CN101466834B - 制备类胡萝卜素合成性微生物的方法和生产类胡萝卜素的方法 - Google Patents
制备类胡萝卜素合成性微生物的方法和生产类胡萝卜素的方法 Download PDFInfo
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Abstract
本发明在于产生能够以工业生产规模生产类胡萝卜素的微生物。本发明者们通过提供制备类胡萝卜素的方法而解决了上述课题,所述制备类胡萝卜素的方法包括:在适宜培养条件下培养用包含任一SEQ IDNO:2-7所示DNA序列的DNA序列所转化的细胞或用具有任一SEQ IDNO:2-7所示DNA序列的载体转化的细胞,并从细胞或培养基中分离类胡萝卜素。
Description
技术领域
本发明涉及制备类胡萝卜素合成性微生物的方法和生产类胡萝卜素的方法。
背景技术
本发明涉及这样的DNA链,其用于合成适用于使养殖鱼类如海鲷、虾和鲑鱼以及鸡蛋恢复颜色的类胡萝卜素和适用于合成可用作食物的着色剂或抗氧化剂的类胡萝卜素如虾青素,并且涉及利用导入了此类DNA链的微生物生产类胡萝卜素如虾青素的方法。
在自然界,超过600种不同的类胡萝卜素已经从植物、微生物等中鉴定。工业用途的类胡萝卜素通常由化学合成方法产生,对于该方法而言可能有不受欢迎的作用如合成辅料的污染是令人担心的。此外,消费者的爱好倾向于侧重天然存在的类胡萝卜素。然而,存在对从植物等天然物中提取的限制,并且没有充分地建立有效的工业方法。作为天然存在的类胡萝卜素的生产方法,微生物发酵方法已经在一些例子中报道,然而,这些例子中没有一个能够以足够用于经济性工业生产的量生产类胡萝卜素。类似于类胡萝卜素的情况,当试图从微生物中产生功能性物质时,人们一般通过广泛筛选而选择充当发酵宿主的微生物。然后,在许多情况下,通过使用化学处理剂的经典突变和培育法,分离高产菌株并且用于生产或研究,原因是来自野生型类胡萝卜素产生微生物的产生量通常是少的。
作为产生有用的类胡萝卜素的微生物,Yokoyama等报道了农杆菌属(Agrobacterium)(后来,再分类成属于副球菌(Paracoccus)属细菌)的海洋细菌(非专利文献1)。这些菌株的特征是以高含量合成作为功能性类胡萝卜素的虾青素。如上所述,副球菌属细菌的虾青素等的产生量可以经突变方法而增加,并且将具有提高产生量的菌株TSN18E7(见日本特开2005-58216号公报)以名称FERM P-19746保藏在独立行政法人产业技术综合研究所专利生物保藏中心。
类胡萝卜素生物合成途径由多种酶构成,并且编码此类酶的基因已经由众多研究人员分析。例如在代表性途径中,类胡萝卜素在其早期通过由类固醇和类萜共有的类异戊二烯生物合成途径,始自作为基础代谢物的甲瓦龙酸而得到合成。由类异戊二烯基础合成系统产生的具有15个碳(C15)的法呢焦磷酸与异戊烯基焦磷酸(IPP)(C5)缩合,以产生牻牛儿基牻牛儿基焦磷酸(GGPP)(C20)。随后经两分子的GGPP缩合,合成首个类胡萝卜素即无色的八氢番茄红素。八氢番茄红素随后经一系列去饱和反应而转化成番茄红素,并且随后番茄红素经环化反应转化成β-胡萝卜素。随后,将羟基和酮基导入β-胡萝卜素,导致合成由虾青素代表的多种叶黄素(图1)。
从这些基因水平的发现中,已经进行意图用基因重组技术改善类胡萝卜素合成的研究。例如见Chia-wei Wang等,Biotechnol.Prog.,16:922-926(2000);Claudia Schmidt-Dannert等,Nat.Biotechnol.,18:750-753(2000);Daisuke Umeno等,Appl.Environ.Microbiol.,69:3573-3579(2003)。在这些研究中,将不合成类胡萝卜素的大肠杆菌作为宿主使用,以至于这些研究因大肠杆菌的类胡萝卜素产量低而难以应用于工业生产。在其它报道中,类胡萝卜素合成量的增加通过将类胡萝卜素基因导入生产类胡萝卜素的细菌(专利文献1)中实现。然而,如此制备的基因重组菌株因其类胡萝卜素合成的量低而依旧难以应用于工业生产。
[非专利文献1]Yokoyama,A.,H.Izumida和W.Miki,通过海洋细菌橙黄农杆菌(Agrobacterium aurantiacum)产生虾青素和4-酮基玉米黄质,Biosci.Biotechnol.Biochem.,58:1842-1844(1994)。
[非专利文献2]Norihiko Misawa,Yoshiko Satomi,Keiji Kondo,Akihiro Yokoyama,Susumu Kajiwara,Tochiko Saito,Takeshi Ohtani和Wataru Miki,对在基因水平上提出的海洋细菌类胡萝卜素生物合成基因簇及虾青素生物合成途径的结构和功能分析,J。Bacteriology 177:6575-6584(1995)。
[非专利文献3]Eric A.Johnson和William A.Schroeder,微生物类胡萝卜素,Advances in Biochemical Engineering Biotechnology,53:119-178(1995)。
[非专利文献4]P.C.Lee和Schmidt-Dannert,对微生物中生物技术生产类胡萝卜素的代谢工程(Metabolic engineering towards biotechnologicalproduction of carotenoids in microorganism),60:1-11(2002)。
[非专利文献5]Kovach,M.E.等,GENE 166,175-176(1995)。
[非专利文献6]R.Simon,U.Priefer和A.Puhler,用于体内基因工程的宽宿主范围转移系统:革兰氏阴性细菌中的转座子诱变,BIO/TECHNOLOFY,1:784-791(1983)。
[非专利文献7]Cedric Y.Szpiper,Michel Faelen和MartineCouturier,宽宿主范围质粒pBBR1的衍生物即pBHR1质粒的转移功能,J.Bacteriology,183:2101-2110(2001)。
[专利文献1]PCT申请JP-A 2004-527265的日文翻译
[专利文献2]日本专利公开号3403381
[专利文献3]日本专利申请号2005-106045
发明简述
发明欲解决的课题
本发明的目的是制备允许工业生产规模的类胡萝卜素产生的微生物。本发明的目的又是使用类胡萝卜素产生新菌株生产类胡萝卜素和提供类胡萝卜素。
用于解决课题的手段
经过解决前述课题的深入研究,本发明人发现类胡萝卜素的合成量通过如此方式得以增加,即通过克隆作为类胡萝卜素合成细菌的副球菌属(Paracoccus)菌株MBIC1143的类胡萝卜素合成基因;将该类胡萝卜素合成基因重组至适宜的质粒载体内;将携带其中插入有类胡萝卜素合成基因的质粒载体通过基因导入技术如接合转移而导入副球菌属野生型菌株、因突变处理而具有增加的类胡萝卜素合成能力的突变菌株、或类胡萝卜素合成耐受菌株中;并且使类胡萝卜素合成基因所编码的类胡萝卜素合成酶表达。
换句话说,本发明人发现类胡萝卜素如虾青素的含量通过向副球菌菌株MBIC1143中导入以下DNA链而明显地得以增加,从而完成本发明,其中所述的DNA链选自(a)编码多肽的DNA链(crtW),其中所述多肽具有将β-芷香酮环4位的亚甲基转化为酮基的酶活性;(b编码多肽的DNA链(crtZ),其中所述多肽具有添加一个羟基至4-酮-β-芷香酮环的3位碳上和/或β-芷香酮环的3位碳上的酶活性;(c)编码多肽的DNA链(crtY),其中所述多肽具有将番茄红素转化成β-胡萝卜素的酶活性;(d)编码多肽的DNA链(crtI),其中所述多肽具有将八氢番茄红素转化成番茄红素的酶活性;(e)编码多肽的DNA链(crtB),其中所述多肽具有前八氢番茄红素(prephytoene)合成酶活性;和(f)编码多肽的DNA链(crtE),其中所述多肽具有牻牛儿基牻牛儿基焦磷酸合成酶活性。
(1)增加类胡萝卜素产生的方法,其中将选上述自(a)、(b)、(c)、(d)、(e)和(f)的DNA链导入类胡萝卜素产生微生物如副球菌,并且将得到的转化微生物在培养基中培养。
(2)根据(1)的增加类胡萝卜素产生的方法,其中具有类胡萝卜素合成活性的多肽是下列(i)或(iii)的多肽。
(i)具有SEQ ID NO:2、3、4、5、6或7所示的氨基酸序列的多肽。
(ii)具有与SEQ ID NO:2、3、4、5、6或7所示氨基酸序列基本上同源的氨基酸序列的多肽。
