagatgccgc aagatctgtt tatggacctt 60
gccaccgcta tcggtgtccg ggccgcgccc tatgtcgatc ctctcgaggc cgcgctggtg 120
gcccaggccg agaagtacat ccccacgatt gtccatcaca cgcgtgggtt cctggtcgcg 180
gtggagtcgc ctttggcccg tgagctgccg ttgatgaacc cgttccacgt gctgttgatc 240
gtgctcgctt atttggtcac ggtctttgtg ggcatgcaga tcatgaagaa ctttgagcgg 300
ttcgaggtca agacgttttc gctcctgcac aacttttgtc tggtctcgat cagcgcctac 360
atgtgcggtg ggatcctgta cgaggcttat caggccaact atggactgtt tgagaacgct 420
gctgatcata ccttcaaggg tcttcctatg gccaagatga tctggctctt ctacttctcc 480
aagatcatgg agtttgtcga caccatgatc atggtcctca agaagaacaa ccgccagatc 540
tccttcttgc acgtttacca ccacagctcc atcttcacca tctggtggtt ggtcaccttt 600
gttgcaccca acggtgaagc ctacttctct gctgcgttga actcgttcat ccatgtgatc 660
atgtacggct actacttctt gtcggccttg ggcttcaagc aggtgtcgtt catcaagttc 720
tacatcacgc gctcgcagat gacacagttc tgcatgatgt cggtccagtc ttcctgggac 780
atgtacgcca tgaaggtcct tggccgcccc ggatacccct tcttcatcac ggctctgctt 840
tggttctaca tgtggaccat gctcggtctc ttctacaact tttacagaaa gaacgccaag 900
ttggccaagc aggccaaggc cgacgctgcc aaggagaagg caaggaagtt gcagtaa 957
<210>8
<211>318
<212>PRT
<213>高山被孢霉AX464731
<400>8
Met Glu Ser Ile Ala Pro Phe Leu Pro Ser Lys Met Pro Gln Asp Leu
1 5 10 15
Phe Met Asp Leu Ala Thr Ala Ile Gly Val Arg Ala Ala Pro Tyr Val
20 25 30
Asp Pro Leu Glu Ala Ala Leu Val Ala Gln Ala Glu Lys Tyr Ile Pro
35 40 45
Thr Ile Val His His Thr Arg Gly Phe Leu Val Ala Val Glu Ser Pro
50 55 60
Leu Ala Arg Glu Leu Pro Leu Met Asn Pro Phe His Val Leu Leu Ile
65 70 75 80
Val Leu Ala Tyr Leu Val Thr Val Phe Val Gly Met Gln Ile Met Lys
85 90 95
Asn Phe Glu Arg Phe Glu Val Lys Thr Phe Ser Leu Leu His Asn Phe
100 105 110
Cys Leu Val Ser Ile Ser Ala Tyr Met Cys Gly Gly Ile Leu Tyr Glu
115 120 125
Ala Tyr Gln Ala Asn Tyr Gly Leu Phe Glu Asn Ala Ala Asp His Thr
130 135 140
Phe Lys Gly Leu Pro Met Ala Lys Met Ile Trp Leu Phe Tyr Phe Ser
145 150 155 160
Lys Ile Met Glu Phe Val Asp Thr Met Ile Met Val Leu Lys Lys Asn
165 170 175
Asn Arg Gln Ile Ser Phe Leu His Val Tyr His His Ser Ser Ile Phe
180 185 190
Thr Ile Trp Trp Leu Val Thr Phe Val Ala Pro Asn Gly Glu Ala Tyr
195 200 205
Phe Ser Ala Ala Leu Asn Ser Phe Ile His Val Ile Met Tyr Gly Tyr
210 215 220
Tyr Phe Leu Ser Ala Leu Gly Phe Lys Gln Val Ser Phe Ile Lys Phe
225 230 235 240
Tyr Ile Thr Arg Ser Gln Met Thr Gln Phe Cys Met Met Ser Val Gln
245 250 255
Ser Ser Trp Asp Met Tyr Ala Met Lys Val Leu Gly Arg Pro Gly Tyr
260 265 270
Pro Phe Phe Ile Thr Ala Leu Leu Trp Phe Tyr Met Trp Thr Met Leu
275 280 285
Gly Leu Phe Tyr Asn Phe Tyr Arg Lys Asn Ala Lys Leu Ala Lys Gln
290 295 300
Ala Lys Ala Asp Ala Ala Lys Glu Lys Ala Arg Lys Leu Gln
305310315
<210>9
<211>1077
<212>DNA
<213>异丝水霉
<400>9
atggctgagg ataagaccaa ggtcgagttc cctaccctga ctgagctgaa gcactctatc 60
cctaacgctt gctttgagtc caacctcgga ctctcgctct actacactgc ccgagcgatc 120
ttcaacgcat ctgcctctgc tgctctgctc tacgctgccc gatctactcc cttcattgcc 180
gataacgttc tgctccacgc tctggtttgc gccacctaca tctacgtgca gggtgtcatc 240
ttctggggtt tctttaccgt cggtcacgac tgtggtcact ctgccttctc ccgataccac 300
tccgtcaact tcatcattgg ctgcatcatg cactctgcca ttctgactcc cttcgagtcc 360
tggcgagtga cccaccgaca ccatcacaag aacactggca acattgataa ggacgagatc 420
ttctaccctc atcggtccgt caaggacctc caggacgtgc gacaatgggt ctacaccctc 480
ggaggtgctt ggtttgtcta cctgaaggtc ggatatgctc ctcgaaccat gtcccacttt 540
gacccctggg accctctcct gcttcgacga gcctccgctg tcatcgtgtc cctcggagtc 600
tgggctgcct tcttcgctgc ctacgcctac ctcacatact cgctcggctt tgccgtcatg 660
ggcctctact actatgctcc tctctttgtc tttgcttcgt tcctcgtcat tactaccttc 720
ttgcatcaca acgacgaagc tactccctgg tacggtgact cggagtggac ctacgtcaag 780
ggcaacctga gctccgtcga ccgatcgtac ggagctttcg tggacaacct gtctcaccac 840
attggcaccc accaggtcca tcacttgttc cctatcattc cccactacaa gctcaacgaa 900
gccaccaagc actttgctgc cgcttaccct cacctcgtga gacgtaacga cgagcccatc 960
attactgcct tcttcaagac cgctcacctc tttgtcaact acggagctgt gcccgagact 1020
gctcagattt tcaccctcaa agagtctgcc gctgcagcca aggccaagag cgactaa 1077
<210>10
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-1A
<400>10
catggctgag gataagacca aggtcgagtt ccctaccctg actgagctga agcactctat 60
ccctaacgct tgctttgagt ccaacctcgg actctcgctc tacta 105
<210>11
<211>106
<212>DNA
<213>人工序列
<220>
<223>引物D17-1B
<400>11
cagtgtagta gagcgagagt ccgaggttgg actcaaagca agcgttaggg atagagtgct 60
tcagctcagt cagggtaggg aactcgacct tggtcttatc ctcagc 106
<210>12
<211>106
<212>DNA
<213>人工序列
<220>
<223>引物D17-2A
<400>12
cactgcccga gcgatcttca acgcatctgc ctctgctgct ctgctctacg ctgcccgatc 60
tactcccttc attgccgata acgttctgct ccacgctctg gtttgc 106
<210>13
<211>106
<212>DNA
<213>人工序列
<220>
<223>引物D17-2B
<400>13
gtggcgcaaa ccagagcgtg gagcagaacg ttatcggcaa tgaagggagt agatcgggca 60
gcgtagagca gagcagcaga ggcagatgcg ttgaagatcg ctcggg 106
<210>14
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-3A
<400>14
gccacctaca tctacgtgca gggtgtcatc ttctggggtt tctttaccgt cggtcacgac 60
tgtggtcact ctgccttctc ccgataccac tccgtcaact tcatc 105
<210>15
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-3B
<400>15
ccaatgatga agttgacgga gtggtatcgg gagaaggcag agtgaccaca gtcgtgaccg 60
acggtaaaga aaccccagaa gatgacaccc tgcacgtaga tgtag 105
<210>16
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-4A
<400>16
attggctgca tcatgcactc tgccattctg actcccttcg agtcctggcg agtgacccac 60
cgacaccatc acaagaacac tggcaacatt gataaggacg agatc 105
<210>17
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-4B
<400>17
tagaagatct cgtccttatc aatgttgcca gtgttcttgt gatggtgtcg gtgggtcact 60
cgccaggact cgaagggagt cagaatggca gagtgcatga tgcag 105
<210>18
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-5A
<400>18
acgagatctt ctaccctcat cggtccgtca aggacctcca ggacgtgcga caatgggtct 60
acaccctcgg aggtgcttgg tttgtctacc tgaaggtcgg atatg 105
<210>19
<211>107
<212>DNA
<213>人工序列
<220>
<223>引物D17-5B
<400>19
aggagcatat ccgaccttca ggtagacaaa ccaagcacct ccgagggtgt agacccattg 60
tcgcacgtcc tggaggtcct tgacggaccg atgagggtag aagatct 107
<210>20
<211>105
<212>DNA
<213>人工序列
<220>
<223>引物D17-6A
<400>20
ctcctcgaac catgtcccac tttgacccct gggaccctct cctgcttcga cgagcctccg 60
ctgtcatcgt gtccctcgga gtctgggctg ccttcttcgc tgcct 105
<210>21
<211>106
<212>DNA
<213>人工序列
<220>
<223>引物D17-6B
<400>21
aggcgtaggc agcgaagaag gcagcccaga ctccgaggga cacgatgaca gcggaggctc 60
gtcgaagcag gagagggtcc caggggtcaa agtgggacat ggttcg 106
<210>22
<211>104
<212>DNA
<213>人工序列
<220>
<223>引物D17-7A
<400>22
acgcctacct cacatactcg ctcggctttg ccgtcatggg cctctactac tatgctcctc 60
tctttgtctt tgcttcgttc ctcgtcatta ctaccttctt gcat 104
<210>23
<211>103
<212>DNA
<213>人工序列
<220>
<223>引物D17-7B
<400>23
ttgtgatgca agaaggtagt aatgacgagg aacgaagcaa agacaaagag aggagcatag 60
tagtagaggc ccatgacggc aaagccgagc gagtatgtga ggt 103
<210>24
<211>106
<212>DNA
<213>人工序列
<220>
<223>引物D17-8A
<400>24
cacaacgacg aagctactcc ctggtacggt gactcggagt ggacctacgt caagggcaac 60
ctgagctccg tcgaccgatc gtacggagct ttcgtggaca acctgt 106
<210>25
<211>106
<212>DNA
<213>人工序列
<220>
<223>引物D17-8B
<400>25
gtgagacagg ttgtccacga aagctccgta cgatcggtcg acggagctca ggttgccctt 60
gacgtaggtc cactccgagt caccgtacca gggagtagct tcgtcg 106
<210>26
<211>102
<212>DNA
<213>人工序列
<220>
<223>引物D17-9A
<400>26
ctcaccacat tggcacccac caggtccatc acttgttccc tatcattccc cactacaagc 60
tcaacgaagc caccaagcac tttgctgccg cttaccctca cc 102
<210>27
<211>102
<212>DNA
<213>人工序列
<220>
<223>引物D17-9B
<400>27
cacgaggtga gggtaagcgg cagcaaagtg cttggtggct tcgttgagct tgtagtgggg 60
aatgataggg aacaagtgat ggacctggtg ggtgccaatg tg 102
<210>28
<211>76
<212>DNA
<213>人工序列
<220>
<223>引物D17-10A
<400>28
tcgtgagacg taacgacgag cccatcatta ctgccttctt caagaccgct cacctctttg 60
tcaactacgg agctgt 76
<210>29
<211>76
<212>DNA
<213>人工序列
<220>
<223>引物D17-10B
<400>29
cgggcacagc tccgtagttg acaaagaggt gagcggtctt gaagaaggca gtaatgatgg 60
gctcgtcgtt acgtct 76
<210>30
<211>67
<212>DNA
<213>人工序列
<220>
<223>引物D17-11A
<400>30
gcccgagact gctcagattt tcaccctcaa agagtctgcc gctgcagcca aggccaagag 60
cgactaa 67
<210>31
<211>62
<212>DNA
<213>人工序列
<220>
<223>引物D17-11B
<400>31
ttagtcgctc ttggccttgg ctgcagcggc agactctttg agggtgaaaa tctgagcagt 60
ct 62
<210>32
<211>32
<212>DNA
<213>人工序列
<220>
<223>引物D17-1
<400>32
tttccatggc tgaggataag accaaggtcg ag 32
<210>33
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物D17-4R
<400>33
ccctagaaga tctcgtcctt atcaatgttg ccag 34
<210>34
<211>27
<212>DNA
<213>人工序列
<220>
<223>引物D17-5
<400>34
cccacgagat cttctaccct catcggt 27
<210>35
<211>24
<212>DNA
<213>人工序列
<220>
<223>引物D17-8D
<400>35
gaaagctccg tacgatcggt cgac 24
<210>36
<211>24
<212>DNA
<213>人工序列
<220>
<223>引物D17-8U
<400>36
gtcgaccgat cgtacggagc tttc 24
<210>37
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物D17-11
<400>37
aaagcggccg cttagtcgct cttggccttg gctg 34
<210>38
<211>19
<212>DNA
<213>人工序列
<220>
<223>引物TEF5’
<400>38
agagaccggg ttggcggcg 19
<210>39
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物TEF3’
<400>39
ttggatcctt tgaatgattc ttatactcag 30
<210>40
<211>29
<212>DNA
<213>人工序列
<220>
<223>引物XPR5’
<400>40
tttccgcggc ccgagattcc ggcctcttc 29
<210>41
<211>31
<212>DNA
<213>人工序列
<220>
<223>引物XPR3’
<400>41
tttccgcgga cacaatatct ggtcaaattt c 31
<210>42
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL21A
<400>42
tttccatggc tgaggataag acgaaggtcg agt 33
<210>43
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL22
<400>43
cccttaatta attagtccga cttggccttg gcggcc 36
<210>44
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL53
<400>44
gccaagtcgg actaagctgc taactagagc ggccgc 36
<210>45
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL54
<400>45
gcggccgctc tagttagcag cttagtccga cttggc 36
<210>46
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物KU5
<400>46
tttgcccggg cgagtatctg tctgactcgt cattg 35
<210>47
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物KU3
<400>47
aaagcccggg caaaggcctg tttctcggtg tac 33
<210>48
<211>1710
<212>DNA
<213>解脂耶氏酵母
<400>48
gtcgacgagt atctgtctga ctcgtcattg ccgcctttgg agtacgactc caactatgag 60
tgtgcttgga tcactttgac gatacattct tcgttggagg ctgtgggtct gacagctgcg 120
ttttcggcgc ggttggccga caacaatatc agctgcaacg tcattgctgg ctttcatcat 180