本发明还涉及下列(3)至(4)的生产类胡萝卜素的方法。
(3)生产类胡萝卜素的方法,其中将选上述自(a)、(b)、(c)、(d)、(e)和(f)的DNA链导入类胡萝卜素产生微生物如副球菌,并且将得到的转化微生物在培养基中培养。
(4)根据(3)的生产类胡萝卜素的方法,其中具有类胡萝卜素合成活性的多肽是下列(i)或(ii)的多肽。
(i)具有SEQ ID NO:2、3、4、5、6或7所示的氨基酸序列的多肽。
(ii)具有与SEQ ID NO:2、3、4、5、6或7所示氨基酸序列基本上同源的氨基酸序列的多肽。
本发明还涉及转化方法,其中将选自以上(a)、(b)、(c)、(d)、(e)和(f)的DNA链或具有在其中插入该DNA链的质粒载体导入类胡萝卜素产生微生物如副球菌。本发明还涉及因向细胞导入质粒载体而具有类胡萝卜素的产量提高的微生物,其中细胞生长不受因导入质粒载体而出现在细胞内的质粒复制影响和/或不受由该质粒编码的类胡萝卜素合成基因产生的类胡萝卜素影响。
发明的效果
根据本发明,提供明显改善微生物在类胡萝卜素的生物合成方面的产生量的DNA链和这样的方法,其涉及将所述DNA链导入类胡萝卜素产生微生物并使所述DNA链表达,因而数倍增加由微生物产生的类胡萝卜素的量。
实施发明的最佳方案
在下文中,将详细描述本发明。
如在″现有技术″部分中详细描述,能够使微生物如大肠杆菌因导入来自类胡萝卜素产生细菌如海洋细菌副球菌等中的类胡萝卜素生物合成基因而产生有用的类胡萝卜素如虾青素、玉米黄质、β-胡萝卜素和番茄红素。在另一方面,为了与有机合成方法的成本竞争,需要尽可能多地增加类胡萝卜素的产生量。本发明的DNA链选自(a)编码多肽的DNA链(crtW),其中所述多肽具有将β-芷香酮环4位的亚甲基转化为酮基的酶活性;(b编码多肽的DNA链(crtZ),其中所述多肽具有添加一个羟基至4-酮-β-芷香酮环的3位碳上和/或β-芷香酮环的3位碳上的酶活性;(c)编码多肽的DNA链(crtY),其中所述多肽具有将番茄红素转化成β-胡萝卜素的酶活性;(d)编码多肽的DNA链(crtI),其中所述多肽具有将八氢番茄红素转化成番茄红素的酶活性;(e)编码多肽的DNA链(crtB),其中所述多肽具有前八氢番茄红素合成酶活性;和(f)编码多肽的DNA链(crtE),其中所述多肽具有牻牛儿基牻牛儿基焦磷酸合成酶活性,并且对于增加类胡萝卜素的产生量、尤其虾青素的产生量是极其有用的。通过借助当前先进的基因工程技术而提高酶等的基因的表达水平,由基因所编码蛋白质的产生量可以相对容易地进行增加。在代谢概念中,存在这样的报道,即位于类胡萝卜素合成系统上游的IPP异构酶基因的导入明显增加类胡萝卜素在表达细胞中的产生(专利文献2)。通过导入IPP异构酶基因而增加类胡萝卜素产生量的成功归因于如此事实,即至多到FPP的上游代谢途径(图1)因这种导入而拓宽,导致增加FPP供应量并且因此增加类胡萝卜素的量。
然而,考虑到本发明的目的之一是维持类胡萝卜素尤其是虾青素的产生,仅上游基因是无法推进其后的代谢反应的,这造成代谢中间体如β-胡萝卜素积累,并且得不到充足的产生量。换句话说,重要的是增加虾青素在类胡萝卜素总量中的量,其中所述的类胡萝卜素包括作为虾青素合成中间体的番茄红素、β-胡萝卜素、海胆酮、β-隐黄素、3’-羟海胆酮、玉米黄质、3-羟海胆酮、角黄素、绿蝇黄质(phonicoxanthin)、4-酮玉米黄质和虾青素等。本发明人发现当导入选自以上(a)、(b)、(c)、(d)、(e)和(f)中的DNA链而非使用IPP异构酶,能充分产生虾青素而不在虾青素代谢中间体处停止时,合成了充足量的虾青素,而代谢中间体在表达细胞中没有积累。本发明人还认为导入DNA链(f)对于增加类胡萝卜素是有效的。换句话说,基于与用于通过导入IPP异构酶而增加表达量的构思可比较的构思,本发明人发现通过导入编码根据代谢概念被认为是上游合成酶的牻牛儿基牻牛儿基焦磷酸合成酶的DNA链,牻牛儿基牻牛儿基焦磷酸合成酶的表达量增加,并且作为产物的牻牛儿基牻牛儿基焦磷酸供应至类胡萝卜素代谢系统,并因此总类胡萝卜素量由于一系列的类胡萝卜素合成酶而增加。选自(a)、(b)、(c)、(d)和(e)的DNA链与DNA链(f)的组合大幅度地增加虾青素的合成量。此外,本发明人发现DNA链(a)、(b)、(c)、(d)、(e)和(f)的组合能够选择性地合成所需的类胡萝卜素。例如为了选择性合成β-胡萝卜素,可以组合(c)、(d)和(e),并且还可以进一步组合(f)以增加产生量。为了选择性合成玉米黄质,可以组合(b)、(c)、(d)和(e),并且还可以进一步组合(f)以增加产生量。为了选择性合成番茄红素,可以组合(d)和(e),并且还可以进一步组合(f)以增加产生量。若(a)与(b)的组合是可获得的,则β-胡萝卜素的氧化选择性地进行,这能够使虾青素高效且选择性地合成。为了进一步增加虾青素的产生量,可以使用(d)、(e)和(f)的组合。
在本发明中,当提及DNA链的组合时,各DNA链可以单独使用,然而可以将它们基因工程地直列连接。可以选择待连接的组合数目以至于所需要的功能在该组合中是最大的。当各DNA链单独使用时,可以将它们插入适宜的质粒载体中。质粒载体应当仅在导入载体的宿主细胞中有功能,并且可以单独使用适宜的质粒载体,或可以使用多种质粒载体,只要它们不受到相容性的限制。
在本发明中,术语“类胡萝卜素”包括八氢番茄红素、番茄红素、β-胡萝卜素、玉米黄质、角黄素、虾青素、侧金盏花黄素、隐黄素、海胆酮、侧金盏花红素及其组合。优选地,它是虾青素。
具体而言,本发明提供了具有增加类胡萝卜素产生量尤其虾青素产生量的特性的DNA链,所述DNA链选自:编码多肽的DNA链(crtW),其中所述多肽具有将β-芷香酮环4位的亚甲基转化为酮基的酶活性;编码多肽的DNA链(crtZ),其中所述多肽具有添加一个羟基至4-酮-β-芷香酮环的3位碳上和/或β-芷香酮环的3位碳上的酶活性;编码多肽的DNA链(crtY),其中所述多肽具有将番茄红素转化成β-胡萝卜素的酶活性;编码多肽的DNA链(crtI),其中所述多肽具有将八氢番茄红素转化成番茄红素的酶活性;编码多肽的DNA链(crtB),其中所述多肽具有前八氢番茄红素合成酶活性;和编码多肽的DNA链(crtE),其中所述多肽具有牻牛儿基牻牛儿基焦磷酸合成酶活性;并且提供了生产类胡萝卜素的方法,所述方法包括将以上DNA链导入类胡萝卜素产生微生物中并在培养基中培养转化的微生物,从而增加培养物的类胡萝卜素含量。
在本发明的另一方面,本发明涉及制备类胡萝卜素生产细胞的方法。该方法包括步骤:将编码在细胞中表达的参与一系列类胡萝卜素合成的酶的DNA链导入该细胞中;并且制备和选择以如此的量生产类胡萝卜素的细胞,其中所述的量是该细胞在导入DNA链前所生产类胡萝卜素的产生水平的约1.1倍-1,000倍。
本发明的DNA链是在(a)、(b)、(c)、(d)、(e)或(f)中描述的DNA链或与该DNA链在严格条件下杂交的DNA链。
术语“在严格条件下杂交”指这样的情况,其中在核酸的复杂混合物中探针与其靶序列而不与其它核酸在严格条件下杂交。严格条件取决于序列,并且根据环境而不同。对于较长的序列,特异性杂交在较高温度实现。通常如此选择高度严格条件以至它在限定的离子强度和pH时比特定序列的解链温度低约5-10℃。通常如此选择低严格条件以至它在限定的离子强度和pH上比解链温度低约15-30℃。″解链温度″是这样的温度,在该温度时50%的与靶核酸互补的探针在限定的离子强度、pH和核酸时处于平衡中。认为既使在严格条件下彼此不杂交的核酸,若由这些核酸编码的多肽是基本上相同的,则这些核酸是基本上相同的。这种情况例如在核酸拷贝通过利用可被遗传编码作用接受的最大密码子简并性而产生时出现。在这种情况下,核酸一般在中等严格杂交条件下杂交。
词组″基本上相同″用于这样的序列或部分序列,其中当两种核酸或多肽通过使用稍后描述的序列比较算法之一或通过手工比对或肉眼检查法加以检验并且进行比对以便在比较窗口中实现最大对应性时,所述的序列或部分序列表现至少60%,优选80%,更优选90%或更多的核苷酸或氨基酸残基同一性。该定义还适用于这样的序列,其中该序列的互补物与试验序列杂交。
为了序列比较,通常制备一种序列作为参考序列而试验序列与参考序列进行比较。当使用序列比较算法时,将试验序列和参考序列输入计算机,并且根据需要指定部分坐标(partial coordinate),并指定序列算法程序的参数。可以使用程序的默认值,或可以赋予备选参数。随后,序列比较算法根据程序的参数而计算试验序列相对于参考序列的序列同一性百分数。用于比较的序列比对方法是本领域已知的。用于比较的优化序列可以例如通过在Smith和Watreman,Adv.Appl.Math.,2:482(1981)中所述的局部同源性算法、在Needleman和Wunsch,J.Mol.Biol.,48:443(1970)中所述的同源性比对算法、在Person和Lipman,Proc.Natl.Acd.Sci.USA,85:2444(1988)中所述的相似性询问方法,以及用计算机实施这些算法或实施手工比对和肉眼检查而进行选择。
PILEUP是有用算法中的一个实例。PILEUP使用连续配对比对从相关序列组中产生多个序列,并给出相关性和序列同一性百分数。PILEUP还标出代表簇相关性的树状图(tree)或枝状图(dendgram)以在产生比对中使用。另一个适合确定序列同一性百分数和序列相似性的算法实例是BLAST算法(Altschul等,J.Mol.Biol.,215:403-410(1990))。在该算法中,字长度对蛋白质固定为3并且对核酸为11(3用于其中序列按总共6个读码框进行翻译的情况)。这些长度是这样的最小值,其能够对充分显著的长度给予高的字分值,并且没有过长以至于不会忽略短小而显著的模式。BLAST算法也实施涉及两种序列的相似性的统计学分析。
由本发明的DNA链编码的多肽具有基本上选自SEQ ID NO:2、3、4、5、6和7中序列的氨基酸序列。在本发明中,由这种DNA链编码的多肽可以具有一些修饰,如在某些氨基酸处的缺失、替换和添加,条件是如上所述增加类胡萝卜素的活性不受到损害。这对应于如此事实,即″氨基酸序列基本上具有基本上选自SEQ ID NO:2、3、4、5、6和7中的序列″。例如,缺少这些酶的首个氨基酸(Met)的那些多肽或酶也包括在具有修饰的氨基酸序列的多肽或酶当中。编码相应多肽的本发明DNA链不仅包括具有如此碱基序列的那些DNA链,其中所述的碱基序列编码SEQ ID NOs:2、3、4、5、6和7所示的氨基酸序列,还包括编码同种多肽但是具有不同简并性密码子的简并异构体。
获得具有以下碱基序列的DNA链的一种方法是根据合成核酸的方法而化学合成该链长度的至少部分,其中所述的碱基序列编码以上蛋白质的氨基酸序列,然而考虑到结合氨基酸的多重性,优选的是制备副球菌等的基因组DNA、通过使用适宜限制性酶如Sau3AI的限制性酶处理而片段化成随机片段、基于粘粒方法制备大肠杆菌文库、和使用借助适宜探针的杂交方法,而非化学合成方法。此外,当可以制造适宜的PCR引物时,所需DNA链可以通过PCR方法使用制备的基因组DNA作为模板而扩增。
DNA链可以在无修饰下用于转化适宜的细胞,然而,它可以在使用前插入质粒载体。DNA链向质粒载体的插入可以基因工程地插入质粒载体的适宜位置中。适宜的位置可以如此选择以至于涉及复制质粒载体、所需抗生素标记和传递性(transmissivity)的区域未受破坏。
在插入质粒载体时,以上DNA链可以在无修饰下基因工程地插入。然而,可以添加具有启动子活性的DNA链。本文中所用术语″启动子″指能够控制蛋白质编码区或功能性RNA表达的DNA序列并且如在大肠杆菌中有功能的lac启动子、trc启动子等可以例举。在DNA链表达于海洋细菌中的情况下,不存在限制,只要DNA链是包括在细胞内有功能的启动子序列的DNA链。优选地,启动子源自海洋细菌。优选地,通过使用SEQID NO:19、20或21的启动子,有可能表达插入的编码类胡萝卜素合成酶的基因。备选地,可以使用SEQ ID NO:19、20或21的多核苷酸的部分。部分区域可以通过比较已知的启动子序列而鉴定。此外,这些序列可以具有碱基的插入或替换。此外,可以随机地导入突变并且可以使用具有提高的启动子活性的多核苷酸。通常,酶蛋白质等的编码区位于启动子序列的3′侧。若可商业获得的质粒载体已经具有启动子序列并且在海洋细菌中具有功能,则它们可以得到使用。此外,DNA链待插入的方向可以是任意方向,只要该DNA链能发挥功能。
就质粒载体而言,可以使用任何载体,只要它们在转化细胞中稳定存在并且是可复制的。此外就质粒载体而言,可以例举用于转化大肠杆菌的pUC系列、pBR系列等以及作为在目的细胞中可复制的质粒载体的穿梭载体。详细内容见公开的文件(Barbara E.Funnell,PLASMID BIOLOGY,ASM出版社)。在本发明的副球菌中,可复制的质粒载体不是具体已知的。当不存在已建立的宿主载体时,可以使用宽宿主范围质粒载体。作为此种载体,可以例举RK2、R751、RSF1010、R1162、pCU1、R46、pSA、R388、RA1(Barbara E.Funnell,PLASMID BIOLOGY,ASM出版社)。此外,可以利用宽宿主范围载体的复制区,将其插入适宜的质粒载体而用作穿梭载体。例如,可以例举这样的穿梭载体,其通过将RK2载体的复制区插入pUC系列载体的适宜位置而制备,并且能够利用大肠杆菌。还可以例举具有相对小的DNA尺寸并且可在类型广泛的宿主中复制的pBBR系列质粒。pBBR系列质粒的实例包括pBBR122、pBBR1MCS、pBBR1MCS2、pBBR1MCS3、pBBR1MCS4和pBBR1MCS5(非专利文献5)。这些质粒载体例如以不同的抗生素标记为特征,并且可以在评价转化细胞的抗生素抗性后得到选择以便使用。此外,可以使用成为转化对象的细胞所具有的质粒。
通过将如上所述的本发明DNA链或将插入适宜质粒载体的DNA链导入适宜的类胡萝卜素产生微生物中,有可能增加类胡萝卜素含量。在本发明中,包括以下表达载体:pBBR1MCS2CRT、pBBR1MCS2CRTrv、pBBR1MCS2CRTWZ、pBBR1MCS2CRTWZrv、pBBR1MCS2PcrtE1crtE、pBBR1MCS2PcrtE2crtE、pBBR1MCS2PcrtE1crtECRT及其组合。这些载体将在稍后给出的实施例中定义。
优选的宿主细胞可以广泛地存在在真菌和细菌科中,并且是在大范围的温度、pH和溶剂耐性中增殖的生物学宿主。例如,细菌、酵母和丝状真菌中的任一种是用于表达本发明DNA链的合适宿主。因为DNA链的转录和翻译机制以及蛋白质的生物合成机制通常与细胞的供应材料无关,故功能性基因将在与培养物培养所用的碳供应物质无关的情况下表达。为了大规模地培养微生物和表达功能性基因,类型广泛的简单或复杂的糖类、有机酸和醇、饱和烃如甲烷可以得到使用,而光合宿主或化能自养宿主可以利用二氧化碳。然而,功能性基因可以通过可包括微量营养物的形式和量在内的特定培养条件加以调节、抑制或降低,其中所述的微量营养物包括氮、磷、硫、氧、碳或无机物。此外,对功能性基因的调节可以由特定调节物实现,其中所述的调节物添加至液体培养物中并通常不视为营养源或能源。
宿主实例包括微生物物种如曲霉属(Aspergillus)、木霉属(Trichoderma)、毕赤酵母属(Pichia)、假丝酵母属(Candida)、汉逊酵母属(Hansenula)、酿酒酵母属(Saccharomyces)、沙门氏菌属(Salmonella)、芽孢杆菌属(Bacillus)、不动杆菌属(Acinetobacter)、发酵单胞菌属(Zymomonas)、农杆菌属(Agrobacterium)、赤细菌属(Erythrobacter)、绿菌属(Chlorobium)、着色菌属(Chromatium)、黄杆菌属(Flavobacterium)、噬纤维菌属(Cytophaga)、红细菌属(Rhodobacter)、红球菌属(Rhocdococcus)、链霉菌属(Streptomyces)、短杆菌属(Brevibacterium)、棒状杆菌属(Corynebacteria)、分枝杆菌属(Mycobacterium)、异常球菌属(Deinococcus)、埃希氏菌属(Escherichia)、欧文氏菌属(Erwinia)、泛菌属(Pantoea)、假单胞菌属(Pseudomonas)、鞘氨醇杆菌属(Sphingomonas)、甲基单胞菌属(Methylomonas)、甲基杆菌属(Methylobacter)、甲基球菌属(Methylococcus)、甲基弯曲菌属(Methylosinus)、甲基微菌属(Methylomicrobium)、甲基孢囊菌属(Methylocystis)、产碱菌属(Alcaligenes)、集胞藻属(Synechocystis)、聚球菌属(Synechococcus)、鱼腥藻属(Anabaena)、粘球菌属(Myxococcus)、硫杆菌属(Thiobacillus)、甲烷杆菌属(Methanobacterium)、副球菌和克雷伯氏菌属(Klebsiella)。