gatcacattt ttgtcggcaa aggcgacgcc cagagagcca ttgacgttct ttctaatttg 240
gaccgatagc cgtatagtcc agtctatcta taagttcaac taactcgtaa ctattaccat 300
aacatatact tcactgcccc agataaggtt ccgataaaaa gttctgcaga ctaaatttat 360
ttcagtctcc tcttcaccac caaaatgccc tcctacgaag ctcgagctaa cgtccacaag 420
tccgcctttg ccgctcgagt gctcaagctc gtggcagcca agaaaaccaa cctgtgtgct 480
tctctggatg ttaccaccac caaggagctc attgagcttg ccgataaggt cggaccttat 540
gtgtgcatga tcaagaccca tatcgacatc attgacgact tcacctacgc cggcactgtg 600
ctccccctca aggaacttgc tcttaagcac ggtttcttcc tgttcgagga cagaaagttc 660
gcagatattg gcaacactgt caagcaccag tacaagaacg gtgtctaccg aatcgccgag 720
tggtccgata tcaccaacgc ccacggtgta cccggaaccg gaatcattgc tggcctgcga 780
gctggtgccg aggaaactgt ctctgaacag aagaaggagg acgtctctga ctacgagaac 840
tcccagtaca aggagttcct ggtcccctct cccaacgaga agctggccag aggtctgctc 900
atgctggccg agctgtcttg caagggctct ctggccactg gcgagtactc caagcagacc 960
attgagcttg cccgatccga ccccgagttt gtggttggct tcattgccca gaaccgacct 1020
aagggcgact ctgaggactg gcttattctg acccccgggg tgggtcttga cgacaaggga 1080
gacgctctcg gacagcagta ccgaactgtt gaggatgtca tgtctaccgg aacggatatc 1140
ataattgtcg gccgaggtct gtacggccag aaccgagatc ctattgagga ggccaagcga 1200
taccagaagg ctggctggga ggcttaccag aagattaact gttagaggtt agactatgga 1260
tatgtcattt aactgtgtat atagagagcg tgcaagtatg gagcgcttgt tcagcttgta 1320
tgatggtcag acgacctgtc tgatcgagta tgtatgatac tgcacaacct gtgtatccgc 1380
atgatctgtc caatggggca tgttgttgtg tttctcgata cggagatgct gggtacaagt 1440
agctaatacg attgaactac ttatacttat atgaggcttg aagaaagctg acttgtgtat 1500
gacttattct caactacatc cccagtcaca ataccaccac tgcactacca ctacaccaaa 1560
accatgatca aaccacccat ggacttcctg gaggcagaag aacttgttat ggaaaagctc 1620
aagagagaga agccaagata ctatcaagac atgtgtcgca acttcaagga ggaccaagct 1680
ctgtacaccg agaaacaggc ctttgtcgac 1710
<210>49
<211>286
<212>PRT
<213>解脂耶氏酵母
<400>49
Met Pro Ser Tyr Glu Ala Arg Ala Asn Val His Lys Ser Ala Phe Ala
1 5 10 15
Ala Arg Val Leu Lys Leu Val Ala Ala Lys Lys Thr Asn Leu Cys Ala
20 25 30
Ser Leu Asp Val Thr Thr Thr Lys Glu Leu Ile Glu Leu Ala Asp Lys
35 40 45
Val Gly Pro Tyr Val Cys Met Ile Lys Thr His Ile Asp Ile Ile Asp
50 55 60
Asp Phe Thr Tyr Ala Gly Thr Val Leu Pro Leu Lys Glu Leu Ala Leu
65 70 75 80
Lys His Gly Phe Phe Leu Phe Glu Asp Arg Lys Phe Ala Asp Ile Gly
85 90 95
Asn Thr Val Lys His Gln Tyr Lys Asn Gly Val Tyr Arg Ile Ala Glu
100 105 110
Trp Ser Asp Ile Thr Asn Ala His Gly Val Pro Gly Thr Gly Ile Ile
115 120 125
Ala Gly Leu Arg Ala Gly Ala Glu Glu Thr Val Ser Glu Gln Lys Lys
130 135 140
Glu Asp Val Ser Asp Tyr Glu Asn Ser Gln Tyr Lys Glu Phe Leu Val
145 150 155 160
Pro Ser Pro Asn Glu Lys Leu Ala Arg Gly Leu Leu Met Leu Ala Glu
165 170 175
Leu Ser Cys Lys Gly Ser Leu Ala Thr Gly Glu Tyr Ser Lys Gln Thr
180 185 190
Ile Glu Leu Ala Arg Ser Asp Pro Glu Phe Val Val Gly Phe Ile Ala
195 200 205
Gln Asn Arg Pro Lys Gly Asp Ser Glu Asp Trp Leu Ile Leu Thr Pro
210 215 220
Gly Val Gly Leu Asp Asp Lys Gly Asp Ala Leu Gly Gln Gln Tyr Arg
225 230 235 240
Thr Val Glu Asp Val Met Ser Thr Gly Thr Asp Ile Ile Ile Val Gly
245 250 255
Arg Gly Leu Tyr Gly Gln Asn Arg Asp Pro Ile Glu Glu Ala Lys Arg
260 265 270
Tyr Gln Lys Ala Gly Trp Glu Ala Tyr Gln Lys Ile Asn Cys
275 280 285
<210>50
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物KI5
<400>50
agagcggccg catgggagaa gtgggaccca caaac 35
<210>51
<211>38
<212>DNA
<213>人工序列
<220>
<223>引物KI3
<400>51
gtggcggccg ctcaaatgtc gttattgtac caataaac 38
<210>52
<211>1152
<212>DNA
<213>Impatients balsama
<400>52
atgggagaag tgggacccac aaaccgaacc aaaaccaagt tggacaagca acaagaatcc 60
gaaaacaggg ttcctcacga gccacctcca ttcacactaa gtgaccttaa gaaagccatc 120
ccaccccatt gcttcgagcg ctccctcgtg aaatcattct accacgtgat tcacgacatt 180
atcatcctgt cctttttcta ctatgtcgcc gccaattaca tccccatgct accccaaaac 240
ctccgttacg ttgcatggcc aatttattgg gccatccaag gctgtgtcca acttggtata 300
ttggtcttag gccatgaatg cggccaccac gccttcagcg actaccaatg ggtagacgac 360
atggtcgggt tcgtcctcca ctcgtcccaa ttgattccct acttctcatg gaaacatagc 420
caccgtcgcc accactccaa cacggcctcc atcgagcgcg acgaggtcta cccgcccgcg 480
tacaaaaacg acctgccgtg gttcgccaaa tacctacgca accccgtcgg tcgtttcctc 540
atgattttcg gggcgctact gttcggctgg ccgtcgtacc ttctgttcaa cgcgaacggc 600
cgtctctacg accgcttcgc ttcccactac gacccgcaat ccccgatctt caacaaccgc 660
gagaggctgc aagtgatcgc gtccgacgtc gggctcgtct tcgcgtactt tgtcctgtac 720
aagatcgcgc tggccaaggg atttgtgtgg ttaatttgtg tgtatggcgt cccgtacgtg 780
atcctcaacg ggcttatcgt cttgatcacg ttcctacagc acacgcaccc gaatctgccc 840
cgttacgacc tttccgagtg ggactggctt aggggagccc tgtcgactgt ggaccgcgat 900
tacgggatgt tgaataaggt gttccataac gtgacggaca cgcacttggt gcatcatttg 960
ttcacgacca tgccacatta tcgcgccaag gaggcgaccg aggtgattaa accgatattg 1020
ggagactact ataagtttga cgacactccg tttctcaaag cgttgtggaa ggacatggga 1080
aagtgtattt atgtggagtc ggacgtgcct ggcaagaaca agggagttta ttggtacaat 1140
aacgacattt ga 1152
<210>53
<211>383
<212>PRT
<213>Impatients balsama
<400>53
Met Gly Glu Val Gly Pro Thr Asn Arg Thr Lys Thr Lys Leu Asp Lys
1 5 10 15
Gln Gln Glu Ser Glu Asn Arg Val Pro His Glu Pro Pro Pro Phe Thr
20 25 30
Leu Ser Asp Leu Lys Lys Ala Ile Pro Pro His Cys Phe Glu Arg Ser
35 40 45
Leu Val Lys Ser Phe Tyr His Val Ile His Asp Ile Ile Ile Leu Ser
50 55 60
Phe Phe Tyr Tyr Val Ala Ala Asn Tyr Ile Pro Met Leu Pro Gln Asn
65 70 75 80
Leu Arg Tyr Val Ala Trp Pro Ile Tyr Trp Ala Ile Gln Gly Cys Val
85 90 95
Gln Leu Gly Ile Leu Val Leu Gly His Glu Cys Gly His His Ala Phe
100 105 110
Ser Asp Tyr Gln Trp Val Asp Asp Met Val Gly Phe Val Leu His Ser
115 120 125
Ser Gln Leu Ile Pro Tyr Phe Ser Trp Lys His Ser His Arg Arg His
130 135 140
His Ser Asn Thr Ala Ser Ile Glu Arg Asp Glu Val Tyr Pro Pro Ala
145 150 155 160
Tyr Lys Asn Asp Leu Pro Trp Phe Ala Lys Tyr Leu Arg Asn Pro Val
165 170 175
Gly Arg Phe Leu Met Ile Phe Gly Ala Leu Leu Phe Gly Trp Pro Ser
180 185 190
Tyr Leu Leu Phe Asn Ala Asn Gly Arg Leu Tyr Asp Arg Phe Ala Ser
195 200 205
His Tyr Asp Pro Gln Ser Pro Ile Phe Asn Asn Arg Glu Arg Leu Gln
210 215 220
Val Ile Ala Ser Asp Val Gly Leu Val Phe Ala Tyr Phe Val Leu Tyr
225 230 235 240
Lys Ile Ala Leu Ala Lys Gly Phe Val Trp Leu Ile Cys Val Tyr Gly
245 250 255
Val Pro Tyr Val Ile Leu Asn Gly Leu Ile Val Leu Ile Thr Phe Leu
260 265 270
Gln His Thr His Pro Asn Leu Pro Arg Tyr Asp Leu Ser Glu Trp Asp
275 280 285
Trp Leu Arg Gly Ala Leu Ser Thr Val Asp Arg Asp Tyr Gly Met Leu
290 295 300
Asn Lys Val Phe His Asn Val Thr Asp Thr His Leu Val His His Leu
305 310 315 320
Phe Thr Thr Met Pro His Tyr Arg Ala Lys Glu Ala Thr Glu Val Ile
325 330 335
Lys Pro Ile Leu Gly Asp Tyr Tyr Lys Phe Asp Asp Thr Pro Phe Leu
340 345 350
Lys Ala Leu Trp Lys Asp Met Gly Lys Cys Ile Tyr Val Glu Ser Asp
355 360 365
Val Pro Gly Lys Asn Lys Gly Val Tyr Trp Tyr Asn Asn Asp Ile
370 375 380
<210>54
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物KTI5
<400>54
aagctcgaga ccgggttggc ggcgtatttg tgtc 34
<210>55
<211>38
<212>DNA
<213>人工序列
<220>
<223>引物KTI3
<400>55
ggtctcgaga tctccaccgc ggacacaata tctggtca 38
<210>56
<211>1756
<212>DNA
<213>人工序列
<220>
<223>TEF/接合酶/XPR嵌合基因
<400>56
gaccgggttg gcggcgtatt tgtgtcccaa aaaacagccc caattgcccc aattgacccc 60
aaattgaccc agtagcgggc ccaaccccgg cgagagcccc cttcacccca catatcaaac 120
ctcccccggt tcccacactt gccgttaagg gcgtagggta ctgcagtctg gaatctacgc 180
ttgttcagac tttgtactag tttctttgtc tggccatccg ggtaacccat gccggacgca 240
aaatagacta ctgaaaattt ttttgctttg tggttgggac tttagccaag ggtataaaag 300
accaccgtcc ccgaattacc tttcctcttc ttttctctct ctccttgtca actcacaccc 360
gaaatcgtta agcatttcct tctgagtata agaatcattc aaaggatcca ctagttctag 420
agcggccgca tgggagaagt gggacccaca aaccgaacca aaaccaagtt ggacaagcaa 480
caagaatccg aaaacagggt tcctcacgag ccacctccat tcacactaag tgaccttaag 540
aaagccatcc caccccattg cttcgagcgc tccctcgtga aatcattcta ccacgtgatt 600
cacgacatta tcatcctgtc ctttttctac tatgtcgccg ccaattacat ccccatgcta 660
ccccaaaacc tccgttacgt tgcatggcca atttattggg ccatccaagg ctgtgtccaa 720
cttggtatat tggtcttagg ccatgaatgc ggccaccacg ccttcagcga ctaccaatgg 780
gtagacgaca tggtcgggtt cgtcctccac tcgtcccaat tgattcccta cttctcatgg 840
aaacatagcc accgtcgcca ccactccaac acgccctcca tcgagcgcga cgaggtctac 900
ccgcccgcgt acaaaaacga cctgccgtgg ttcgccaaat acctacgcaa ccccgtcggt 960
cgtttcctca tgattttcgg ggcgctactg ttcggctggc cgtcgtacct tctgttcaac 1020
gcgaacggcc gtctctacga ccgcttcgct tcccactacg acccgcaatc cccgatcttc 1080
aacaaccgcg agaggctgca agtgatcgcg tccgacgtcg ggctcgtctt cgcgtacttt 1140
gtcctgtaca agatcgcgct ggccaaggga tttgtgtggt taatttgtgt gtatggcgtc 1200
ccgtacgtga tcctcaacgg gcttatcgtc ttgatcacgt tcctacagca cacgcacccg 1260
aatctgcccc gttacgacct ttccgagtgg gactggctta ggggagccct gtcgactgtg 1320
gaccgcgatt acgggatgtt gaataaggtg ttccataacg tgacggacac gcacttggtg 1380
catcatttgt tcacgaccat gccacattat cgcgccaagg aggcgaccga ggtgattaaa 1440
ccgatattgg gagactacta taagtttgac gacactccgt ttctcaaagc gttgtggaag 1500
gacatgggaa agtgtattta tgtggagtcg gacgtgcctg gcaagaacaa gggagtttat 1560
tggtacaata acgacatttg agcggccgcc accgcggccc gagattccgg cctcttcggc 1620
cgccaagcga cccgggtgga cgtctagagg tacctagcaa ttaacagata gtttgccggt 1680
gataattctc ttaacctccc acactccttt gacataacga tttatgtaac gaaactgaaa 1740
tttgaccaga tattgt 1756
<210>57
<211>383
<212>PRT
<213>人工序列
<220>
<223>TEF/接合酶/XPR嵌合蛋白
<400>57
Met Gly Glu Val Gly Pro Thr Asn Arg Thr Lys Thr Lys Leu Asp Lys
1 5 10 15
Gln Gln Glu Ser Glu Asn hrg Val Pro His Glu Pro Pro Pro Phe Thr
20 25 30
Leu Ser Asp Leu Lys Lys Ala Ile Pro Pro His Cys Phe Glu Arg Ser
35 40 45
Leu Val Lys Ser Phe Tyr His Val Ile His Asp Ile Ile Ile Leu Ser
50 55 60
Phe Phe Tyr Tyr Val Ala Ala Asn Tyr Ile Pro Met Leu Pro Gln Asn
65 70 75 80
Leu Arg Tyr Val Ala Trp Pro Ile Tyr Trp Ala Ile Gln Gly Cys Val
85 90 95
Gln Leu Gly Ile Leu Val Leu Gly His Glu Cys Gly His His Ala Phe
100 105 110
Ser Asp Tyr Gln Trp Val Asp Asp Met Val Gly Phe Val Leu His Ser
115 120 125
Ser Gln Leu Ile Pro Tyr Phe Ser Trp Lys His Ser His Arg Arg His
130 135 140
His Ser Asn Thr Ala Ser Ile Glu Arg Asp Glu Val Tyr Pro Pro Ala
145 150 155 160
Tyr Lys Asn Asp Leu Pro Trp Phe Ala Lys Tyr Leu Arg Asn Pro Val