优选属于副球菌属的细菌,其可以方便地由本领域技术人员通过采用编码16SrRNA的DNA序列作为指标予以鉴定。更优选类胡萝卜素产生量得到报道的副球菌菌株MBIC1143。编码副球菌菌株MBIC1143的16S rRNA的DNA碱基序列对公众公开。见例如作为官方数据库的国家生物技术信息中心(National Center for BiotechnologyInformation)(http://www.ncbi.nlm.nih.gov/)的登录号AB008114。编码副球菌菌株MBIC1143的16S rRNA的DNA链的碱基序列如SEQ ID NO:24所示。更优选菌株TSN18E7(见日本特开2005-58216号公报)和菌株TSTT001(见日本专利申请号2005-314667的说明书),它们是从副球菌菌株MBIC1143衍生的突变体。尤其是这样的突变衍生性菌株,其因类胡萝卜素的胞内积累而没有对涉及细胞生长的多种代谢系统的调节。换句话说,它是因突变处理等而取消调节的突变菌株。在细胞中,当特定代谢产积累时,反馈抑制等可以因代谢产物终止该代谢产物的后续合成而出现。词组″调节的取消″意指阻遏细胞中的调节机制。在氨基酸的赖氨酸发酵中存在工业性成功例子。突变处理可以使用本领域众所周知的突变处理剂如亚硝基胍、甲磺酸乙酯、紫外线、放射线等实施。对其取消调节的菌株可以是天然突变体。备选地,突变处理后的突变体和天然突变体可以利用类胡萝卜素的代谢类似物从选择培养基中分离和得到。该代谢类似物是具有与类胡萝卜素相似的化学结构的物质,或是这样的物质,其显示与类胡萝卜素在多种胞内反应系统中的生理反应相似的生理反应。代谢类似物的实例包括β-芷香酮和α-芷香酮。此外,可以产生宿主细胞的基因表达芯片,并且表达谱可以在多种培养条件下精确地进行分析,并且基于在类胡萝卜素以高密度积累的环境下的基因表达谱,可以产生和使用基因敲除或敲入菌株。
下文描述对所需微生物的基因导入法的概要。用于向微生物如大肠杆菌导入并表达外源基因的方法包括在基因工程领域中通常使用的那些方法以及在本发明中显示如下的那些方法,并且可以根据此类方法(例如,“用于克隆基因的载体”,Method in Enzymology,216,第469-631页,1992,Academic Press;和“其它细菌系统”,Method in Enzymology,204,第305-636页,1991,Academic Press)实施。具体实例包括热休克法和电穿孔法。
对于本发明中基因导入至副球菌的方法,已知没有已建立的技术。在这种情况下,作为在温和条件下导入基因的方法,例举了使用大肠杆菌的接合转移法。接合转移法是其中质粒通过这些细菌间的接合从供体细菌导入到受体细菌的方法,并且其有利之处在于对受体细菌的损伤微小。使用大肠杆菌的接合转移方法分成两种方法:双亲转移方法和三亲转移方法。在双亲转移方法中,通过质粒供体细菌与受体细菌的共培养,其中所述的质粒供体细菌是在其染色体中掺入负责自我转移能力的tra区的大肠杆菌菌株S17-1,有可能通过tra的作用而将质粒从供体细菌导入受体细菌(非专利文献6).此外,当使用具有mob基因(非专利文献7)的质粒载体(例如上文的pBBR1MCS)时,有可能有效地将质粒导入受体细菌。三亲转移方法是其中通过混合具有辅助质粒(例如RK1)的大肠杆菌、具有适宜质粒载体的大肠杆菌和待导入基因的细菌而使结合发生的方法。
两种方法均涉及在膜盘(membrane disc)上于一定温度的介质(如缓冲液)中混合细胞后,在滤膜上温育某段时间。就对于这些情况的接合条件而言,温度通常是,但不限于20-30℃,并且优选是25℃。温育时间通常从几个小时至数日,大肠杆菌与待导入基因的细菌的混合比率不具体地加以限制。这是因为当待进行接合的大肠杆菌或酵母即便以痕量存在,接合体也会得到,并且这种接合体可以通过分离和培养得到增殖。为了实现有效接合,大肠杆菌与待导入基因的细菌的比率例如是1∶1或0.1∶1。
在接合转移后,接合转移的细胞可以基于其因接合转移所获得的特性而与其它细胞分离。例如,使用导入所用质粒载体的抗生素抗性,仅其中导入质粒载体的接合转移细胞可以得到增殖和分离。这些方法均是本领域技术人员众所周知的。此外,通过组合使用防止大肠杆菌生长的抗生素,其中所述的大肠杆菌是接合转移的供体,对接合转移细胞的更高效选择得以实现。抗生素的实例包括羧苄青霉素、氨苄青霉素、头孢唑林、哌拉西林、磷霉素、庆大霉素、链霉素、新霉素、丁胺卡那霉素、四环素、红霉素、林可霉素、利福平、萘啶酸和新生霉素。可以在适宜的液体培养中培养后通过质粒提取、PCR等技术确认接合转移细胞的分离。
根据如上所述的用于将基因导入微生物中并表达的手段或方法,使得通过导入并表达一组类胡萝卜素合成基因,有可能得到能够产生大量类胡萝卜素的微生物。
使用这些转化体和适宜的培养基,有可能使得多种类胡萝卜素积累于细胞中。为收集类胡萝卜素,积累类胡萝卜素的微生物可以从培养基中收集并从适宜的有机溶剂中提取。作为有机溶剂,例举甲醇、乙醇、异丙醇、丙酮、甲基乙基酮、甲基异丁基酮、二氯甲烷、氯仿、二甲基甲酰胺和二甲亚砜,优选丙酮。此外,使用液相色谱,高纯度分离得以实现。作为液相色谱的分离原理,可以例举离子交换、疏水性相互作用、分子筛等。优选反向色谱和正向色谱。
如下实施例意图用于具体解释本发明并且不意图限制本发明。本文中进行的基因重组实验基于标准方法(Sambrook,J.,Fritch,E.F.,Maniatis,T.,“Molecular cloning第三版”,Cold Spring Harbor Laboratory Press)进行,除非另外说明。
[实施例1]
制备来自副球菌菌株MBIC1143的基因组DNA及克隆类胡萝卜素合
成基因
副球菌菌株MBIC1143在OEG培养基(2g/L胰酪胨、1g/L酵母提取物、8.8g/L NaCl、0.73g/L七水硫酸镁、3.6g/L无水磷酸氢二钾、1.4g/L磷酸二氢钾、1g/L D-葡萄糖)中于25℃(以120转/分钟旋转振荡)培养3日。副球菌菌株MBIC1143由海洋生物技术研究所有限公司(MarinBiotechnology Institute Co.,Ltd.)提供。
基因组DNA使用可从Gentra systems,Inc.(Puregen基因组DNA分离试剂盒)获得的试剂盒制备(约50ng/ml)。使用制备的DNA作为模板,由PCR扩增类胡萝卜素合成基因。构成副球菌菌株MBIC1143的类胡萝卜素合成基因群的基因(crtW、crtZ、crtY、crtI、crtB、crtE)的碱基序列在非专利文献2和专利文献3中描述。参考这些公开的数据,我们产生了含有以上基因的碱基序列。SEQ ID NO:1显示7,029个碱基的序列。图1显示基因簇的结构。参考非专利文献2产生PCR引物(SEQ ID NO:13:5’-gcggatccggcgaccttgcggcgctg-3’)和SEQ ID NO:14:5’-cgggatcctgtcgcggtccctgggg-3’)。PCR以下列方式实施。向1.0μL制备的DNA中添加13.5μL水和25μL 2×高GC缓冲液(TAKARA BIO INC.),并在94℃加热10分钟。在冰上冷却后,添加8μL dNTP、1.0μL 10pmol/μL的SEQ ID NO:8所示的正向引物和1.0μL 10pmol/μL的SEQ ID NO:9所示的反向引物,并且最后添加0.5μL的exTaqDNA聚合酶(TAKARABIO INC.)。反应包括30个循环(每个循环由第一步骤94℃30秒、第二步骤60℃30秒和第三步骤72℃4分钟组成),随后是72℃10分钟的反应。得到的PCR产物用酚/氯仿处理,并且随后进行0.9%琼脂糖电泳以提取并纯化目的产物(约5.4k碱基)(从QIAGEN可获得的QIAgen凝胶提取试剂盒)。碱基序列如SEQ ID NO:8所示。纯化的DNA(通过PCR引物对其插入BamHI酶的限制性位点)用限制性酶BamHI处理,并通过酚/氯仿处理和乙醇沉淀得到纯化。随后以限制性酶处理的DNA连接到pUC19质粒载体(TAKARA BIO INC.)的BamHI位点,并且在通过热休克法实现基因导入后,大肠杆菌菌株JM109在含有100μg/mL羧苄青霉素的LB(Luria-Bertani)琼脂培养基中转化。
将任意转化体在LB培养基中培养(37℃,18小时),并且质粒使用质粒提取试剂盒(从QIAGEN可获得)提取。用限制性酶BamHI对质粒的处理表明存在预期的插入物。其中克隆了来自副球菌的类胡萝卜素合成基因的质粒载体称作pUCCRT。制备的质粒的结构在图3中显示。根据如上文提及的日本专利申请号2005-106045的方法,对pUCCRT检查在大肠杆菌中类胡萝卜素合成活性的表现。