165 170 175
Gly Arg Phe Leu Met Ile Phe Gly Ala Leu Leu Phe Gly Trp Pro Ser
180 185 190
Tyr Leu Leu Phe Asn Ala Asn Gly Arg Leu Tyr Asp Arg Phe Ala Ser
195 200 205
His Tyr Asp Pro Gln Ser Pro Ile Phe Asn Asn Arg Glu Arg Leu Gln
210 215 220
Val Ile Ala Ser Asp Val Gly Leu Val Phe Ala Tyr Phe Val Leu Tyr
225 230 235 240
Lys Ile Ala Leu Ala Lys Gly Phe Val Trp Leu Ile Cys Val Tyr Gly
245 250 255
Val Pro Tyr Val Ile Leu Asn Gly Leu Ile Val Leu Ile Thr Phe Leu
260 265 270
Gln His Thr His Pro Asn Leu Pro Arg Tyr Asp Leu Ser Glu Trp Asp
275 280 285
Trp Leu Arg Gly Ala Leu Ser Thr Val Asp Arg Asp Tyr Gly Met Leu
290 295 300
Asn Lys Val Phe His Asn Val Thr Asp Thr His Leu Val His His Leu
305 310 315 320
Phe Thr Thr Met Pro His Tyr Arg Ala Lys Glu Ala Thr Glu Val Ile
325 330 335
Lys Pro Ile Leu Gly Asp Tyr Tyr Lys Phe Asp Asp Thr Pro Phe Leu
340 345 350
Lys Ala Leu Trp Lys Asp Met Gly Lys Cys Ile Tyr Val Glu Ser Asp
355 360 365
Val Pro Gly Lys Asn Lys Gly Val Tyr Trp Tyr Asn Asn Asp Ile
370 375 380
<210>58
<211>32
<212>DNA
<213>人工序列
<220>
<223>引物KH5
<400>58
tagagcggcc gcttaaacca tgaaaaagcc tg 32
<210>59
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物KH3
<400>59
gtggcggccg ctttaggtac ctcactattc ctt 33
<210>60
<211>1026
<212>DNA
<213>大肠杆菌
<400>60
atgaa2aagc ctgaactcac cgcgacgtct gtcgagaagt ttctgatcga aaagttcgac 60
agcgtctccg acctgatgca gctctcggag ggcgaagaat ctcgtgcttt cagcttcgat 120
gtaggagggc gtggatatgt cctgcgggta aatagctgcg ccgatggttt ctacaaagat 180
cgttatgttt atcggcactt tgcatcggcc gcgctcccga ttccggaagt gcttgacatt 240
ggggaattca gcgagagcct gacctattgc atctcccgcc gtgcacaggg tgtcacgttg 300
caagacctgc ctgaaaccga actgcccgct gttctgcagc cggtcgcgga ggccatggat 360
gcgatcgctg cggccgatct tagccagacg agcgggttcg gcccattcgg accgcaagga 420
atcggtcaat acactacatg gcgtgatttc atatgcgcga ttgctgatcc ccatgtgtat 480
cactggcaaa ctgtgatgga cgacaccgtc agtgcgtccg tcgcgcaggc tctcgatgag 540
ctgatgcttt gggccgagga ctgccccgaa gtccggcacc tcgtgcacgc ggatttcggc 600
tccaacaatg tcctgacgga caatggccgc ataacagcgg tcattgactg gagcgaggcg 660
atgttcgggg attcccaata cgaggtcgcc aacatcttct tctggaggcc gtggttggct 720
tgtatggagc agcagacgcg ctacttcgag cggaggcatc cggagcttgc aggatcgccg 780
cggctccggg cgtatatgct ccgcattggt cttgaccaac tctatcagag cttggttgac 840
ggcaatttcg atgatgcagc ttgggcgcag ggtcgatgcg acgcaatcgt ccgatccgga 900
gccgggactg tcgggcgtac acaaatcgcc cgcagaagcg cggccgtctg gaccgatggc 960
tgtgtagaag tactcgccga tagtggaaac cgacgcccca gcactcgtcc gagggcaaag 1020
gaatag 1026
<210>61
<211>341
<212>PRT
<213>大肠杆菌
<400>61
Met Lys Lys Pro Glu Leu Thr Ala Thr Ser Val Glu Lys Phe Leu Ile
1 5 10 15
Glu Lys Phe Asp Ser Val Ser Asp Leu Met Gln Leu Ser Glu Gly Glu
20 25 30
Glu Ser Arg Ala Phe Ser Phe Asp Val Gly Gly Arg Gly Tyr Val Leu
35 40 45
Arg Val Asn Ser Cys Ala Asp Gly Phe Tyr Lys Asp Arg Tyr Val Tyr
50 55 60
Arg His Phe Ala Ser Ala Ala Leu Pro Ile Pro Glu Val Leu Asp Ile
65 70 75 80
Gly Glu Phe Ser Glu Ser Leu Thr Tyr Cys Ile Ser Arg Arg Ala Gln
85 90 95
Gly Val Thr Leu Gln Asp Leu Pro Glu Thr Glu Leu Pro Ala Val Leu
100 105 110
Gln Pro Val Ala Glu Ala Met Asp Ala Ile Ala Ala Ala Asp Leu Ser
115 120 125
Gln Thr Ser Gly Phe Gly Pro Phe Gly Pro Gln Gly Ile Gly Gln Tyr
130 135 140
Thr Thr Trp Arg Asp Phe Ile Cys Ala Ile Ala Asp Pro His Val Tyr
145 150 155 160
His Trp Gln Thr Val Met Asp Asp Thr Val Ser Ala Ser Val Ala Gln
165 170 175
Ala Leu Asp Glu Leu Met Leu Trp Ala Glu Asp Cys Pro Glu Val Arg
180 185 190
His Leu Val His Ala Asp Phe Gly Ser Asn Asn Val Leu Thr Asp Asn
195 200 205
Gly Arg Ile Thr Ala Val Ile Asp Trp Ser Glu Ala Met Phe Gly Asp
210 215 220
Ser Gln Tyr Glu Val Ala Asn Ile Phe Phe Trp Arg Pro Trp Leu Ala
225 230 235 240
Cys Met Glu Gln Gln Thr Arg Tyr Phe Glu Arg Arg His Pro Glu Leu
245 250 255
Ala Gly Ser Pro Arg Leu Arg Ala Tyr Met Leu Arg Ile Gly Leu Asp
260 265 270
Gln Leu Tyr Gln Ser Leu Val Asp Gly Asn Phe Asp Asp Ala Ala Trp
275 280 285
Ala Gln Gly Arg Cys Asp Ala Ile Val Arg Ser Gly Ala Gly Thr Val
290 295 300
Gly Arg Thr Gln Ile Ala Arg Arg Ser Ala Ala Val Trp Thr Asp Gly
305 310 315 320
Cys Val Glu Val Leu Ala Asp Ser Gly Asn Arg Arg Pro Ser Thr Arg
325 330 335
Pro Arg Ala Lys Glu
340
<210>62
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物KTH5
<400>62
tttagatctc gagaccgggt tggcggcgta tttg 34
<210>63
<211>31
<212>DNA
<213>人工序列
<220>
<223>引物KTH3
<400>63
tttagatctc caccgcggac acaatatctg g 31
<210>64
<211>1650
<212>DNA
<213>人工序列
<220>
<223>TEF::HPT::KPR融合体
<400>64
gaccgggttg gcggcgtatt tgtgtcccaa aaaacagccc caattgcccc aattgacccc 60
aaattgaccc agtagcgggc ccaaccccgg cgagagcccc cttcacccca catatcaaac 120
ctcccccggt tcccacactt gccgttaagg gcgtagggta ctgcagtctg gaatctacgc 180
ttgttcagac tttgtactag tttctttgtc tggccatccg ggtaacccat gccggacgca 240
aaatagacta ctgaaaattt ttttgctttg tggttgggac tttagccaag ggtataaaag 300
accaccgtcc ccgaattacc tttcctcttc ttttctctct ctccttgtca actcacaccc 360
gaaatcgtta agcatttcct tctgagtata agaatcattc aaaggatcca ctagttctag 420
agcggccgct taaaccatga aaaagcctga actcaccgcg acgtctgtcg agaagtttct 480
gatcgaaaag ttcgacagcg tctccgacct gatgcagctc tcggagggcg aagaatctcg 540
tgctttcagc ttcgatgtag gagggcgtgg atatgtcctg cgggtaaata gctgcgccga 600
tggtttctac aaagatcgtt atgtttatcg gcactttgca tcggccgcgc tcccgattcc 660
ggaagtgctt gacattgggg aattcagcga gagcctgacc tattgcatct cccgccgtgc 720
acagggtgtc acgttgcaag acctgcctga aaccgaactg cccgctgttc tgcagccggt 780
cgcggaggcc atggatgcga tcgctgcggc cgatcttagc cagacgagcg ggttcggccc 840
attcggaccg caaggaatcg gtcaatacac tacatggcgt gatttcatat gcgcgattgc 900
tgatccccat gtgtatcact ggcaaactgt gatggacgac accgtcagtg cgtccgtcgc 960
gcaggctctc gatgagctga tgctttgggccgaggactgc cccgaagtcc ggcacctcgt 1020
gcacgcggat ttcggctcca acaatgtcct gacggacaat ggccgcataa cagcggtcat 1080
tgactggagc gaggcgatgt tcggggattc ccaatacgag gtcgccaaca tcttcttctg 1140
gaggccgtgg ttggcttgta tggagcagca gacgcgctac ttcgagcgga ggcatccgga 1200
gcttgcagga tcgccgcggc tccgggcgta tatgctccgc attggtcttg accaactcta 1260
tcagagcttg gttgacggca atttcgatga tgcagcttgg gcgcagggtc gatgcgacgc 1320
aatcgtccga tccggagccg ggactgtcgg gcgtacacaa atcgcccgca gaagcgcggc 1380
cgtctggacc gatggctgtg tagaagtact cgccgatagt ggaaaccgac gccccagcac 1440
tcgtccgagg gcaaaggaat agtgaggtac ctaaagcggc cgccaccgcg gcccgagatt 1500
ccggcctctt cggccgccaa gcgacccggg tggacgtcta gaggtaccta gcaattaaca 1560
gatagtttgc cggtgataat tctcttaacc tcccacactc ctttgacata acgatttatg 1620
taacgaaact gaaatttgac cagatattgt 1650
<210>65
<211>341
<212>PRT
<213>人工序列
<220>
<223>TEF::HPT::XPR融合体
<400>65
Met Lys Lys Pro Glu Leu Thr Ala Thr Ser Val Glu Lys Phe Leu Ile
1 5 10 15
Glu Lys Phe Asp Ser Val Ser Asp Leu Met Gln Leu Ser Glu Gly Glu
20 25 30
Glu Ser Arg Ala Phe Ser Phe Asp Val Gly Gly Arg Gly Tyr Val Leu
35 40 45
Arg Val Asn Ser Cys Ala Asp Gly Phe Tyr Lys Asp Arg Tyr Val Tyr
50 55 60
Arg His Phe Ala Ser Ala Ala Leu Pro Ile Pro Glu Val Leu Asp Ile
65 70 75 80
Gly Glu Phe Ser Glu Ser Leu Thr Tyr Cys Ile Ser Arg Arg Ala Gln
85 90 95
Gly Val Thr Leu Gln Asp Leu Pro Glu Thr Glu Leu Pro Ala Val Leu
100 105 110
Gln Pro Val Ala Glu Ala Met Asp Ala Ile Ala Ala Ala Asp Leu Ser
115 120 125
Gln Thr Ser Gly Phe Gly Pro Phe Gly Pro Gln Gly Ile Gly Gln Tyr
130 135 140
Thr Thr Trp Arg Asp Phe Ile Cys Ala Ile Ala Asp Pro His Val Tyr
145 150 155 160
His Trp Gln Thr Val Met Asp Asp Thr Val Ser Ala Ser Val Ala Gln
165 170 175
Ala Leu Asp Glu Leu Met Leu Trp Ala Glu Asp Cys Pro Glu Val Arg
180 185 190
His Leu Val His Ala Asp Phe Gly Ser Asn Asn Val Leu Thr Asp Asn
195 200 205
Gly Arg Ile Thr Ala Val Ile Asp Trp Ser Glu Ala Met Phe Gly Asp
210 215 220
Ser Gln Tyr Glu Val Ala Asn Ile Phe Phe Trp Arg Pro Trp Leu Ala
225 230 235 240
Cys Met Glu Gln Gln Thr Arg Tyr Phe Glu Arg Arg His Pro Glu Leu
245 250 255
Ala Gly Ser Pro Arg Leu Arg Ala Tyr Met Leu Arg Ile Gly Leu Asp
260 265 270
Gln Leu Tyr Gln Ser Leu Val Asp Gly Asn Phe Asp Asp Ala Ala Trp
275 28 0285
Ala Gln Gly Arg Cys Asp Ala Ile Val Arg Ser Gly Ala Gly Thr Val
290 295 300
Gly Arg Thr Gln Ile Ala Arg Arg Ser Ala Ala Val Trp Thr Asp Gly
305 310 315 320
Cys Val Glu Val Leu Ala Asp Ser Gly Asn Arg Arg Pro Ser Thr Arg
325 330 335
Pro Arg Ala Lys Glu
340
<210>66
<211>401
<212>DNA
<213>解脂耶氏酵母
<400>66
cgagtatctg tctgactcgt cattgccgcc tttggagtac gactccaact atgagtgtgc 60
ttggatcact ttgacgatac attcttcgtt ggaggctgtg ggtctgacag ctgcgttttc 120
ggcgcggttg gccgacaaca atatcagctg caacgtcatt gctggctttc atcatgatca 180
catttttgtc ggcaaaggcg acgcccagag agccattgac gttctttcta atttggaccg 240
atagccgtat agtccagtct atctataagt tcaactaact cgtaactatt accataacat 300
atacttcact gccccagata aggttccgat aaaaagttct gcagactaaa tttatttcag 360
tctcctcttc accaccaaaa tgccctccta cgaagctcga g 401
<210>67
<211>568
<212>DNA
<213>解脂耶氏酵母
<400>67
atcataattg tcggccgagg tctgtacggc cagaaccgag atcctattga ggaggccaag 60
cgataccaga aggctggctg ggaggcttac cagaagatta actgttagag gttagactat 120
ggatatgtca tttaactgtg tatatagaga gcgtgcaagt atggagcgct tgttcagctt 180
gtatgatggt cagacgacct gtctgatcga gtatgtatga tactgcacaa cctgtgtatc 240
cgcatgatct gtccaatggg gcatgttgtt gtgtttctcg atacggagat gctgggtaca 300
agtagctaat acgattgaac tacttatact tatatgaggc ttgaagaaag ctgacttgtg 360
tatgacttat tctcaactac atccccagtc acaataccac cactgcacta ccactacacc 420
aaaaccatga tcaaaccacc catggacttc ctggaggcag aagaacttgt tatggaaaag 480
ctcaagagag agaagccaag atactatcaa gacatgtgtc gcaacttcaa ggaggaccaa 540
gctctgtaca ccgagaaaca ggcctttg 568
<210>68
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL63
<400>68
ttatgatatc gaattaatta acctgcagcc cggggg 36
<210>69
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL64
<400>69
cccccgggct gcaggttaat taattcgata tcataa 36
<210>70
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL65
<400>70
tacgccgcca acccgtacgt ctcgagcttc gta 33
<210>71
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL66
<400>71
tacgaagctc gagacgtacg ggttggcggc gta 33
<210>72
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物YL11
<400>72
ttttccatgg gaacggacca aggaaaaacc 30
<210>73
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物YL12
<400>73
tttgcggccg cctactcttc cttgggacgg 30
<210>74
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL81
<400>74
gttatccgct cacaagcttc cacacaacgt acg 33
<210>75
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL82
<400>75
cgtacgttgt gtggaagctt gtgagcggat aac 33
<210>76
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL83
<400>76
atttgaatcg aatcgatgag cctaaaatga acc 33
<210>77
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL84
<400>77
ggttcatttt aggctcatcg attcgattca aat 33
<210>78
<211>38
<212>DNA
<213>人工序列
<220>
<223>引物YL105
<400>78
ccaagcacta acctaccgtt taaacaccac taaaaccc 38
<210>79
<211>38
<212>DNA
<213>人工序列
<220>
<223>引物YL106
<400>79
gggttttagt ggtgtttaaa cggtaggtta gtgcttgg 38
<210>80
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL119
<400>80
cgggaaacct gtcgtggcgc gccagctgca ttaatg 36
<210>81
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL120
<400>81
cattaatgca gctggcgcgc cacgacaggt ttcccg 36
<210>82
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物YL121
<400>82
tttggcgcgc ctatcacatc acgctctcat caag 34
<210>83
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物YL122
<400>83
tttcgtacga accaccaccg tcagcccttc tgac 34
<210>84
<211>440
<212>DNA
<213>解脂耶氏酵母
<400>84
aaccaccacc gtcagccctt ctgactcacg tattgtagcc accgacacag gcaacagtcc 60
gtggatagca gaatatgtct tgtcggtcca tttctcacca actttaggcg tcaagtgaat 120
gttgcagaag aagtatgtgc cttcattgag aatcggtgtt gctgatttca ataaagtctt 180
gagatcagtt tggccagtca tgttgtgggg ggtaattgga ttgagttatc gcctacagtc 240
tgtacaggta tactcgctgc ccactttata ctttttgatt ccgctgcact tgaagcaatg 300
tcgtttacca aaagtgagaa tgctccacag aacacacccc agggtatggt tgagcaaaaa 360
ataaacactc cgatacgggg aatcgaaccc cggtctccac ggttctcaag aagtattctt 420
gatgagagcg tgatgtgata 440
<210>85
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物YL114
<400>85
tgatagtatc ttggcgcgcc ttctctctct tgagc 35
<210>86
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物YL115
<400>86
gctcaagaga gagaaggcgc gccaagatac tatca 35
<210>87
<211>5218
<212>DNA
<213>人工序列
<220>
<223>用于整合和表达Δ-5去饱和酶基因的5218bp片段
<400>87
tatcacatca cgctctcatc aagaatactt cttgagaacc gtggagaccg gggttcgatt 60
ccccgtatcg gagtgtttat tttttgctca accataccct ggggtgtgtt ctgtggagca 120
ttctcacttt tggtaaacga cattgcttca agtgcagcgg aatcaaaaag tataaagtgg 180
gcagcgagta tacctgtaca gactgtaggc gataactcaa tccaattacc ccccacaaca 240
tgactggcca aactgatctc aagactttat tgaaatcagc aacaccgatt ctcaatgaag 300
gcacatactt cttctgcaac attcacttga cgcctaaagt tggtgagaaa tggaccgaca 360
agacatattc tgctatccac ggactgttgc ctgtgtcggt ggctacaata cgtgagtcag 420
aagggctgac ggtggtggtt cgtacgttgt gtggaagctt gtgagcggat aacaatttca 480
cacaggaaac agctatgacc atgattacgc caagctcgaa attaaccctc actaaaggga 540
acaaaagctg gagctccacc gcggacacaa tatctggtca aatttcagtt tcgttacata 600
aatcgttatg tcaaaggagt gtgggaggtt aagagaatta tcaccggcaa actatctgtt 660
aattgctagg tacctctaga cgtccacccg ggtcgcttgg cggccgaaga ggccggaatc 720
tcgggccgcg gtggcggccg cctactcttc cttgggacgg agtccaagaa cacgcaagtg 780
ctccaaatgt gaagcaaatg cttgccaaaa cgtatccttg acaaggtatg gaaccttgta 840
ctcgctgcag gtgttcttga tgatggccag aatatcggga taatggtgct gcgacacgtt 900
ggggaacaga tggtgcacag ccggtagttc aagctgccag tgatgctggt ccagaggtgc 960
gaatcgtgtg cgtaatcctg cgtagtctcg acctgcatag ctgcccagtc cttttggatg 1020
atcccgttct cgtcaggcaa cggccactga acttcctcaa caacgtggtt cgcctggaag 1080
gtcagcgcca gccagtaaga cgacaccatg tccgcgaccg tgaacaagag cagcaccttg 1140
cccaggggca gatactgcag gggaacaatc aggcgatacc agacaaagaa agccttgccg 1200
ccccagaaca tcacagtgtg ccatgtcgag atgggattga cacgaatagc gtcattggtc 1260
ttgacaaagt acaaaatgtt gatgtcctga atgcgcacct tgaacgccag cagtccgtac 1320
aggaaaggaa caaacatgtg ctggttgatg tggttgacaa accacttttg gttgggcttg 1380
atacgacgaa catcgggctc agacgtcgac acgtcgggat ctgctccagc aatgttggtg 1440
taggggtgat ggccgagcat atgttggtac atccacacca ggtacgatgc tccgttgaaa 1500
aagtcgtgcg tggctcccag aatcttccag acagtggggt tgtgggtcac tgaaaagtga 1560
gacgcatcat gaagagggtt gagtccgact tgtgcgcacg caaatcccat gatgattgca 1620
aacaccacct gaagccatgt gcgttcgaca acgaaaggca caaagagctg cgcgtagtag 1680
gaagcgatca aggatccaaa gataagagcg tatcgtcccc agatctctgg tctattcttg 1740
ggatcaatgt tccgatccgt aaagtagccc tcgactctcg tcttgatggt tttgtggaac 1800
accgttggct ccgggaagat gggcagctca ttcgagacca gtgtaccgac atagtacttc 1860
ttcataatgg catctgcagc cccaaacgcg tgatacatct caaagaccgg agtaacatct 1920
cggccagctc cgagcaggag agtgtccact ccaccaggat ggcggctcaa gaactttgtg 1980
acatcgtaca ccctgccgcg gatggccaag agtaggtcgt ccttggtgtt atgggccgcc 2040
agctcttccc aggtgaaggt ttttccttgg tccgttccca tggtgaatga ttcttatact 2100
cagaaggaaa tgcttaacga tttcgggtgt gagttgacaa ggagagagag aaaagaagag 2160
gaaaggtaat tcggggacgg tggtctttta tacccttggc taaagtccca accacaaagc 2220
aaaaaaattt tcagtagtct attttgcgtc cggcatgggt tacccggatg gccagacaaa 2280
gaaactagta caaagtctga acaagcgtag attccagact gcagtaccct acgcccttaa 2340
cggcaagtgt gggaaccggg ggaggtttga tatgtggggt gaagggggct ctcgccgggg 2400
ttgggcccgc tactgggtca atttggggtc aattggggca attggggctg ttttttggga 2460
cacaaatacg ccgccaaccc ggtctctcct gaattctgca gatgggctgc aggaattccg 2520
tcgtcgcctg agtcgacatc atttatttac cagttggcca caaacccttg acgatctcgt 2580
atgtcccctc cgacatactc ccggccggct ggggtacgtt cgatagcgct atcggcatcg 2640
acaaggtttg ggtccctagc cgataccgca ctacctgagt cacaatcttc ggaggtttag 2700
tcttccacat agcacgggca aaagtgcgta tatatacaag agcgtttgcc agccacagat 2760
tttcactcca cacaccacat cacacataca accacacaca tccacaatgg aacccgaaac 2820
taagaagacc aagactgact ccaagaagat tgttcttctc ggcggcgact tctgtggccc 2880
cgaggtgatt gccgaggccg tcaaggtgct caagtctgtt gctgaggcct ccggcaccga 2940
gtttgtgttt gaggaccgac tcattggagg agctgccatt gagaaggagg gcgagcccat 3000
caccgacgct actctcgaca tctgccgaaa ggctgactct attatgctcg gtgctgtcgg 3060
aggcgctgcc aacaccgtat ggaccactcc cgacggacga accgacgtgc gacccgagca 3120
gggtctcctc aagctgcgaa aggacctgaa cctgtacgcc aacctgcgac cctgccagct 3180
gctgtcgccc aagctcgccg atctctcccc catccgaaac gttgagggca ccgacttcat 3240
cattgtccga gagctcgtcg gaggtatcta ctttggagag cgaaaggagg atgacggatc 3300
tggcgtcgct tccgacaccg agacctactc cgttcctgag gttgagcgaa ttgcccgaat 3360
ggccgccttc ctggcccttc agcacaaccc ccctcttccc gtgtggtctc ttgacaaggc 3420
caacgtgctg gcctcctctc gactttggcg aaagactgtc actcgagtcc tcaaggacga 3480
attcccccag ctcgagctca accaccagct gatcgactcg gccgccatga tcctcatcaa 3540
gcagccctcc aagatgaatg gtatcatcat caccaccaac atgtttggcg atatcatctc 3600
cgacgaggcc tccgtcatcc ccggttctct gggtctgctg ccctccgcct ctctggcttc 3660
tctgcccgac accaacgagg cgttcggtct gtacgagccc tgtcacggat ctgcccccga 3720
tctcggcaag cagaaggtca accccattgc caccattctg tctgccgcca tgatgctcaa 3780
gttctctctt aacatgaagc ccgccggtga cgctgttgag gctgccgtca aggagtccgt 3840
cgaggctggt atcactaccg ccgatatcgg aggctcttcc tccacctccg aggtcggaga 3900
cttgttgcca acaaggtcaa ggagctgctc aagaaggagt aagtcgtttc tacgacgcat 3960
tgatggaagg agcaaactga cgcgcctgcg ggttggtcta ccggcagggt ccgctagtgt 4020
ataagactct ataaaaaggg ccctgccctg ctaatgaaat gatgatttat aatttaccgg 4080
tgtagcaacc ttgactagaa gaagcagatt gggtgtgttt gtagtggagg acagtggtac 4140
gttttggaaa cagtcttctt gaaagtgtct tgtctacagt atattcactc ataacctcaa 4200
tagccaaggg tgtagtcggt ttattaaagg aagggagttg tggctgatgt ggatagatat 4260
ctttaagctg gcgactgcac ccaacgagtg tggtggtagc ttgttactgt atattcggta 4320
agatatattt tgtggggttt tagtggtgtt taaacggtag gttagtgctt ggtatatgag 4380
ttgtaggcat gacaatttgg aaaggggtgg actttgggaa tattgtggga tttcaatacc 4440
ttagtttgta cagggtaatt gttacaaatg atacaaagaa ctgtatttct tttcatttgt 4500
tttaattggt tgtatatcaa gtccgttaga cgagctcagt gccttggctt ttggcactgt 4560
atttcatttt tagaggtaca ctacattcag tgaggtatgg taaggttgag ggcataatga 4620
aggcaccttg tactgacagt cacagacctc tcaccgagaa ttttatgaga tatactcggg 4680
ttcattttag gctcatcgat tcgattcaaa ttaattaatt cgatatcata attgtcggcc 4740
gaggtctgta cggccagaac cgagatccta ttgaggaggc caagcgatac cagaaggctg 4800
gctgggaggc ttaccagaag attaactgtt agaggttaga ctatggatat gtcatttaac 4860
tgtgtatata gagagcgtgc aagtatggag cgcttgttca gcttgtatga tggtcagacg 4920
acctgtctga tcgagtatgt atgatactgc acaacctgtg tatccgcatg atctgtccaa 4980
tggggcatgt tgttgtgttt ctcgatacgg agatgctggg tacaagtagc taatacgatt 5040
gaactactta tacttatatg aggcttgaag aaagctgact tgtgtatgac ttattctcaa 5100
ctacatcccc agtcacaata ccaccactgc actaccacta caccaaaacc atgatcaaac 5160
cacccatgga cttcctggag gcagaagaac ttgttatgga aaagctcaag agagagaa 5218
<210>88
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL61
<400>88
acaattccac acaacgtacg agccggaagc ata 33
<210>89
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL62
<400>89
tatgcttccg gctcgtacgt tgtgtggaat tgt 33
<210>90
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL69
<400>90
agcccatctg cagaagcttc aggagagacc ggg 33
<210>91
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL70
<400>91
cccggtctct cctgaagctt ctgcagatgg gct 33
<210>92
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL77
<400>92
tagtgagggt taattaatcg agcttggcgt aat 33
<210>93
<211>33
<212>DNA
<213>人工序列
<220>
<223>引物YL78
<400>93
attacgccaa gctcgattaa ttaaccctca cta 33
<210>94
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物YL79A
<400>94
attcctgcag cccatcgatg cagaattcag gaga 34
<210>95
<211>34
<212>DNA
<213>人工序列
<220>
<223>引物YL80A
<400>95
tctcctgaat tctgcatcga tgggctgcag gaat 34
<210>96
<211>8894
<212>DNA
<213>人工序列
<220>
<223>用于整合和表达Δ-6Δ-5去饱和酶基因和延伸酶基因的8894bp片段
<400>96
tatcacatca cgctctcatc aagaatactt cttgagaacc gtggagaccg gggttcgatt 60
ccccgtatcg gagtgtttat tttttgctca accataccct ggggtgtgtt ctgtggagca 120
ttctcacttt tggtaaacga cattgcttca agtgcagcgg aatcaaaaag tataaagtgg 180
gcagcgagta tacctgtaca gactgtaggc gataactcaa tccaattacc ccccacaaca 240
tgactggcca aactgatctc aagactttat tgaaatcagc aacaccgatt ctcaatgaag 300
gcacatactt cttctgcaac attcacttga cgcctaaagt tggtgagaaa tggaccgaca 360
agacatattc tgctatccac ggactgttgc ctgtgtcggt ggctacaata cgtgagtcag 420
aagggctgac ggtggtggtt cgtacgttgt gtggaattgt gagcggataa caatttcaca 480
caggaaacag ctatgaccat gattacgcca agctcgaaat taaccctcac taaagggaac 540
aaaagctgga gctccaccgc ggacacaata tctggtcaaa tttcagtttc gttacataaa 600