[实施例2]
副球菌表达载体的制备
质粒载体pUCCRT用限制性酶BamHI处理,并且得到类胡萝卜素合成基因片段(约5.4k碱基)。随后将该片段插入宽宿主范围载体pBBR1MCS2的BamHI位点。向大肠杆菌菌株JM109中的基因导入通过热休克法实施,并且随后实施在含有50μg/mL卡那霉素的LB琼脂培养基中的转化。将具有获得性卡那霉素抗性的任意转化体在LB培养基中培养(37℃,18小时),并且使用质粒提取试剂盒(从QIAGEN可获得)提取质粒。用限制性酶BamHI对质粒的处理表明存在预期的插入物。对插入片段的插入而言存在两个方向。具体而言是其中lac启动子与插入片段在pBBR1MCS2载体中的转录方向相同的载体(pBBR1MCS2CRT)以及其中lac启动子与插入片段在pBBR1MCS2载体中的转录方向相反的载体(pBBR1MCS2CRTrv)。制备的载体的结构在图4中显示。
[实施例3]
类胡萝卜素合成基因在副球菌属细菌中的同源表达
其中克隆了类胡萝卜素合成基因片段的载体pBBR1MCS2CRT和pBBR1MCS2CRTrv通过热休克法各自导入大肠杆菌菌株S17-1,并且转化在含有50μg/mL卡那霉素和10μg/mL链霉素的LB琼脂培养基中实施。将具有获得性卡那霉素抗性的任意转化体在LB培养基中培养(37℃,18小时),并且质粒使用质粒提取试剂盒(从QIAGEN可获得)提取以检查目的质粒是否导入。随后通过用限制性酶BamHI处理,检查质粒是否在大肠杆菌菌株S17-1中正确复制。两种不同的质粒载体分别得以复制,未在大肠杆菌菌株S17-1中出现重组。
具有其中插入类胡萝卜素合成基因的pBBR1MCS2CRT质粒载体的大肠杆菌菌株S17-1在含有50μg/mL卡那霉素和10μg/mL链霉素的LB培养基中培养(37℃),并且得到含有处于对数生长期的细胞的液体培养物。测定浊度(OD 660nm),并且将该培养物在相同培养基中稀释直至浊度是0.1。与此平行地,副球菌属细菌在实施例1的OEG培养基中培养(25℃),并且得到含有处于对数生长期的细胞的液体培养物。以如上所述的相同方式,测定浊度并且将该培养物在OEG培养基中稀释以至于浊度是1.0。将每1.0mL的这些溶液放入5mL容量的注射器中,并且使注射器中的溶液经过与膜支架(从Advantec可获得)连接的膜以收集细胞。在收集细胞后,将膜从支架中取下并(细胞面朝上)放置在OEG琼脂培养基上,并实施用于引起接合转移的培养(25℃,4小时)。在培养后,将膜放入1.0mL的OEG培养基中,并且接合转移的细胞通过搅拌而从滤膜移去。溶液随后在OEG培养基中稀释至适宜的浓度,并且在含有50μg/mL卡那霉素和15μg/mL丁胺卡那霉素(从Sigma可获得)的OEG琼脂培养基上涂布并在25℃培养。添加丁胺卡那霉素以抑制大肠杆菌的生长。
挑取培养3日出现的菌落,并且在含有50μg/mL卡那霉素的OEG培养基中培养(25℃)以提取质粒。质粒提取如大肠杆菌菌株JM109例子那样利用可从QIAGEN获得的质粒提取试剂盒加以实施。在0.9%琼脂糖中电泳得到的液体提取物,产生如与大肠杆菌菌株S17-1中所携带pBBR1MCS2CRT的结果相同的结果。这表明从大肠杆菌至副球菌属细菌的质粒转移成功地进行。对pBBR1MCS2CRTrv实施相同的检验。
[实施例4]
对转化的副球菌属细菌中虾青素产生的定量
具有质粒pBBR1MCS2CRT和pBBR1MCS2CRTrv中任一种质粒的副球菌属细菌分别在含有100μg/mL卡那霉素的OEG培养基中培养(25℃)。培养在置于配有挡板的100mL容量锥形瓶内的60mL培养基中实施,其中所述的锥形瓶放置在以120转/分钟旋转的旋转振荡培养箱内。
采样在适宜的时间点上进行,并且在通过离心操作收集细胞后,用丙酮提取类胡萝卜素并定量。类胡萝卜素的量通过使用反向柱的高效液相色谱(HPLC)测定,并且以如下操作方法实施。更具体而言,将液体培养物的部分离心以收集细胞,并且细胞以适宜量的纯水添加并由管式混合器(tubemixer)混悬10分钟。随后添加相对于纯水9倍量的丙酮并由管式混合器搅拌30分钟。此后,在14,000转/分钟实施离心5分钟,并且对上清液通过HPLC定量。就HPLC柱而言,使用TSK凝胶ODS-80(从TOSOH公司可获得),并且测定在流速1.0ml/分钟和检测波长470nm处实施。使用标准品虾青素(从Sigma可获得)产生校正曲线并且计算培养物中虾青素的产生量。作为导入质粒的菌株的对照,也制备仅具有其中没有插入类胡萝卜素合成基因的pBBR1MCS2载体的菌株。如表1中所示,观察到在具有类胡萝卜素合成基因的副球菌属细菌中虾青素产生量的显著增加。
此外,将野生型副球菌菌株MBIC1143进行诱变,并且向具有提高的虾青素合成量的菌株TSN18E7中的基因导入以相似方式通过接合转移而实施。如用菌株MBIC1143的情形那样,观察到虾青素产生量的显著增加(表1)。
在基因导入的突变菌株TSN18E7中,增加尤其在培养72小时是显著的。能够在短时间内合成作为类胡萝卜素合成终产物的虾青素说明了通过插入类胡萝卜素合成基因而制备的质粒载体的作用。副球菌菌株TSN18E7以编号FERM P-19746保藏在独立行政法人产业技术综合研究所专利生物保藏中心。
表1.由基因导入的副球菌属细菌产生的虾青素的产生量
[实施例5]
对所插入的类胡萝卜素合成基因的启动子序列的分析
类似于实施例4,将类胡萝卜素合成基因片段插入载体pBBR1MCS2中并在副球菌属细菌中同源表达。观察到作为类胡萝卜素中一个种类的虾青素的产生量显著增加。此外,观察到与插入载体的方向无关的活性改善。这提示类胡萝卜素合成基因在没有利用插入载体pBBR1MCS2中的lac启动子的功能下受到表达。鉴于此,我们对位于所扩增类胡萝卜素合成基因的转录方向上游侧的序列(在SEQ ID NO:1中描述的从1-450位碱基)进行启动子分析。为了分析,使用可商业获得的软件GENETYX(从GENETICS可获得)。作为分析结果,发现作为启动子发挥作用的序列位于所扩增DNA中crtW基因的上游侧(表2)。从SEQ ID NO:19的第一位至紧邻crtW基因间的碱基序列可以被估计为具有在副球菌中启动子活性的碱基序列。下表中的启动子分值是由GENETYX软件计算的值,并且它可以解读为该值越高,启动子活性存在的可能性越高。
表2.所分析的启动子序列
[实施例6]
β-胡萝卜素氧化酶表达载体的制备
副球菌的基因组DNA以如实施例1中所述的相似方式制备。随后,含有crtW和crtZ(它们是β-胡萝卜素氧化酶基因)的区域由PCR扩增。碱基序列在SEQ ID NO:9中显示。为进行PCR,使用引物SEQ ID NO:13和SEQ ID NO:15(5’-cgggatccgcagggcgatcagcccgttggcaagg-3’)。随后,向1.0μL起模板作用的已制备DNA中添加16.5μL水和25μL 2×高GC缓冲液(TAKARA BIO INC.),并在94℃加热10分钟。在冰上冷却后,添加5μLdNTP、2.0μL的10pmol/μL由SEQ ID NO:13所示的正向引物和2.0μL的10pmol/μL由SEQ ID NO:15所示的反向引物、并且最后添加0.5μL的exTaqDNA聚合酶(TAKARA BIO INC.)。反应包括30个循环(每个循环由第一步骤94℃30秒、第二步骤60℃30秒和第三步骤72℃2分钟组成),随后是72℃7分钟的反应。扩增片段由琼脂糖电泳检验并进行提取和纯化(从QIAGEN可获得的QIAgen凝胶提取试剂盒)。由于存在允许插入质粒载体pBBR1MCS2的BamHI位点,纯化的DNA用限制性酶BamHI消化。在连接后,通过热休克法实施向大肠杆菌菌株JM109中的基因导入,随后在含有50μg/mL卡那霉素的LB琼脂培养基中转化。具有获得性卡那霉素抗性的任意转化体在LB培养基中培养(37℃,18小时),并且质粒使用质粒提取试剂盒(从QIAGEN可获得)提取。用限制性酶BamHI对质粒的处理表明存在预期的插入物。对插入片段的插入而言存在两个方向。具体而言是其中lac启动子与插入片段在pBBR1MCS2载体中的转录方向相同的载体(pBBR1MCS2CRTWZ)以及其中lac启动子与插入片段在pBBR1MCS2载体中的转录方向相反的载体(pBBR1MCS2CRTWZrv)。制备的载体的结构在图5中显示。
[实施例7]
β-胡萝卜素氧化酶表达载体在副球菌中的表达