tcgttatgtc aaaggagtgt gggaggttaa gagaattatc accggcaaac tatctgttaa 660
ttgctaggta cctctagacg tccacccggg tcgcttggcg gccgaagagg ccggaatctc 720
gggccgcggt ggcggccgct tactgcaact tccttgcctt ctccttggca gcgtcggcct 780
tggcctgctt ggccaacttg gcgttctttc tgtaaaagtt gtagaagaga ccgagcatgg 840
tccacatgta gaaccaaagc agagccgtga tgaagaaggg gtatccgggg cggccaagga 900
ccttcatggc gtacatgtcc caggaagact ggaccgacat catgcagaac tgtgtcatct 960
gcgagcgcgt gatgtagaac ttgatgaacg acacctgctt gaagcccaag gccgacaaga 1020
agtagtagcc gtacatgatc acatggatga acgagttcaa cgcagcagag aagtaggctt 1080
caccgttggg tgcaacaaag gtgaccaacc accagatggt gaagatggag ctgtggtggt 1140
aaacgtgcaa gaaggagatc tggcggttgt tcttcttgag gaccatgatc atggtgtcga 1200
caaactccat gatcttggag aagtagaaga gccagatcat cttggccata ggaagaccct 1260
tgaaggtatg atcagcagcg ttctcaaaca gtccatagtt ggcctgataa gcctcgtaca 1320
ggatcccacc gcacatgtag gcgctgatcg agaccagaca aaagttgtgc aggagcgaaa 1380
acgtcttgac ctcgaaccgc tcaaagttct tcatgatctg catgcccaca aagaccgtga 1440
ccaaataagc gagcacgatc aacagcacgt ggaacgggtt catcaacggc agctcacggg 1500
ccaaaggcga ctccaccgcg accaggaacc cacgcgtgtg atggacaatc gtggggatgt 1560
acttctcggc ctgggccacc agcgcggcct cgagaggatc gacatagggc gcggcccgga 1620
caccgatagc ggtggcaagg tccataaaca gatcttgcgg catctttgat gggaggaatg 1680
gcgcaatcga ctccatgcgg ccgctctaga actagtggat cctttgaatg attcttatac 1740
tcagaaggaa atgcttaacg atttcgggtg tgagttgaca aggagagaga gaaaagaaga 1800
ggaaaggtaa ttcggggacg gtggtctttt atacccttgg ctaaagtccc aaccacaaag 1860
caaaaaaatt ttcagtagtc tattttgcgt ccggcatggg ttacccggat ggccagacaa 1920
agaaactagt acaaagtctg aacaagcgta gattccagac tgcagtaccc tacgccctta 1980
acggcaagtg tgggaaccgg gggaggtttg atatgtgggg tgaagggggc tctcgccggg 2040
gttgggcccg ctactgggtc aatttggggt caattggggc aattggggct gttttttggg 2100
acacaaatac gccgccaacc cggtctctcc tgaagcttgt gagcggataa caatttcaca 2160
caggaaacag ctatgaccat gattacgcca agctcgaaat taaccctcac taaagggaac 2220
aaaagctgga gctccaccgc ggacacaata tctggtcaaa tttcagtttc gttacataaa 2280
tcgttatgtc aaaggagtgt gggaggttaa gagaattatc accggcaaac tatctgttaa 2340
ttgctaggta cctctagacg tccacccggg tcgcttggcg gccgaagagg ccggaatctc 2400
gggccgcggt ggcggccgcc tactcttcct tgggacggag tccaagaaca cgcaagtgct 2460
ccaaatgtga agcaaatgct tgccaaaacg tatccttgac aaggtatgga accttgtact 2520
cgctgcaggt gttcttgatg atggccagaa tatcgggata atggtgctgc gacacgttgg 2580
ggaacagatg gtgcacagcc tggtagttca agctgccagt gatgctggtc cagaggtgcg 2640
aatcgtgtgc gtaatcctgc gtagtctcga cctgcatagc tgcccagtcc ttttggatga 2700
tcccgttctc gtcaggcaac ggccactgaa cttcctcaac aacgtggttc gcctggaagg 2760
tcagcgccag ccagtaagac gacaccatgt ccgcgaccgt gaacaagagc agcaccttgc 2820
ccaggggcag atactgcagg ggaacaatca ggcgatacca gacaaagaaa gccttgccgc 2880
cccagaacat cacagtgtgc catgtcgaga tgggattgac acgaatagcg tcattggtct 2940
tgacaaagta caaaatgttg atgtcctgaa tgcgcacctt gaacgccagc agtccgtaca 3000
ggaaaggaac aaacatgtgc tggttgatgt ggttgacaaa ccacttttgg ttgggcttga 3060
tacgacgaac atcgggctca gacgtcgaca cgtcgggatc tgctccagca atgttggtgt 3120
aggggtgatg gccgagcata tgttggtaca tccacaccag gtacgatgct ccgttgaaaa 3180
agtcgtgcgt ggctcccaga atcttccaga cagtggggtt gtgggtcact gaaaagtgag 3240
acgcatcatg aagagggttg agtccgactt gtgcgcacgc aaatcccatg atgattgcaa 3300
acaccacctg aagccatgtg cgttcgacaa cgaaaggcac aaagagctgc gcgtagtagg 3360
aagcgatcaa ggatccaaag ataagagcgt atcgtcccca gatctctggt ctattcttgg 3420
gatcaatgtt ccgatccgta aagtagccct cgactctcgt cttgatggtt ttgtggaaca 3480
ccgttggctc cgggaagatg ggcagctcat tcgagaccag tgtaccgaca tagtacttct 3540
tcataatggc atctgcagcc ccaaacgcgt gatacatctc aaagaccgga gtaacatctc 3600
ggccagctcc gagcaggaga gtgtccactc caccaggatg gcggctcaag aactttgtga 3660
catcgtacac cctgccgcgg atggccaaga gtaggtcgtc cttggtgtta tgggccgcca 3720
gctcttccca ggtgaaggtt tttccttggt ccgttcccat ggtgaatgat tcttatactc 3780
agaaggaaat gcttaacgat ttcgggtgtg agttgacaag gagagagaga aaagaagagg 3840
aaaggtaatt cggggacggt ggtcttttat acccttggct aaagtcccaa ccacaaagca 3900
aaaaaatttt cagtagtcta ttttgcgtcc ggcatgggtt acccggatgg ccagacaaag 3960
aaactagtac aaagtctgaa caagcgtaga ttccagactg cagtacccta cgcccttaac 4020
ggcaagtgtg ggaaccgggg gaggtttgat atgtggggtg aagggggctc tcgccggggt 4080
tgggcccgct actgggtcaa tttggggtca attggggcaa ttggggctgt tttttgggac 4140
acaaatacgc cgccaacccg gtctctcctg aattctgcag atgggctgca ggaattccgt 4200
cgtcgcctga gtcgacatca tttatttacc agttggccac aaacccttga cgatctcgta 4260
tgtcccctcc gacatactcc cggccggctg gggtacgttc gatagcgcta tcggcatcga 4320
caaggtttgg gtccctagcc gataccgcac tacctgagtc acaatcttcg gaggtttagt 4380
cttccacata gcacgggcaa aagtgcgtat atatacaaga gcgtttgcca gccacagatt 4440
ttcactccac acaccacatc acacatacaa ccacacacat ccacaatgga acccgaaact 4500
aagaagacca agactgactc caagaagatt gttcttctcg gcggcgactt ctgtggcccc 4560
gaggtgattg ccgaggccgt caaggtgctc aagtctgttg ctgaggcctc cggcaccgag 4620
tttgtgtttg aggaccgact cattggagga gctgccattg agaaggaggg cgagcccatc 4680
accgacgcta ctctcgacat ctgccgaaag gctgactcta ttatgctcgg tgctgtcgga 4740
ggcgctgcca acaccgtatg gaccactccc gacggacgaa ccgacgtgcg acccgagcag 4800
ggtctcctca agctgcgaaa ggacctgaac ctgtacgcca acctgcgacc ctgccagctg 4860
ctgtcgccca agctcgccga tctctccccc atccgaaacg ttgagggcac cgacttcatc 4920
attgtccgag agctcgtcgg aggtatctac tttggagagc gaaaggagga tgacggatct 4980
ggcgtcgctt ccgacaccga gacctactcc gttcctgagg ttgagcgaat tgcccgaatg 5040
gccgccttcc tggcccttca gcacaacccc cctcttcccg tgtggtctct tgacaaggcc 5100
aacgtgctgg cctcctctcg actttggcga aagactgtca ctcgagtcct caaggacgaa 5160
ttcccccagc tcgagctcaa ccaccagctg atcgactcgg ccgccatgat cctcatcaag 5220
cagccctcca agatgaatgg tatcatcatc accaccaaca tgtttggcga tatcatctcc 5280
gacgaggcct ccgtcatccc cggttctctg ggtctgctgc cctccgcctc tctggcttct 5340
ctgcccgaca ccaacgaggc gttcggtctg tacgagccct gtcacggatc tgcccccgat 5400
ctcggcaagc agaaggtcaa ccccattgcc accattctgt ctgccgccat gatgctcaag 5460
ttctctctta acatgaagcc cgccggtgac gctgttgagg ctgccgtcaa ggagtccgtc 5520
gaggctggta tcactaccgc cgatatcgga ggctcttcct ccacctccga ggtcggagac 5580
ttgttgccaa caaggtcaag gagctgctca agaaggagta agtcgtttct acgacgcatt 5640
gatggaagga gcaaactgac gcgcctgcgg gttggtctac cggcagggtc cgctagtgta 5700
taagactcta taaaaagggc cctgccctgc taatgaaatg atgatttata atttaccggt 5760
gtagcaacct tgactagaag aagcagattg ggtgtgtttg tagtggagga cagtggtacg 5820
ttttggaaac agtcttcttg aaagtgtctt gtctacagta tattcactca taacctcaat 5880
agccaagggt gtagtcggtt tattaaagga agggagttgt ggctgatgtg gatagatatc 5940
tttaagctgg cgactgcacc caacgagtgt ggtggtagct tgttactgta tattcggtaa 6000
gatatatttt gtggggtttt agtggtgttt aaacggtagg ttagtgcttg gtatatgagt 6060
tgtaggcatg acaatttgga aaggggtgga ctttgggaat attgtgggat ttcaatacct 6120
tagtttgtac agggtaattg ttacaaatga tacaaagaac tgtatttctt ttcatttgtt 6180
ttaattggtt gtatatcaag tccgttagac gagctcagtg ccttggcttt tggcactgta 6240
tttcattttt agaggtacac tacattcagt gaggtatggt aaggttgagg gcataatgaa 6300
ggcaccttgt actgacagtc acagacctct caccgagaat tttatgagat atactcgggt 6360
tcattttagg ctcatcgatg cagaattcag gagagaccgg gttggcggcg tatttgtgtc 6420
ccaaaaaaca gccccaattg ccccaattga ccccaaattg acccagtagc gggcccaacc 6480
ccggcgagag cccccttcac cccacatatc aaacctcccc cggttcccac acttgccgtt 6540
aagggcgtag ggtactgcag tctggaatct acgcttgttc agactttgta ctagtttctt 6600
tgtctggcca tccgggtaac ccatgccgga cgcaaaatag actactgaaa atttttttgc 6660
tttgtggttg ggactttagc caagggtata aaagaccacc gtccccgaat tacctttcct 6720
cttcttttct ctctctcctt gtcaactcac acccgaaatc gttaagcatt tccttctgag 6780
tataagaatc attcaccatg gctgctgctc ccagtgtgag gacgtttact cgggccgagg 6840
ttttgaatgc cgaggctctg aatgagggca agaaggatgc cgaggcaccc ttcttgatga 6900
tcatcgacaa caaggtgtac gatgtccgcg agttcgtccc tgatcatccc ggtggaagtg 6960
tgattctcac gcacgttggc aaggacggca ctgacgtctt tgacactttt caccccgagg 7020
ctgcttggga gactcttgcc aacttttacg ttggtgatat tgacgagagc gaccgcgata 7080
tcaagaatga tgactttgcg gccgaggtcc gcaagctgcg taccttgttc cagtctcttg 7140
gttactacga ttcttccaag gcatactacg ccttcaaggt ctcgttcaac ctctgcatct 7200
ggggtttgtc gacggtcatt gtggccaagt ggggccagac ctcgaccctc gccaacgtgc 7260
tctcggctgc gcttttgggt ctgttctggc agcagtgcgg atggttggct cacgactttt 7320
tgcatcacca ggtcttccag gaccgtttct ggggtgatct tttcggcgcc ttcttgggag 7380
gtgtctgcca gggcttctcg tcctcgtggt ggaaggacaa gcacaacact caccacgccg 7440
cccccaacgt ccacggcgag gatcccgaca ttgacaccca ccctctgttg acctggagtg 7500
agcatgcgtt ggagatgttc tcggatgtcc cagatgagga gctgacccgc atgtggtcgc 7560
gtttcatggt cctgaaccag acctggtttt acttccccat tctctcgttt gcccgtctct 7620
cctggtgcct ccagtccatt ctctttgtgc tgcctaacgg tcaggcccac aagccctcgg 7680
gcgcgcgtgt gcccatctcg ttggtcgagc agctgtcgct tgcgatgcac tggacctggt 7740
acctcgccac catgttcctg ttcatcaagg atcccgtcaa catgctggtg tactttttgg 7800
tgtcgcaggc ggtgtgcgga aacttgttgg ccatcgtgtt ctcgctcaac cacaacggta 7860
tgcctgtgat ctcgaggagg aggcggtcga tatggatttc ttcacgaagc agatcatcac 7920
gggtcgtgat gtccacccgg gtctatttgc caactggttc acgggtggat tgaactatca 7980
gatcgagcac cacttgttcc cttcgatgcc tcgccacaac ttttcaaaga tccagcctgc 8040
tgtcgagacc ctgtgcaaaa agtacaatgt ccgataccac accaccggta tgatcgaggg 8100
aactgcagag gtctttagcc gtctgaacga ggtctccaag gctacctcca agatgggtaa 8160
ggcgcagtaa gcggccgcca ccgcggcccg agattccggc ctcttcggcc gccaagcgac 8220
ccgggtggac gtctagaggt acctagcaat taacagatag tttgccggtg ataattctct 8280
taacctccca cactcctttg acataacgat ttatgtaacg aaactgaaat ttgaccagat 8340
attgtgtccg cggtggagct ccagcttttg ttccctttag tgagggttaa ttaattcgat 8400
atcataattg tcggccgagg tctgtacggc cagaaccgag atcctattga ggaggccaag 8460
cgataccaga aggctggctg ggaggcttac cagaagatta actgttagag gttagactat 8520
ggatatgtca tttaactgtg tatatagaga gcgtgcaagt atggagcgct tgttcagctt 8580
gtatgatggt cagacgacct gtctgatcga gtatgtatga tactgcacaa cctgtgtatc 8640
cgcatgatct gtccaatggg gcatgttgtt gtgtttctcg atacggagat gctgggtaca 8700
agtagctaat acgattgaac tacttatact tatatgaggc ttgaagaaag ctgacttgtg 8760
tatgacttat tctcaactac atccccagtc acaataccac cactgcacta ccactacacc 8820
aaaaccatga tcaaaccacc catggacttc ctggaggcag aagaacttgt tatggaaaag 8880
ctcaagagag agaa 8894
<210>97
<211>31
<g1g>DNA
<213>人工序列
<220>
<223>引物YL101
<400>97
gagcttggcg taatcgatgg tcatagctgt t 31
<210>98
<211>31
<212>DNA
<213>人工序列
<220>