类似上文实施例3,将pBBR1MCS2CRTWZ和pBBR1MCS2CRTWZrv各自导入大肠杆菌菌株S17-1,并且通过接合转移转化副球菌的突变株。在培养3日后,由HPLC定量类胡萝卜素。结果在表3中显示。在该表中,″Ax″代表虾青素,且″TC″代表总类胡萝卜素。
表3.由基因导入的副球菌属细菌产生的类胡萝卜素的产生量
如表3中所示,虾青素的合成因所导入基因构建体的作用即β-胡萝卜素氧化酶的表达量增加而得以明显增加,而没有观察到对总类胡萝卜的增加作用。
[实施例8]
牻牛儿基牻牛儿基焦磷酸合成基因表达载体的制备
副球菌的基因组DNA以如与实施例1相似的方式制备。随后,由PCR扩增牻牛儿基牻牛儿基焦磷酸合成酶基因(crtE)区。因为预计存在于crtE基因上游侧的启动子区是未知的,参考SEQ ID NO:1的碱基序列,我们设计并使用具有不同杂交区的两组PCR引物:由SEQ ID NO:16(5’-ctagtctagatgcttgacaatccgggtgacgcgg-3’)和SEQ ID NO:17(5’-tgggagctcatcacgcctaggcgcgcgcggcgtag-3’)代表的引物组和由SEQ IDNO:18(5’-ctagtctagagccggtccactgaccttgttggac-3’)和SEQ ID NO:17代表的引物组。前一引物组扩增约1.2k碱基的区域,而后一引物组扩增约1.1k碱基的区域。相应的碱基序列由SEQ ID NO:10和SEQ ID NO:11显示。较长的扩增区称作PcrtE1crtE,而较短的扩增区称作PcrtE2crtE。对于PcrtE1crtE,首先,向1.0μL充当PCR模板作用的已制备DNA添加16.5μL水和25μL 2×高GC缓冲液(TAKARA BIO INC.),并在94℃加热10分钟。在冰上冷却后,添加5μL dNTP,2.0μL的10pmol/μL由SEQ ID NO:16所示的正向引物和2.0μL的10pmol/μL由SEQ ID NO:17所示的反向引物,并且最后添加0.5μL的exTaqDNA聚合酶(TAKARA BIO INC.)。反应包括30个循环(每个循环由第一步骤94℃30秒、第二步骤60℃30秒和第三步骤72℃2分钟组成),随后是72℃7分钟的反应。扩增片段由琼脂糖电泳检验并进行提取和纯化(从QIAGEN获得的QIAgen凝胶提取试剂盒)。此外,用于插入质粒载体的末端以限制性酶Xba I和SacI进行消化。以相似方式,使用在SEQ ID NO:17和SEQ ID NO:18中描述的引物制备PcrtE2。
其次,其中插入物待插入的质粒载体pBBR1MCS2用限制性酶BtsI和Bsu36I消化以便使不需要的DNA链脱离。在酚/氯仿提取后,实施乙醇沉淀以便纯化。此外,使在SEQ ID NO:22(5’-tcatctagaggtaccatatgaagcttgagctcct-3’)和23(5’-gagctcaagcttcatatggtacctctaga-3’)中描述的单链寡核苷酸复性,并且将得到的双链体与纯化的DNA片段连接。设计该双链体包括限制性酶SacI和XbaI的限制性位点。在连接后,在含有50μg/mL卡那霉素的LB琼脂培养基中转化大肠杆菌JM109,以便得到其中插入该双链体的载体,该载体称作pBBR1MCS2oligo。
随后,pBBR1MCS2oligo用限制性酶SacI和XbaI消化以排布用于使插入物插入的末端。在连接后,大肠杆菌JM109在含有50μg/mL卡那霉素的LB琼脂培养基中转化。挑取并培养任意菌落,并且制备质粒。将质粒进行电泳以证实它是预期的构建体。具有较长区域的插入物的构建体称作pBBR1MCS2PcrtE1crtE而具有较短区域的插入物的构建体称作pBBR1MCS2PcrtE2crtE。相应的结构在图6中显示。
[实施例9]
牻牛儿基牻牛儿基焦磷酸合成酶在副球菌属细菌中的表达
类似上文实施例3,将pBBR1MCS2PcrtE1crtE和pBBR1MCS2PcrtE2crtE各自导入大肠杆菌菌株S17-1,并且通过接合转移转化副球菌的突变株。在如同实施例4那样培养5日后,对类胡萝卜素定量。结果在表4中显示。
表4.由基因导入的副球菌属细菌产生的类胡萝卜素的产生量
如表4中所示,在其中导入这些基因构建体的突变株TSN18E7中,观察到细菌裂解,并且没有观察到类胡萝卜素合成量的增加。在另一方面,在具有提高的生长能力的突变株TSTT001中,作为产物的牻牛儿基牻牛儿基焦磷酸的供应量因这些构建体的作用即增加的牻牛儿基牻牛儿基焦磷酸合成酶表达量而增加,并且类胡萝卜素合成量因副球菌的染色体所编码的类胡萝卜素合成酶系列而增加。突变菌株TSTT001以编号FERM P-20670保藏在独立行政法人产业技术综合研究所专利生物保藏中心。
[实施例10]
在牻牛儿基牻牛儿基焦磷酸合成基因上游侧的启动子序列
如实施例7中所述,发现当将上游序列添加至882个碱基的编码牻牛儿基牻牛儿基焦磷酸合成酶的区域时,类胡萝卜素合成量明显增加。换句话说,发现位于牻牛儿基牻牛儿基焦磷酸合成酶的ORF上游侧的约300个碱基或约200个碱基的碱基序列是具有启动子活性的DNA链。这些碱基序列在SEQ ID NO:20和SEQ ID NO:21中描述。
[实施例11]
组合牻牛儿基牻牛儿基焦磷酸合成基因和类胡萝卜素合成基因的质粒
载体的制备
在实施例7中描述的质粒pBBR1MCS2PcrtE1crtE用限制性酶XbaI消化。切割的末端用DNA平端化试剂盒(TAKARA BIO INC.)进行平端化,并且实施酚/氯仿提取及通过乙醇沉淀的纯化。随后,将在实施例2中制备并用限制性酶BamHI消化的类胡萝卜素合成基因片段类似地平端化,随后酚/氯仿提取及通过乙醇沉淀纯化。随后连接这些基因片段,并且在含有50μg/mL卡那霉素的LB琼脂培养基中转化大肠杆菌JM109。挑取并培养任意菌落,并且制备质粒。将质粒进行电泳以证实它是预期的构建体。制备的插入片段的碱基序列在SEQ ID NO:12中显示。该构建体称作pBBR1MCS2PcrtE1crtECRT。图7显示了该构建体的结构。
[实施例12]
组合牻牛儿基牻牛儿基焦磷酸合成基因和类胡萝卜素合成基因的质粒载体
的表达
类似上文实施例3,将pBBR1MCS2PcrtE1crtECRT导入大肠杆菌菌株S17-1,并且通过接合转移转化副球菌的突变株。类似于实施例4,类胡萝卜素在培养5日后通过HPLC定量。定量的结果在表5中显示。在该表中,″Ax″代表虾青素,且″TC″代表总类胡萝卜素。图8显示菌株TSTT001在培养3日时的HPLC模式。
表5.由基因导入的副球菌属细菌产生的类胡萝卜素的产生量
如表5中所示,虾青素和类胡萝卜素的产生量因构建体pBBR1MCS2PcrtE1crtECRT而得以明显增加。也即因为牻牛儿基牻牛儿基焦磷酸合成酶的表达,作为类胡萝卜素的合成材料的牻牛儿基牻牛儿基焦磷酸以高浓度合成,并且随后一系列类胡萝卜素合成酶因导入的构建体而过量表达以至引起虾青素的高效合成。如可从图8中看到,在培养3日时,菌株TSTT001的虾青素的合成量因导入基因pBBR1MCS2PcrtE1crtECRT而明显增加。
工业应用
在本发明中,我们揭示了增加类胡萝卜素产生量的基因或基因群的功能,并且成功地改良了能产生类胡萝卜素的天然微生物。因此,通过使用由本发明改良的微生物,有可能大幅度地增加用作饲料或食物的类胡萝卜素的产量。
附图简述
[图1]类胡萝卜素生物合成途径的示意图。
[图2]显示类胡萝卜素合成基因的图。
[图3]显示质粒载体pUCCRT结构的图。
[图4]显示质粒载体pBBR1MCS2CRT和pBBR1MCS2CRTrv结构的图。
[图5]显示质粒载体pBBR1MCS2CRTWZ和pBBR1MCS2CRTWZrv结构的图。
[图6]显示质粒载体pBBR1MCS2PcrtE1crtE和pBBR1MCS2PcrtE2crtE结构的图。
[图7]显示质粒载体pBBR1MCS2PcrtE1crtECRT结构的图。
[图8]显示由质粒载体pBBR1MCS2PcrtE1crtECRT重组的细菌类胡萝卜素合成量增大的作用的图。
SEQUENCE LISTING
<110>TOSOH CORPORATION
<120>Method for producing carotenoids using genetically modified microorganisim
<130>TS05092
<160>24
<170>PatentIn version 3.1
<210>1
<211>7029
<212>DNA
<213>Paracoccus sp.
<220>
<221>misc_feature
<222>(7024)..(7024)
<223>a,t,g,c
<400>1
ggatccggcg accttgcggc gctgcgccgc gcgcctttgc tggtgcctgg gccgggtggc 60
caatggtcgc aagcaacggg gatggaaacc ggcgatgcgg gactgtagtc tgcgcggatc 120
gccggtccgg gggacaagat gagcgcacat gccctgccca aggcagatct gaccgccacc 180
agcctgatcg tctcgggcgg catcatcgcc gcttggctgg ccctgcatgt gcatgcgctg 240
tggtttctgg acgcagcggc gcatcccatc ctggcgatcg caaatttcct ggggctgacc 300
tggctgtcgg tcggattgtt catcatcgcg catgacgcga tgcacgggtc ggtggtgccg 360
gggcgtccgc gcgccaatgc ggcgatgggc cagcttgtcc tgtggctgta tgccggattt 420
tcgtggcgca agatgatcgt caagcacatg gcccatcacc gccatgccgg aaccgacgac 480
gaccccgatt tcgaccatgg cggcccggtc cgctggtacg cccgcttcat cggcacctat 540
ttcggctggc gcgaggggct gctgctgccc gtcatcgtga cggtctatgc gctgatcctt 600
ggggatcgct ggatgtacgt ggtcttctgg ccgctgccgt cgatcctggc gtcgatccag 660
ctgttcgtgt tcggcacctg gctgccgcac cgccccggcc acgacgcgtt cccggaccgc 720
cacaatgcgc ggtcgtcgcg gatcagcgac cccgtgtcgc tgctgacctg ctttcacttt 780
ggcggttatc atcacgaaca ccacctgcac ccgacggtgc cgtggtggcg cctgcccagc 840
acccgcacca agggggacac cgcatgacca atttcctgat cgtcgtcgcc accgtgctgg 900
tgatggagtt gacggcctat tccgtccacc gctggatcat gcacggcccc ctgggctggg 960
gctggcacaa gtcccaccac gaggaacacg accacgcgct ggaaaagaac gacctgtacg 1020
gcctggtctt tgcggtgatc gccacggtgc tgttcacggt gggctggatc tgggcgccgg 1080
tcctgtggtg gatcgccttg ggcatgactg tctatgggct gatctatttc gtcctgcatg 1140
acgggctggt gcatcagcgc tggccgttcc gttatatccc gcgcaagggc tatgccagac 1200
gcctgtatca ggcccaccgc ctgcaccatg cggtcgaggg gcgcgaccat tgcgtcagct 1260
tcggcttcat ctatgcgccc ccggtcgaca agctgaagca ggacctgaag atgtcgggcg 1320
tgctgcgggc cgaggcgcag gagcgcacgt gacccatgac gtgctgctgg caggggcggg 1380
ccttgccaac gggctgatcg ccctggcgct gcgcgcggcg cggcccgacc tgcgcgtgct 1440
gctgctggac catgccgcag gaccgtcaga cggccacacc tggtcctgcc acgaccccga 1500
cctgtcgccg gactggctgg cgcggctgaa gcccctgcgc cgcgccaact ggcccgacca 1560
ggaggtgcgc tttccccgcc atgcccggcg gctggccacc ggttacgggt cgctggacgg 1620
ggcggcgctg gcggatgcgg tggtccggtc gggcgccgag atccgctggg acagcgacat 1680
cgccctgctg gatgcgcagg gggcgacgct gtcctgcggc acccggatcg aggcgggcgc 1740
ggtcctggac gggcggggcg cgcagccgtc gcggcatctg accgtgggtt tccagaaatt 1800
cgtgggtgtc gagatcgaga ccgaccgccc ccacggcgtg ccccgcccga tgatcatgga 1860
cgcgaccgtc acccagcagg acgggtaccg cttcatctat ctgctgccct tctctccgac 1920
gcgcatcctg atcgaggaca cgcgctattc cgatggcggc gatctggacg acgacgcgct 1980
ggcggcggcg tcccacgact atgcccgcca gcagggctgg accggggccg aggtccggcg 2040
cgaacgcggc atccttccca tcgcgctggc ccatgatgcg gcgggcttct gggccgatca 2100
cgcggcgggg cctgttcccg tgggactgcg cgcggggttc tttcatccgg tcaccggcta 2160
ttcgctgccc tatgcggcac aggtggcgga cgtggtggcg ggtctgtccg ggccgcccgg 2220
caccgacgcg ctgcgcggcg ccatccgcga ttacgcgatc gaccgggcgc gccgcgaccg 2280
ctttctgcgc cttttgaacc ggatgctgtt ccgcggctgc gcgcccgacc ggcgctatac 2340
cctgctgcag cggttctacc gcatgccgca tggactgatc gaacggttct atgccggccg 2400
gctgagcgtg gcggatcagc tgcgcatcgt gaccggcaag cctcccattc cccttggcac 2460
ggccatccgc tgcctgcccg aacgtcccct gctgaaggaa aacgcatgaa cgcccattcg 2520
cccgcggcca agaccgccat cgtgatcggc gcaggctttg gcgggctggc cctggccatc 2580
cgcctgcagt ccgcgggcat cgccaccacc ctggtcgagg cccgggacaa gcccggcggg 2640
cgcgcctatg tctggcacga tcagggccat ctcttcgacg cgggcccgac cgtcatcacc 2700
gaccccgatg cgctgaaaga gctgtgggcc ctgaccgggc aggacatggc gcgcgacgtg 2760
acgctgatgc cggtctcgcc cttctatcgg ctgatgtggc cgggcgggaa ggtcttcgat 2820
tacgtgaacg aggccgatca gctggaacgc cagatcgccc agttcaaccc ggacgacctg 2880
gagggatacc gccgcttccg tgattacgct gaggaggtgt accaggaggg ctacgtcaag 2940
ctgggcaccg tgcccttcct caagctgggc cagatgctca aggccgcgcc cgcgctgatg 3000
aagttggagg cctacaagtc ggtccatgcc aaggtcgcga ccttcatcaa ggacccctat 3060
ctgcggcagg cgttttcgta tcacacgctg ctggtgggcg ggaatccctt ctcgaccagc 3120
tcgatctatg cgctgaacca cgcgctggag cggcgcggcg gggtctggtt cgccaagggc 3180
ggcaccaacc agctggttgc gggcatggtc gcgctgttcg aacggcttgg cgggcagatg 3240
ctgctaaacg ccaaggtcgc gcggatcgac acggacgggc cgcgcgcgac cggcgtgacc 3300
ctggccgacg ggcgcgcctt gaccgccgac atggtcgcca gcaacggcga cgtgatgcac 3360
aactatcgcg acctgctggg ccataccgcc cgcgggcaga gccgggcgaa atcgctgaac 3420
gcgaagcgct ggtccatgtc gctcttcgtg ctgcatttcg gcctgcgcga ggcgcccaag 3480
gacgtggcgc atcacaccat cctgttcggc ccccgctaca aggagctggt caacgagatc 3540
ttcaagggcc cgaagctggc cgaggatttc tcgctctatc tgcattcgcc ctgcacgacc 3600
gacccggaga tggcgcctcc gggcatgtcc acgcattacg tcctggcccc ggtgccgcat 3660
ctgggccgcg cggacattga ttgggcggtc gaggggccgc gctatgccga ccgcatcctg 3720
gccagcctgg aggagcggct gatcccgaac ctgcgcgcca acctgaccac gacgcgcatc 3780
ttcaccccgt ccgatttcgc cagcgaactg aacgcccatc atggcagcgc cttctcggtc 3840
gagccgatcc tgacgcaatc cgcgtggttc cggccgcaca accgcgacaa gacgatccgc 3900
aacttctatc tggtcggcgc gggcacccat ccgggcgcgg ggattccggg cgtcgtgggc 3960
tcggccaagg ccacggccca ggtgatgctg tccgacctgg cgagcgcatg agcgatctgg 4020
tcctgacctc gaccgaggcg atcacccaag ggtcgcaaag ctttgccacg gcggccaagc 4080
tgatgccgcc gggcatccgc gacgacacgg tgatgctcta tgcctggtgc cgccacgcgg 4140
atgacgtgat cgacggtcag gccctgggca gctgccccga ggcggtgaac gacccgcagg 4200
cgcggctgga cggcctgcgc gccgacacgc tggccgcgtt gcagggcgac ggtccggtga 4260
ccccgccctt tgcctgcgcg gtggcgcggc ggcatgattt tccgcaggcc tggcccatgg 4320
acctgatcga aggctttgcg atggatgtcg aggcgcgcga ctatcgcacg ctggacgacg 4380
tgctggaata ttcctatcac gtcgcgggca tcgtcggcgt gatgatggcc cgtgtgatgg 4440
gcgtgcgcga cgatcctgtc ctggaccgtg cctgcgacct ggggctggcg ttccagctga 4500
ccaacatcgc gcgcgacgtg atcgacgacg cgcgcatcgg gcggtgctat ctgccaggcg 4560
actggctgga tcaggcgggc gcgcgggtcg acgggccggt gccgtcgccg gagctgtaca 4620
ccgtgatcct gcgcctgctg gatgcggctg aactctatta cgcgtcggcg cgggtgggtc 4680
tggcggatct gccgccgcgc tgcgcctggt ccatcgccgc cgcgttgcgg atctatcgcg 4740
ccatcgggct gcgcatccgc aagggcgggc cggaggccta tcgccagcgg atcagcacgt 4800
ccaaggccgc caagatcggg ctgctgggca tcgggggctg ggatgtcgcc gatcacgcct 4860