<223>引物YL102
<400>98
aacagctatg accatcgatt acgccaagct c 31
<210>99
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL103
<400>99
atgatgactc aggcgtttaa acgacggaat tcctgc 36
<210>100
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL104
<400>100
gcaggaattc cgtcgtttaa acgcctgagt catcat 36
<210>101
<211>10328
<212>DNA
<213>人工序列
<220>
<223>用于整合和表达Δ-6,Δ-5和Δ-17去饱和酶基因和延伸酶基因的10328bp片段
<400>101
tatcacatca cgctctcatc aagaatactt cttgagaacc gtggagaccg gggttcgatt 60
ccccgtatcg gagtgtttat tttttgctca accataccct ggggtgtgtt ctgtggagca 120
ttctcacttt tggtaaacga cattgcttca agtgcagcgg aatcaaaaag tataaagtgg 180
gcagcgagta tacctgtaca gactgtaggc gataactcaa tccaattacc ccccacaaca 240
tgactggcca aactgatctc aagactttat tgaaatcagc aacaccgatt ctcaatgaag 300
gcacatactt cttctgcaac attcacttga cgcctaaagt tggtgagaaa tggaccgaca 360
agacatattc tgctatccac ggactgttgc ctgtgtcggt ggctacaata cgtgagtcag 420
aagggctgac ggtggtggtt cgtacgttgt gtggaattgt gagcggataa caatttcaca 480
caggaaacag ctatgaccat gattacgcca agctcgaaat taaccctcac taaagggaac 540
aaaagctgga gctccaccgc ggacacaata tctggtcaaa tttcagtttc gttacataaa 600
tcgttatgtc aaaggagtgt gggaggttaa gagaattatc accggcaaac tatctgttaa 660
ttgctaggta cctctagacg tccacccggg tcgcttggcg gccgaagagg ccggaatctc 720
gggccgcggt ggcggccgct tactgcaact tccttgcctt ctccttggca gcgtcggcct 780
tggcctgctt ggccaacttg gcgttctttc tgtaaaagtt gtagaagaga ccgagcatgg 840
tccacatgta gaaccaaagc agagccgtga tgaagaaggg gtatccgggg cggccaagga 900
ccttcatggc gtacatgtcc caggaagact ggaccgacat catgcagaac tgtgtcatct 960
gcgagcgcgt gatgtagaac ttgatgaacg acacctgctt gaagcccaag gccgacaaga 1020
agtagtagcc gtacatgatc acatggatga acgagttcaa cgcagcagag aagtaggctt 1080
caccgttggg tgcaacaaag gtgaccaacc accagatggt gaagatggag ctgtggtggt 1140
aaacgtgcaa gaaggagatc tggcggttgt tcttcttgag gaccatgatc atggtgtcga 1200
caaactccat gatcttggag aagtagaaga gccagatcat cttggccata ggaagaccct 1260
tgaaggtatg atcagcagcg ttctcaaaca gtccatagtt ggcctgataa gcctcgtaca 1320
ggatcccacc gcacatgtag gcgctgatcg agaccagaca aaagttgtgc aggagcgaaa 1380
acgtcttgac ctcgaaccgc tcaaagttct tcatgatctg catgcccaca aagaccgtga 1440
ccaaataagc gagcacgatc aacagcacgt ggaacgggtt catcaacggc agctcacggg 1500
ccaaaggcga ctccaccgcg accaggaacc cacgcgtgtg atggacaatc gtggggatgt 1550
acttctcggc ctgggccacc agcgcggcct cgagaggatc gacatagggc gcggcccgga 1620
caccgatagc ggtggcaagg tccataaaca gatcttgcgg catctttgat gggaggaatg 1680
gcgcaatcga ctccatgcgg ccgctctaga actagtggat cctttgaatg attcttatac 1740
tcagaaggaa atgcttaacg atttcgggtg tgagttgaca aggagagaga gaaaagaaga 1800
ggaaaggtaa ttcggggacg gtggtctttt atacccttgg ctaaagtccc aaccacaaag 1860
caaaaaaatt ttcagtagtc tattttgcgt ccggcatggg ttacccggat ggccagacaa 1920
agaaactagt acaaagtctg aacaagcgta gattccagac tgcagtaccc tacgccctta 1980
acggcaagtg tgggaaccgg gggaggtttg atatgtgggg tgaagggggc tctcgccggg 2040
gttgggcccg ctactgggtc aatttggggt caattggggc aattggggct gttttttggg 2100
acacaaatac gccgccaacc cggtctctcc tgaagcttgt gagcggataa caatttcaca 2160
caggaaacag ctatgaccat gattacgcca agctcgaaat taaccctcac taaagggaac 2220
aaaagctgga gctccaccgc ggacacaata tctggtcaaa tttcagtttc gttacataaa 2280
tcgttatgtc aaaggagtgt gggaggttaa gagaattatc accggcaaac tatctgttaa 2340
ttgctaggta cctctagacg tccacccggg tcgcttggcg gccgaagagg ccggaatctc 2400
gggccgcggt ggcggccgcc tactcttcct tgggacggag tccaagaaca cgcaagtgct 2460
ccaaatgtga agcaaatgct tgccaaaacg tatccttgac aaggtatgga accttgtact 2520
cgctgcaggt gttcttgatg atggccagaa tatcgggata atggtgctgc gacacgttgg 2580
ggaacagatg gtgcacagcc tggtagttca agctgccagt gatgctggtc cagaggtgcg 2640
aatcgtgtgc gtaatcctgc gtagtctcga cctgcatagc tgcccagtcc ttttggatga 2700
tcccgttctc gtcaggcaac ggccactgaa cttcctcaac aacgtggttc gcctggaagg 2760
tcagcgccag ccagtaagac gacaccatgt ccgcgaccgt gaacaagagc agcaccttgc 2820
ccaggggcag atactgcagg ggaacaatca ggcgatacca gacaaagaaa gccttgccgc 2880
cccagaacat cacagtgtgc catgtcgaga tgggattgac acgaatagcg tcattggtct 2940
tgacaaagta caaaatgttg atgtcctgaa tgcgcacctt gaacgccagc agtccgtaca 3000
ggaaaggaac aaacatgtgc tggttgatgt ggttgacaaa ccacttttgg ttgggcttga 3060
tacgacgaac atcgggctca gacgtcgaca cgtcgggatc tgctccagca atgttggtgt 3120
aggggtgatg gccgagcata tgttggtaca tccacaccag gtacgatgct ccgttgaaaa 3180
agtcgtgcgt ggctcccaga atcttccaga cagtggggtt gtgggtcact gaaaagtgag 3240
acgcatcatg aagagggttg agtccgactt gtgcgcacgc aaatcccatg atgattgcaa 3300
acaccacctg aagccatgtg cgttcgacaa cgaaaggcac aaagagctgc gcgtagtagg 3360
aagcgatcaa ggatccaaag ataagagcgt atcgtcccca gatctctggt ctattcttgg 3420
gatcaatgtt ccgatccgta aagtagccct cgactctcgt cttgatggtt ttgtggaaca 3480
ccgttggctc cgggaagatg ggcagctcat tcgagaccag tgtaccgaca tagtacttct 3540
tcataatggc atctgcagcc ccaaacgcgt gatacatctc aaagaccgga gtaacatctc 3600
ggccagctcc gagcaggaga gtgtccactc caccaggatg gcggctcaag aactttgtga 3660
catcgtacac cctgccgcgg atggccaaga gtaggtcgtc cttggtgtta tgggccgcca 3720
gctcttccca ggtgaaggtt tttccttggt ccgttcccat ggtgaatgat tcttatactc 3780
agaaggaaat gcttaacgat ttcgggtgtg agttgacaag gagagagaga aaagaagagg 3840
aaaggtaatt cggggacggt ggtcttttat acccttggct aaagtcccaa ccacaaagca 3900
aaaaaatttt cagtagtcta ttttgcgtcc ggcatgggtt acccggatgg ccagacaaag 3960
aaactagtac aaagtctgaa caagcgtaga ttccagactg cagtacccta cgcccttaac 4020
ggcaagtgtg ggaaccgggg gaggtttgat atgtggggtg aagggggctc tcgccggggt 4080
tgggcccgct actgggtcaa tttggggtca attggggcaa ttggggctgt tttttgggac 4140
acaaatacgc cgccaacccg gtctctcctg aattctgcag atgggctgca ggaattccgt 4200
cgtcgcctga gtcgacatca tttatttacc agttggccac aaacccttga cgatctcgta 4260
tgtcccctcc gacatactcc cggccggctg gggtacgttc gatagcgcta tcggcatcga 4320
caaggtttgg gtccctagcc gataccgcac tacctgagtc acaatcttcg gaggtttagt 4380
cttccacata gcacgggcaa aagtgcgtat atatacaaga gcgtttgcca gccacagatt 4440
ttcactccac acaccacatc acacatacaa ccacacacat ccacaatgga acccgaaact 4500
aagaagacca agactgactc caagaagatt gttcttctcg gcggcgactt ctgtggcccc 4560
gaggtgattg ccgaggccgt caaggtgctc aagtctgttg ctgaggcctc cggcaccgag 4620
tttgtgtttg aggaccgact cattggagga gctgccattg agaaggaggg cgagcccatc 4680
accgacgcta ctctcgacat ctgccgaaag gctgactcta ttatgctcgg tgctgtcgga 4740
ggcgctgcca acaccgtatg gaccactccc gacggacgaa ccgacgtgcg acccgagcag 4800
ggtctcctca agctgcgaaa ggacctgaac ctgtacgcca acctgcgacc ctgccagctg 4860
ctgtcgccca agctcgccga tctctccccc atccgaaacg ttgagggcac cgacttcatc 4920
attgtccgag agctcgtcgg aggtatctac tttggagagc gaaaggagga tgacggatct 4980
ggcgtcgctt ccgacaccga gacctactcc gttcctgagg ttgagcgaat tgcccgaatg 5040
gccgccttcc tggcccttca gcacaacccc cctcttcccg tgtggtctct tgacaaggcc 5100
aacgtgctgg cctcctctcg actttggcga aagactgtca ctcgagtcct caaggacgaa 5160
ttcccccagc tcgagctcaa ccaccagctg atcgactcgg ccgccatgat cctcatcaag 5220
cagccctcca agatgaatgg tatcatcatc accaccaaca tgtttggcga tatcatctcc 5280
gacgaggcct ccgtcatccc cggttctctg ggtctgctgc cctccgcctc tctggcttct 5340
ctgcccgaca ccaacgaggc gttcggtctg tacgagccct gtcacggatc tgcccccgat 5400
ctcggcaagc agaaggtcaa ccccattgcc accattctgt ctgccgccat gatgctcaag 5460
ttctctctta acatgaagcc cgccggtgac gctgttgagg ctgccgtcaa ggagtccgtc 5520
gaggctggta tcactaccgc cgatatcgga ggctcttcct ccacctccga ggtcggagac 5580
ttgttgccaa caaggtcaag gagctgctca agaaggagta agtcgtttct acgacgcatt 5640
gatggaagga gcaaactgac gcgcctgcgg gttggtctac cggcagggtc cgctagtgta 5700
taagactcta taaaaagggc cctgccctgc taatgaaatg atgatttata atttaccggt 5760
gtagcaacct tgactagaag aagcagattg ggtgtgtttg tagtggagga cagtggtacg 5820
ttttggaaac agtcttcttg aaagtgtctt gtctacagta tattcactca taacctcaat 5880
agccaagggt gtagtcggtt tattaaagga agggagttgt ggctgatgtg gatagatatc 5940
tttaagctgg cgactgcacc caacgagtgt ggtggtagct tgttactgta tattcggtaa 6000
gatatatttt gtggggtttt agtggtgttt aaacgacgga attcctgcag cccatctgca 6060
gaattcagga gagaccgggt tggcggcgta tttgtgtccc aaaaaacagc cccaattgcc 6120
ccaattgacc ccaaattgac ccagtagcgg gcccaacccc ggcgagagcc cccttcaccc 6180
cacatatcaa acctcccccg gttcccacac ttgccgttaa gggcgtaggg tactgcagtc 6240
tggaatctac gcttgttcag actttgtact agtttctttg tctggccatc cgggtaaccc 6300
atgccggacg caaaatagac tactgaaaat ttttttgctt tgtggttggg actttagcca 6360
agggtataaa agaccaccgt ccccgaatta cctttcctct tcttttctct ctctccttgt 6420
caactcacac ccgaaatcgt taagcatttc cttctgagta taagaatcat tcaccatggc 6480
tgaggataag accaaggtcg agttccctac cctgactgag ctgaagcact ctatccctaa 6540
cgcttgcttt gagtccaacc tcggactctc gctctactac actgcccgag cgatcttcaa 6600
cgcatctgcc tctgctgctc tgctctacgc tgcccgatct actcccttca ttgccgataa 6660
cgttctgctc cacgctctgg tttgcgccac ctacatctac gtgcagggtg tcatcttctg 6720
gggtttcttt accgtcggtc acgactgtgg tcactctgcc ttctcccgat accactccgt 6780
caacttcatc attggctgca tcatgcactc tgccattctg actcccttcg agtcctggcg 6840
agtgacccac cgacaccatc acaagaacac tggcaacatt gataaggacg agatcttcta 6900
ccctcatcgg tccgtcaagg acctccagga cgtgcgacaa tgggtctaca ccctcggagg 6960
tgcttggttt gtctacctga aggtcggata tgctcctcga accatgtccc actttgaccc 7020
ctgggaccct ctcctgcttc gacgagcctc cgctgtcatc gtgtccctcg gagtctgggc 7080
tgccttcttc gctgcctacg cctacctcac atactcgctc ggctttgccg tcatgggcct 7140
ctactactat gctcctctct ttgtctttgc ttcgttcctc gtcattacta ccttcttgca 7200
tcacaacgac gaagctactc cctggtacgg tgactcggag tggacctacg tcaagggcaa 7260
cctgagctcc gtcgaccgat cgtacggagc tttcgtggac aacctgtctc accacattgg 7320
cacccaccag gtccatcact tgttccctat cattccccac tacaagctca acgaagccac 7380
caagcacttt gctgccgctt accctcacct cgtgagacgt aacgacgagc ccatcattac 7440
tgccttcttc aagaccgctc acctctttgt caactacgga gctgtgcccg agactgctca 7500
gattttcacc ctcaaagagt ctgccgctgc agccaaggcc aagagcgacc accaccatca 7560
ccaccattaa gcggccgcca ccgcggcccg agattccggc ctcttcggcc gccaagcgac 7620
ccgggtggac gtctagaggt acctagcaat taacagatag tttgccggtg ataattctct 7680
taacctccca cactcctttg acataacgat ttatgtaacg aaactgaaat ttgaccagat 7740
attgtgtccg cggtggagct ccagcttttg ttccctttag tgagggttaa tttcgagctt 7800
ggcgtaatcg atgcagaatt caggagagac cgggttggcg gcgtatttgt gtcccaaaaa 7860
acagccccaa ttgccccaat tgaccccaaa ttgacccagt agcgggccca accccggcga 7920
gagccccctt caccccacat atcaaacctc ccccggttcc cacacttgcc gttaagggcg 7980
tagggtactg cagtctggaa tctacgcttg ttcagacttt gtactagttt ctttgtctgg 8040
ccatccgggt aacccatgcc ggacgcaaaa tagactactg aaaatttttt tgctttgtgg 8100
ttgggacttt agccaagggt ataaaagacc accgtccccg aattaccttt cctcttcttt 8160
tctctctctc cttgtcaact cacacccgaa atcgttaagc atttccttct gagtataaga 8220
atcattcacc atggctgctg ctcccagtgt gaggacgttt actcgggccg aggttttgaa 8280
tgccgaggct ctgaatgagg gcaagaagga tgccgaggca cccttcttga tgatcatcga 8340
caacaaggtg tacgatgtcc gcgagttcgt ccctgatcat cccggtggaa gtgtgattct 8400
cacgcacgtt ggcaaggacg gcactgacgt ctttgacact tttcaccccg aggctgcttg 8460
ggagactctt gccaactttt acgttggtga tattgacgag agcgaccgcg atatcaagaa 8520
tgatgacttt gcggccgagg tccgcaagct gcgtaccttg ttccagtctc ttggttacta 8580
cgattcttcc aaggcatact acgccttcaa ggtctcgttc aacctctgca tctggggttt 8640
gtcgacggtc attgtggcca agtggggcca gacctcgacc ctcgccaacg tgctctcggc 8700
tgcgcttttg ggtctgttct ggcagcagtg cggatggttg gctcacgact ttttgcatca 8760
ccaggtcttc caggaccgtt tctggggtga tcttttcggc gccttcttgg gaggtgtctg 8820
ccagggcttc tcgtcctcgt ggtggaagga caagcacaac actcaccacg ccgcccccaa 8880
cgtccacggc gaggatcccg acattgacac ccaccctctg ttgacctgga gtgagcatgc 8940
gttggagatg ttctcggatg tcccagatga ggagctgacc cgcatgtggt cgcgtttcat 9000
ggtcctgaac cagacctggt tttacttccc cattctctcg tttgcccgtc tctcctggtg 9060
cctccagtcc attctctttg tgctgcctaa cggtcaggcc cacaagccct cgggcgcgcg 9120
tgtgcccatc tcgttggtcg agcagctgtc gcttgcgatg cactggacct ggtacctcgc 9180
caccatgttc ctgttcatca aggatcccgt caacatgctg gtgtactttt tggtgtcgca 9240
ggcggtgtgc ggaaacttgt tggccatcgt gttctcgctc aaccacaacg gtatgcctgt 9300
gatctcgaag gaggaggcgg tcgatatgga tttcttcacg aagcagatca tcacgggtcg 9360
tgatgtccac ccgggtctat ttgccaactg gttcacgggt ggattgaact atcagatcga 9420
gcaccacttg ttcccttcga tgcctcgcca caacttttca aagatccagc ctgctgtcga 9480
gaccctgtgc aaaaagtaca atgtccgata ccacaccacc ggtatgatcg agggaactgc 9540
agaggtcttt agccgtctga acgaggtctc caaggctacc tccaagatgg gtaaggcgca 9600
gtaagcggcc gccaccgcgg cccgagattc cggcctcttc ggccgccaag cgacccgggt 9660
ggacgtctag aggtacctag caattaacag atagtttgcc ggtgataatt ctcttaacct 9720
cccacactcc tttgacataa cgatttatgt aacgaaactg aaatttgacc agatattgtg 9780
tccgcggtgg agctccagct tttgttccct ttagtgaggg ttaattaatt cgatatcata 9840
attgtcggcc gaggtctgta cggccagaac cgagatccta ttgaggaggc caagcgatac 9900
cagaaggctg gctgggaggc ttaccagaag attaactgtt agaggttaga ctatggatat 9960
gtcatttaac tgtgtatata gagagcgtgc aagtatggag cgcttgttca gcttgtatga 10020
tggtcagacg acctgtctga tcgagtatgt atgatactgc acaacctgtg tatccgcatg 10080
atctgtccaa tggggcatgt tgttgtgttt ctcgatacgg agatgctggg tacaagtagc 10140
taatacgatt gaactactta tacttatatg aggcttgaag aaagctgact tgtgtatgac 10200
ttattctcaa ctacatcccc agtcacaata ccaccactgc actaccacta caccaaaacc 10260
atgatcaaac cacccatgga cttcctggag gcagaagaac ttgttatgga aaagctcaag 10320
agagagaa 10328
<210>102
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物YL1
<400>102
cagtgccaaa agccaaggca ctgagctcgt 30
<210>103
<211>31
<212>DNA
<213>人工序列
<220>
<223>引物YL2
<400>103
gacgagctca gtgccttggc ttttggcact g 31
<210>104
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL3
<400>104
gtataagaat cattcaccat ggatccacta gttcta 36
<210>105
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL4
<400>105
tagaactagt ggatccatgg tgaatgattc ttatac 36
<210>106
<211>39
<212>DNA
<213>人工序列
<220>
<223>引物YL5
<400>106
cccccctcga ggtcgatggt gtcgataagc ttgatatcg 39
<210>107
<211>39
<212>DNA
<213>人工序列
<220>
<223>引物YL6
<400>107
cgatatcaag cttatcgaca ccatcgacct cgagggggg 39
<210>108
<211>37
<212>DNA
<213>人工序列
<220>
<223>引物YL7
<400>108
caaccgattt cgacagttaa ttaataattt gaatcga 37
<210>109
<211>37
<212>DNA
<213>人工序列
<220>
<223>引物YL8
<400>109
tcgattcaaa ttattaatta actgtcgaaa tcggttg 37
<210>110
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物YL9
<400>110
tggtaaataa atgatgtcga ctcaggcgac gacgg 35
<210>111
<211>35
<212>DNA
<213>人工序列
<220>
<223>引物YL10
<400>111
ccgtcgtcgc ctgagtcgac atcatttatt tacca 35
<210>112
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL23
<400>112
atggatccac tagttaatta actagagcgg ccgcca 36
<210>113
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL24
<400>113
tggcggccgc tctagttaat taactagtgg atccat 36
<210>114
<211>1413
<212>DNA
<213>异丝水霉(ATCC#56851)
<400>114
atggccccgc agacggagct ccgccagcgc cacgccgccg tcgccgagac gccggtggcc 60
ggcaagaagg cctttacatg gcaggaggtc gcgcagcaca acacggcggc ctcggcctgg 120
atcattatcc gcggcaaggt ctacgacgtg accgagtggg ccaacaagca ccccggcggc 180
cgcgagatgg tgctgctgca cgccggtcgc gaggccaccg acacgttcga ctcgtaccac 240
ccgttcagcg acaaggccga gtcgatcttg aacaagtatg agattggcac gttcacgggc 300
ccgtccgagt ttccgacctt caagccggac acgggcttct acaaggagtg ccgcaagcgc 360
gttggcgagt acttcaagaa gaacaacctc catccgcagg acggcttccc gggcctctgg 420
cgcatgatgg tcgtgtttgc ggtcgccggc ctcgccttgt acggcatgca cttttcgact 480
atctttgcgc tgcagctcgc ggccgcggcg ctctttggcg tctgccaggc gctgccgctg 540
ctccacgtca tgcacgactc gtcgcacgcg tcgtacacca acatgccgtt cttccattac 600
gtcgtcggcc gctttgccat ggactggttt gccggcggct cgatggtgtc atggctcaac 660
cagcacgtcg tgggccacca catctacacg aacgtcgcgg gctcggaccc ggatcttccg 720
gtcaacatgg acggcgacat ccgccgcatc gtgaaccgcc aggtgttcca gcccatgtac 780
gcattccagc acatctacct tccgccgctc tatggcgtgc ttggcctcaa gttccgcatc 840
caggacttca ccgacacgtt cggctcgcac acgaacggcc cgatccgcgt caacccgcac 900
gcgctctcga cgtggatggc catgatcagc tccaagtcgt tctgggcctt ctaccgcgtg 960
taccttccgc ttgccgtgct ccagatgccc atcaagacgt accttgcgat cttcttcctc 1020
gccgagtttg tcacgggctg gtacctcgcg ttcaacttcc aagtaagcca tgtctcgacc 1080
gagtgcggct acccatgcgg cgacgaggcc aagatggcgc tccaggacga gtgggcagtc 1140
tcgcaggtca agacgtcggt cgactacgcc catggctcgt ggatgacgac gttccttgcc 1200
ggcgcgctca actaccaggt cgtgcaccac ttgttcccca gcgtgtcgca gtaccactac 1260
ccggcgatcg cgcccatcat cgtcgacgtc tgcaaggagt acaacatcaa gtacgccatc 1320
ttgccggact ttacggcggc gttcgttgcc cacttgaagc acctccgcaa catgggccag 1380
cagggcatcg ccgccacgat ccacatgggc taa 1413
<210>115
<211>470
<212>PRT
<213>异丝水霉(ATCC#56851)
<400>115
Met Ala Pro Gln Thr Glu Leu Arg Gln Arg His Ala Ala Val Ala Glu
1 5 10 15
Thr Pro Val Ala Gly Lys Lys Ala Phe Thr Trp Gln Glu Val Ala Gln
20 25 30
His Asn Thr Ala Ala Ser Ala Trp Ile Ile Ile Arg Gly Lys Val Tyr
35 40 45
Asp Val Thr Glu Trp Ala Asn Lys His Pro Gly Gly Arg Glu Met Val
50 55 60
Leu Leu His Ala Gly Arg Glu Ala Thr Asp Thr Phe Asp Ser Tyr His
65 70 75 80
Pro Phe Ser Asp Lys Ala Glu Ser Ile Leu Asn Lys Tyr Glu Ile Gly
85 90 95
Thr Phe Thr Gly Pro Ser Glu Phe Pro Thr Phe Lys Pro Asp Thr Gly
100 105 110
Phe Tyr Lys Glu Cys Arg Lys Arg Val Gly Glu Tyr Phe Lys Lys Asn
115 120 125
Asn Leu His Pro Gln Asp Gly Phe Pro Gly Leu Trp Arg Met Met Val
130 135 140
Val Phe Ala Val Ala Gly Leu Ala Leu Tyr Gly Met His Phe Ser Thr
145 150 155 160
Ile Phe Ala Leu Gln Leu Ala Ala Ala Ala Leu Phe Gly Val Cys Gln
165 170 175
Ala Leu Pro Leu Leu His Val Met His Asp Ser Ser His Ala Ser Tyr
180 185 190
Thr Asn Met Pro Phe Phe His Tyr Val Val Gly Arg Phe Ala Met Asp
195 200 205
Trp Phe Ala Gly Gly Ser Met Val Ser Trp Leu Asn Gln His Val Val
210 215 220
Gly His His Ile Tyr Thr Asn Val Ala Gly Ser Asp Pro Asp Leu Pro
225 230 235 240
Val Asn Met Asp Gly Asp Ile Arg Arg Ile Val Asn Arg Gln Val Phe
245 250 255
Gln Pro Met Tyr Ala Phe Gln His Ile Tyr Leu Pro Pro Leu Tyr Gly
260 265 270
Val Leu Gly Leu Lys Phe Arg Ile Gln Asp Phe Thr Asp Thr Phe Gly
275 280 285
Ser His Thr Asn Gly Pro Ile Arg Val Asn Pro His Ala Leu Ser Thr
290 295 300
Trp Met Ala Met Ile Ser Ser Lys Ser Phe Trp Ala Phe Tyr Arg Val
305 310 315 320
Tyr Leu Pro Leu Ala Val Leu Gln Met Pro Ile Lys Thr Tyr Leu Ala
325 330 335
Ile Phe Phe Leu Ala Glu Phe Val Thr Gly Trp Tyr Leu Ala Phe Asn
340 345 350
Phe Gln Val Ser His Val Ser Thr Glu Cys Gly Tyr Pro Cys Gly Asp
355 360 365
Glu Ala Lys Met Ala Leu Gln Asp Glu Trp Ala Val Ser Gln Val Lys
370 375 380
Thr Ser Val Asp Tyr Ala His Gly Ser Trp Met Thr Thr Phe Leu Ala
385 390 395 400
Gly Ala Leu Asn Tyr Gln Val Val His His Leu Phe Pro Ser Val Ser
405 410 415
Gln Tyr His Tyr Pro Ala Ile Ala Pro Ile Ile Val Asp Val Cys Lys
420 425 430
Glu Tyr Asn Ile Lys Tyr Ala Ile Leu Pro Asp Phe Thr Ala Ala Phe
435 440 445
Val Ala His Leu Lys His Leu Arg Asn Met Gly Gln Gln Gly Ile Ala
450 455 460
Ala Thr Ile His Met Gly
465 470
<210>116
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物YL13A
<400>116
ttggatccgc agacggagct ccgccagcgc 30
<210>117
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL14
<400>117
cccttaatta aattagccca tgtggatcgt ggcggc 36
<210>118
<211>1329
<212>DNA
<213>Isochrysis galbana CCMP1323
<400>118
atggtggcag gcaaatcagg cgctgcggcg cacgtgactc acagctcgac attgccccgt 60
gagtaccatg gcgcgaccaa cgactcgcgc tctgaggcgg ccgacgtcac cgtctctagc 120
atcgatgctg aaaaggagat gatcatcaac ggccgcgtgt atgacgtgtc gtcatttgtg 180
aagcggcacc caggtggctc ggtgatcaag ttccagctgg gcgccgacgc gagcgacgcg 240
tacaacaact ttcacgtccg ctccaagaag gcggacaaga tgctgtattc gctcccgtcc 300
cggccggccg aggccggcta cgcccaggac gacatctccc gcgactttga gaagctgcgc 360
ctcgagctga aggaggaggg ctacttcgag cccaacctgg tgcacgtgag ctacaggtgt 420
gtggaggttc ttgccatgta ctgggctggc gtccagctca tctggtccgg gtactggttc 480
ctcggcgcga tcgtggccgg cattgcgcag ggccgctgcg gctggctcca gcatgagggt 540
gggcactact cgctcaccgg caacatcaag atcgaccggc atctgcagat ggccatctat 600
gggcttggct gcggcatgtc gggctgctac tggcgcaacc agcacaacaa gcaccacgcc 660
acgccgcaga agctcgggac cgaccccgac ctgcagacga tgccgctggt ggccttccac 720
aagatcgtcg gcgccaaggc gcgaggcaag ggcaaggcgt ggctggcgtg gcaggcgccg 780
ctcttctttg gcgggatcat ctgctcgctc gtctctttcg gctggcagtt cgtgctccac 840
cccaaccacg cgctgcgcgt gcacaatcac ctggagctcg cgtacatggg cctgcggtac 900
gtgctgtggc acctggcctt tggccacctc gggctgctga gctcgctccg cctgtacgcc 960
ttttacgtgg ccgtgggcgg cacctacatc ttcaccaact tcgccgtctc gcacacccac 1020
aaggacgtcg tcccgcccac caagcacatc tcgtgggcac tctactcggc caaccacacg 1080
accaactgct ccgactcgcc ctttgtcaac tggtggatgg cctacctcaa cttccagatc 1140
gagcaccacc tcttcccgtc gatgccgcag tacaaccacc ccaagatcgc cccgcgggtg 1200
cgcgcgctct tcgagaagca cggggtcgag tatgacgtcc ggccatacct ggagtgtttt 1260
cgggtcacgt acgtcaacct gctcgccgta ggcaacccgg agcactccta ccacgagcac 1320
acgcactag 1329
<210>119
<211>442
<212>PRT
<213>Isochrysis galbana CCMP1323
<400>119
Met Val Ala Gly Lys Ser Gly Ala Ala Ala His Val Thr His Ser Ser
1 5 10 15
Thr Leu Pro Arg Glu Tyr His Gly Ala Thr Asn Asp Ser Arg Ser Glu
20 25 30
Ala Ala Asp ValThr Val Ser Ser Ile Asp Ala Glu Lys Glu Met Ile
35 40 45
Ile Asn Gly Arg Val Tyr Asp Val Ser Ser Phe ValLys Arg His Pro
50 55 60
Gly Gly Ser Val Ile Lys Phe Gln Leu Gly Ala Asp Ala Ser Asp Ala
65 70 75 80
Tyr Asn Asn Phe His Val Arg Ser Lys Lys Ala Asp Lys Met Leu Tyr
85 90 95
Ser Leu Pro Ser Arg Pro Ala Glu Ala Gly Tyr Ala Gln Asp Asp Ile
100 105 110
Ser Arg Asp Phe Glu Lys Leu Arg Leu Glu Leu Lys Glu Glu Gly Tyr
115 120 125
Phe Glu Pro Asn Leu Val His Val Ser Tyr Arg Cys Val Glu Val Leu
130 135 140
Ala Met Tyr Trp Ala Gly Val Gln Leu Ile Trp Ser Gly Tyr Trp Phe
145 150 155 160
Leu Gly Ala Ile Val Ala Gly Ile Ala Gln Gly Arg Cys Gly Trp Leu
165 170 175
Gln His Glu Gly Gly His Tyr Ser Leu Thr Gly Asn Ile Lys Ile Asp
180 185 190
Arg His Leu Gln Met Ala Ile Tyr Gly Leu Gly Cys Gly Met Ser Gly
195 200 205
Cys Tyr Trp Arg Asn Gln His Asn Lys His His Ala Thr Pro Gln Lys
210 215 220
Leu Gly Thr Asp Pro Asp Leu Gln Thr Met Pro Leu Val Ala Phe His
225 230 235 240
Lys Ile Val Gly Ala Lys Ala Arg Gly Lys Gly Lys Ala Trp Leu Ala
245 250 255
Trp Gln Ala Pro Leu Phe Phe Gly Gly Ile Ile Cys Ser Leu Val Ser
260 265 270
Phe Gly Trp Gln Phe Val Leu His Pro Asn His Ala Leu Arg Val His
275 280 285
Asn His Leu Glu Leu Ala Tyr Met Gly Leu Arg Tyr Val Leu Trp His
290 295 300
Leu Ala Phe Gly His Leu Gly Leu Leu Ser Ser Leu Arg Leu Tyr Ala
305 310 315 320
Phe Tyr Val Ala Val Gly Gly Thr Tyr Ile Phe Thr Asn Phe Ala Val
325 330 335
Ser His Thr His Lys Asp Val Val Pro Pro Thr Lys His Ile Ser Trp
340 345 350
Ala Leu Tyr Ser Ala Asn His Thr Thr Asn Cys Ser Asp Ser Pro Phe
355 360 365
Val Asn Trp Trp Met Ala Tyr Leu Asn Phe Gln Ile Glu His His Leu
370 375 380
Phe Pro Ser Met Pro Gln Tyr Asn His Pro Lys Ile Ala Pro Arg Val
385 390 395 400
Arg Ala Leu Phe Glu Lys His Gly Val Glu Tyr Asp Val Arg Pro Tyr
405 410 415
Leu Glu Cys Phe Arg Val Thr Tyr Val Asn Leu Leu Ala Val Gly Asn
420 425 430
Pro Glu His Ser Tyr His Glu His Thr His
435 440
<210>120
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL19A
<400>120
tttggatccg gcaggcaaat caggcgctgc ggcgca 36
<210>121
<211>36
<212>DNA
<213>人工序列
<220>
<223>引物YL20
<400>121
ccttaattaa ctagtgcgtg tgctcgtggt aggagt 36
<210>122
<211>1320
<212>DNA
<213>Thraustochytrium aureum(ATCC#34304)
<400>122
atgggacgcg gcggcgaagg tcaggtgaac agcgcgcagg tggcacaagg cggtgcggga 60
acgcgaaaga cgatcctgat cgagggcgag gtctacgatg tcaccaactt taggcacccc 120
ggcgggtcga tcatcaagtt tctcacgacc gacggcaccg aggctgtgga cgcgacgaac 180
gcgtttcgcg agtttcactg ccggtcgggc aaggcggaaa agtacctcaa gagcctgccc 240
aagctcggcg cgccgagcaa gatgaagttt gacgccaagg agcaggcccg gcgcgacgcg 300
atcacgcgag actacgtcaa gctgcgcgag gagatggtgg ccgagggcct cttcaagccc 360
gcgcccctcc acattgtcta caggtttgcg gagatcgcag ccctgttcgc ggcctcgttc 420
tacctgtttt cgatgcgcgg aaacgtgttc gccacgctcg cggccatcgc agtcgggggc 480
atcgcgcagg gccgctgcgg ctggctcatg cacgagtgcg gacacttctc gatgaccggg 540
tacatcccgc ttgacgtgcg cctgcaggag ctggtgtacg gcgtggggtg ctcgatgtcg 600
gcgagctggt ggcgcgttca gcacaacaag caccacgcga ccccgcagaa actcaagcac 660
gacgtcgacc tcgacaccct gccgctcgtt gcgttcaacg agaagatcgc cgccaaggtg 720
cgccccggct cgttccaggc caagtggctc tcggcgcagg cgtacatttt tgcgccggtg 780
tcctgcttcc tggttggtct ettctggacc ctgtttctgc acccgcgcca catgccgcgc 840
acgagccact ttgctgagat ggccgccgtc gcggtgcgcg tcgtgggctg ggcggcgctc 900
atgcactcgt tcgggtacag cgggagcgac tcgttcggtc tctacatggc cacctttggc 960
tttggctgca cctacatctt caccaacttt gcggtcagcc acacgcacct cgacgtcacc 1020
gagccggacg agttcctgca ctgggtcgag tacgccgcgc tgcacacgac caacgtgtcc 1080
aacgactcgt ggttcatcac ctggtggatg tcgtacctca actttcagat cgagcaccac 1140
ctctttccgt cgctgcccca gctcaacgcc ccgcgcgtcg ccccgcgcgt ccgcgccctc 1200
ttcgagaagc acggcatggc ttacgacgag cgcccgtacc ttaccgcgct tggcgacacg 1260
tttgccaacc tgcacgccgt gggccaaaac gcgggccagg cggcggccaa ggccgcttag 1320
<210>123
<211>439
<212>PRT
<213>Thraustochytrium aureum(ATCC #34304)
<400>123
Met Gly Arg Gly Gly Glu Gly Gln Val Asn Ser Ala Gln Val Ala Gln
1 5 10 15
Gly Gly Ala Gly Thr Arg Lys Thr Ile Leu Ile Glu Gly Glu Val Tyr
20 25 30
Asp Val Thr Asn Phe Arg His Pro Gly Gly Ser Ile Ile Lys Phe Leu
35 40 45
Thr Thr Asp Gly Thr Glu Ala Val Asp Ala Thr Asn Ala Phe Arg Glu
50 55 60
Phe His Cys Arg Ser Gly Lys Ala Glu Lys Tyr Leu Lys Ser Leu Pro
65 70 75 80
Lys Leu Gly Ala Pro Ser Lys Met Lys Phe Asp Ala Lys Glu Gln Ala
85 90 95
Arg Arg Asp Ala Ile Thr Arg Asp Tyr Val Lys Leu Arg Glu Glu Met
100 105 110
Val Ala Glu Gly Leu Phe Lys Pro Ala Pro Leu His Ile Val Tyr Arg
115 120 125
Phe Ala Glu Ile Ala Ala Leu Phe Ala Ala Ser Phe Tyr Leu Phe Ser
130 135 140
Met Arg Gly Asn Val Phe Ala Thr Leu Ala Ala Ile Ala Val Gly Gly
145 150 155 160
Ile Ala Gln Gly Arg Cys Gly Trp Leu Met His Glu Cys Gly His Phe
165 170 175
Ser Met Thr Gly Tyr Ile Pro Leu Asp Val Arg Leu Gln Glu Leu Val
180 185 190
Tyr Gly Val Gly Cys Ser Met Ser Ala Ser Trp Trp Arg Val Gln His
195 200 205
Asn Lys His His Ala Thr Pro Gln Lys Leu Lys His Asp Val Asp Leu
210 215 220
Asp Thr Leu Pro Leu Val Ala Phe Asn Glu Lys Ile Ala Ala Lys Val
225 230 235 240
Arg Pro Gly Ser Phe Gln Ala Lys Trp Leu Ser Ala Gln Ala Tyr Ile
245 250 255
Phe Ala Pro Val Ser Cys Phe Leu Val Gly Leu Phe Trp Thr Leu Phe
260 265 270
Leu His Pro Arg His Met Pro Arg Thr Ser His Phe Ala Glu Met Ala
275 280 285
Ala Val Ala Val Arg Val Val Gly Trp Ala Ala Leu Met His Ser Phe
290 295 300
Gly Tyr Ser Gly Ser Asp Ser Phe Gly Leu Tyr Met Ala Thr Phe Gly
305 310 315 320
Phe Gly Cys Thr Tyr Ile Phe Thr Asn Phe Ala Val Ser His Thr His
325 330 335
Leu Asp Val Thr Glu Pro Asp Glu Phe Leu His Trp Val Glu Tyr Ala
340 345 350
Ala Leu His Thr Thr Asn Val Ser Asn Asp Ser Trp Phe Ile Thr Trp
355 360 365
Trp Met Ser Tyr Leu Asn Phe Gln Ile Glu His His Leu Phe Pro Ser
370 375 380
Leu Pro Gln Leu Asn Ala Pro Arg Val Ala Pro Arg Val Arg Ala Leu
385 390 395 400
Phe Glu Lys His Gly Met Ala Tyr Asp Glu Arg Pro Tyr Leu Thr Ala
405 410 415
Leu Gly Asp Thr Phe Ala Asn Leu His Ala Val Gly Gln Asn Ala Gly
420 425 430
Gln Ala Ala Ala Lys Ala Ala
435
<210>124
<211>30
<212>DNA
<213>人工序列
<220>
<223>引物YL15
<400>124
ttttccatgg gacgcggcgg cgaaggtcag 30
<210>125
<211>37
<212>DNA
<213>人工序列
<220>
<223>引物YL16B
<400>125
ttttgcggcc gctaagcggc cttggccgcc gcctggc 37
<210>126
<211>10
<212>DNA
<213>解脂耶氏酵母
<220>
<221>misc_feature
<222>(8)..(8)
<223>n是a,c,g,或t
<400>126
mammatgnhs 10
Claims (5)
1.生产ω-3或ω-6脂肪酸的方法,包括:
a)提供包括编码功能性ω-3/ω-6脂肪酸生物合成途径的基因的含油酵母,所述含油酵母产生占干细胞重量至少25%的油;
b)在可发酵碳源的存在下生长步骤(a)的酵母,从而生产一种或多种ω-3或ω-6脂肪酸;并且
c)任选回收ω-3或ω-6脂肪酸。
2.权利要求1的方法,其中所述编码功能性ω-3/ω-6脂肪酸生物合成途径的基因选自:Δ12去饱和酶,Δ6去饱和酶,延伸酶,Δ5去饱和酶,Δ17去饱和酶,Δ15去饱和酶,Δ9去饱和酶和Δ4去饱和酶。
3.权利要求1的方法,其中所述可发酵碳源选自单糖,寡糖,多糖,甘油单酯,甘油二酯,甘油三酯,甲醇以及含碳的胺。
4.权利要求1的方法,其中所述含油酵母选自下组:耶氏酵母属,假丝酵母属,红酵母属,红冬孢属,隐球酵母属,丝孢酵母属和油脂酵母属。
5.权利要求4的方法,其中所述含油酵母是解脂耶氏酵母。
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US46867703P | 2003-05-07 | 2003-05-07 | |
US60/468,677 | 2003-05-07 |
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CN200480019580A Expired - Fee Related CN100591773C (zh) | 2003-05-07 | 2004-05-07 | 在含油酵母中生产多不饱和脂肪酸 |
CNA200480019355XA Pending CN1816630A (zh) | 2003-05-07 | 2004-05-07 | 用于改变含油酵母内多不饱和脂肪酸水平的△-12去饱和酶基因 |
CN200910266075A Pending CN101824441A (zh) | 2003-05-07 | 2004-05-07 | 在含油酵母中生产多不饱和脂肪酸 |
CNA2004800193545A Pending CN1816559A (zh) | 2003-05-07 | 2004-05-07 | 用于在含油酵母中生产多不饱和脂肪酸的密码子优化的基因 |
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CNA200480019355XA Pending CN1816630A (zh) | 2003-05-07 | 2004-05-07 | 用于改变含油酵母内多不饱和脂肪酸水平的△-12去饱和酶基因 |
CN200910266075A Pending CN101824441A (zh) | 2003-05-07 | 2004-05-07 | 在含油酵母中生产多不饱和脂肪酸 |
CNA2004800193545A Pending CN1816559A (zh) | 2003-05-07 | 2004-05-07 | 用于在含油酵母中生产多不饱和脂肪酸的密码子优化的基因 |
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US (5) | US7238482B2 (zh) |
EP (4) | EP2392665A3 (zh) |
JP (1) | JP2007504839A (zh) |
KR (1) | KR20060018832A (zh) |
CN (4) | CN100591773C (zh) |
BR (1) | BRPI0410688A (zh) |
CA (1) | CA2526935C (zh) |
DK (3) | DK2402448T3 (zh) |
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US7267976B2 (en) | 2003-07-02 | 2007-09-11 | E.I. Du Pont De Nemours And Company | Acyltransferases for alteration of polyunsaturated fatty acids and oil content in oleaginous yeasts |
PT1766023E (pt) * | 2004-06-04 | 2010-12-09 | Fluxome Sciences As | Células metabolicamente manipuladas para a produção de ácidos gordos poliinsaturados |
WO2006012326A1 (en) * | 2004-06-25 | 2006-02-02 | E.I. Dupont De Nemours And Company | Delta-8 desaturase and its use in making polyunsaturated fatty acids |
US7465564B2 (en) * | 2004-08-10 | 2008-12-16 | E.I. Du Pont De Nemours And Company | Production of γ-linolenic acid in oleaginous yeast |
US7264949B2 (en) | 2004-09-15 | 2007-09-04 | E.I. Du Pont De Nemours And Company | Glycerol-3-phosphate o-acyltransferase promoter for gene expression in oleaginous yeast |
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US20060094102A1 (en) | 2004-11-04 | 2006-05-04 | Zhixiong Xue | Ammonium transporter promoter for gene expression in oleaginous yeast |
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US7192762B2 (en) | 2004-11-04 | 2007-03-20 | E. I. Du Pont De Nemours And Company | Mortierella alpina glycerol-3-phosphate o-acyltransferase for alteration of polyunsaturated fatty acids and oil content in oleaginous organisms |
US7588931B2 (en) | 2004-11-04 | 2009-09-15 | E. I. Du Pont De Nemours And Company | High arachidonic acid producing strains of Yarrowia lipolytica |
KR20070101862A (ko) * | 2004-12-14 | 2007-10-17 | 아베스타 겐그레인 테크놀로지스 피브이티 리미티드 | 효모 내에서 도코사헥사에노산(dha)의 재조합 생산 |
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US7364883B2 (en) * | 2004-05-07 | 2008-04-29 | Yeastern Biotech Co., Ltd. | Process for producing poly-unsaturated fatty acids by oleaginous yeasts |
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