gccgggggcg gcgtgtcgcg acaggcctct ggacccggcc gcatcacgcc taggcgcgcg 4920
cggcgtaggg cagaacccgt tccagcaggg ccgcgatttc cggagcctga aggcgcttgc 4980
tgcgcagcat cgcgtccagc tgggcgcggc tggcctcata gtggcgggac acgttctgca 5040
ggtctgacac ggccagaagg ccgcgccgcg ggccgggggc cgcggcatcg cgaccggtat 5100
ccttgccaag cgccgcctgg tcgcccacga cgtccagcag gtcgtcatag gactggaaca 5160
cccggcccag ctgacggcca aagtcgatca tctgggtctg ctcctcggcg tcgaactcct 5220
tgatcacggc cagcgtctcc agcccggcga tgaacagcac gccggtcttc aggtcctgtt 5280
cctgttcgac ccccgcgccg ttcttggccg cgtgcaggtc caggtcctgg ccggcgcaca 5340
ggccctgcgg ccccagggac cgcgacagga tccgcaccag ctgcgcccgc cccgtgcccg 5400
acgcgccgcg cgcaccggcc agcagggcca tcgcctcggt gatcagggcg atgccgccca 5460
gcacggcgcg gctttcgcca tgcgccacat gggtcgcgga ctggccgcgg cgcagcccgg 5520
catcgtccat gcagggcagg tcgtcgaaga tcagcgatgc ggcatgcacc atctcgaccg 5580
cgcaggcggc gtcgacgatc gtgtcgcaga ccccgcccga ggcctctgcc gcaagcagca 5640
tcagcatgcc gcggaaccgc ttgcccgacg acagcgcgcc atggctcatg gccgcgccga 5700
gcggctgcga cacggcaccg aatccctggg cgatctcctc aagtctggtc tgcagaaggg 5760
tggcgtggat cgggttgacg tctcgtctca tcagtgccct cgcgctgggg ttctgacctg 5820
gcgggaaggt caggccgggg cggcaccccg tgacccgtca tccaccgtca acagtcccca 5880
tgttggaacg gttcacgccc gattgcgagc cttttcgacg gcgacgcggg gtcgcgcggc 5940
aatttgtcca acaaggtcag tggaccggcg cgccgatggc cgcgcgcagc caggcatcct 6000
tggccggaaa cacccgcgcc gcatcatgat cggccaggat cgtccggcgc gcggcgcggc 6060
gcaggtcggc cgcgtcaccc ggattgtcaa gcacccaggc catcgcatcc gcgacctcgt 6120
ccgcgtcgtc catgtcgacg atcaggccgt tctccatgtc gcggaccagt tcgcgcaccg 6180
gggcggtgtt cgatccgatc accaggcacc cggtggccat cgcctcggac agggaccagg 6240
aggtgacgaa gggctcggtg aaatagacat gtgcgtgcga ggcctgcagc gtgcggacat 6300
attcatcgcg cgggcgcatg gcgttcacgt ggatgcggcg gtggtccagg tccagctggt 6360
cgatcatccg cagccaccag ccgtcgccgc gcgccagcgg tcgaccatag gacacgctgt 6420
cattggccag gatcaccgtg ccgaagtcgt cacgccgcgc ctgcaggcgg gcgacgccgc 6480
gcaggaattg cggaaagccg cgcaagggct ccatcccgcg ggtggtatag gtgatcacgg 6540
ggcggtcggc gggcaggcgc agccagtcga aatcgatgcg cgcctgcggg tcggggcggt 6600
gcaggtcgca atcgacccca tccggcatca cggtgatctg gcggcgcagg accggaggaa 6660
agcggctggc ctggaacagc gtcgggcacc agctggcatc ggccaggtcg aattcgccgg 6720
tgatcggcag gttgcgcatc cggtccgaga tcatcaccgc caggtcggcg ggcttttccg 6780
cccggcgctt gtcccagttg cggtcggtgt aataccattc gtgataggcg acataggtgc 6840
agtccggcca gaccagcttg acccccagcc ccacgcccca gcccgcatgg gccaccacga 6900
cgtccgggac atagccttcg gaatggcgca tgcggaacat cagctcggtc gcgccccggc 6960
agttctgcgc ggcgtggtcc aggatgtgac gcggatcgcc cgtggggatc gtggtgtcgc 7020
gcancgcga 7029
<210>2
<211>242
<212>PRT
<213>Paracoccus sp.
<400>2
Met Ser Ala His Ala Leu Pro Lys Ala Asp Leu Thr Ala Thr Ser Leu
1 5 10 15
Ile Val Ser Gly Gly Ile Ile Ala Ala Trp Leu Ala Leu His Val His
20 25 30
Ala Leu Trp Phe Leu Asp Ala Ala Ala His Pro Ile Leu Ala Ile Ala
35 40 45
Asn Phe Leu Gly Leu Thr Trp Leu Ser Val Gly Leu Phe Ile Ile Ala
50 55 60
His Asp Ala Met His Gly Ser Val Val Pro Gly Arg Pro Arg Ala Asn
65 70 75 80
Ala Ala Met Gly Gln Leu Val Leu Trp Leu Tyr Ala Gly Phe Ser Trp
85 90 95
Arg Lys Met Ile Val Lys His Met Ala His His Arg His Ala Gly Thr
100 105 110
Asp Asp Asp Pro Asp Phe Asp His Gly Gly Pro Val Arg Trp Tyr Ala
115 120 125
Arg Phe Ile Gly Thr Tyr Phe Gly Trp Arg Glu Gly Leu Leu Leu Pro
130 135 140
Val Ile Val Thr Val Tyr Ala Leu Ile Leu Gly Asp Arg Trp Met Tyr
145 150 155 160
Val Val Phe Trp Pro Leu Pro Ser Ile Leu Ala Ser Ile Gln Leu Phe
165 170 175
Val Phe Gly Thr Trp Leu Pro His Arg Pro Gly His Asp Ala Phe Pro
180 185 190
Asp Arg His Asn Ala Arg Ser Ser Arg Ile Ser Asp Pro Val Ser Leu
195 200 205
Leu Thr Cys Phe His Phe Gly Gly Tyr His His Glu His His Leu His
210 215 220
Pro Thr Val Pro Trp Trp Arg Leu Pro Ser Thr Arg Thr Lys Gly Asp
225 230 235 240
Thr Ala
<210>3
<211>162
<212>PRT
<213>Paracoccus sp.
<400>3
Met Thr Asn Phe Leu Ile Val Val Ala Thr Val Leu Val Met Glu Leu
1 5 10 15
Thr Ala Tyr Ser Val His Arg Trp Ile Met His Gly Pro Leu Gly Trp
20 25 30
Gly Trp His Lys Ser His His Glu Glu His Asp His Ala Leu Glu Lys
35 40 45
Asn Asp Leu Tyr Gly Leu Val Phe Ala Val Ile Ala Thr Val Leu Phe
50 55 60
Thr Val Gly Trp Ile Trp Ala Pro Val Leu Trp Trp Ile Ala Leu Gly
65 70 75 80
Met Thr Val Tyr Gly Leu Ile Tyr Phe Val Leu His Asp Gly Leu Val
85 90 95
His Gln Arg Trp Pro Phe Arg Tyr Ile Pro Arg Lys Gly Tyr Ala Arg
100 105 110
Arg Leu Tyr Gln Ala His Arg Leu His His Ala Val Glu Gly Arg Asp
115 120 125
His Cys Val Ser Phe Gly Phe Ile Tyr Ala Pro Pro Val Asp Lys Leu
130 135 140
Lys Gln Asp Leu Lys Met Ser Gly Val Leu Arg Ala Glu Ala Gln Glu
145 150 155 160
Arg Thr
<210>4
<211>386
<212>PRT
<213>Paracoccus sp.
<400>4
Met Thr His Asp Val Leu Leu Ala Gly Ala Gly Leu Ala Asn Gly Leu
1 5 10 15
Ile Ala Leu Ala Leu Arg Ala Ala Arg Pro Asp Leu Arg Val Leu Leu
20 25 30
Leu Asp His Ala Ala Gly Pro Ser Asp Gly His Thr Trp Ser Cys His
35 40 45
Asp Pro Asp Leu Ser Pro Asp Trp Leu Ala Arg Leu Lys Pro Leu Arg
50 55 60
Arg Ala Asn Trp Pro Asp Gln Glu Val Arg Phe Pro Arg His Ala Arg
65 70 75 80
Arg Leu Ala Thr Gly Tyr Gly Ser Leu Asp Gly Ala Ala Leu Ala Asp
85 90 95
Ala Val Val Arg Ser Gly Ala Glu Ile Arg Trp Asp Ser Asp Ile Ala
100 105 110
Leu Leu Asp Ala Gln Gly Ala Thr Leu Ser Cys Gly Thr Arg Ile Glu
115 120 125
Ala Gly Ala Val Leu Asp Gly Arg Gly Ala Gln Pro Ser Arg His Leu
130 135 140
Thr Val Gly Phe Gln Lys Phe Val Gly Val Glu Ile Glu Thr Asp Arg
145 150 155 160
Pro His Gly Val Pro Arg Pro Met Ile Met Asp Ala Thr Val Thr Gln
165 170 175
Gln Asp Gly Tyr Arg Phe Ile Tyr Leu Leu Pro Phe Ser Pro Thr Arg
180 185 190
Ile Leu Ile Glu Asp Thr Arg Tyr Ser Asp Gly Gly Asp Leu Asp Asp
195 200 205
Asp Ala Leu Ala Ala Ala Ser His Asp Tyr Ala Arg Gln Gln Gly Trp
210 215 220
Thr Gly Ala Glu Val Arg Arg Glu Arg Gly Ile Leu Pro Ile Ala Leu
225 230 235 240
Ala His Asp Ala Ala Gly Phe Trp Ala Asp His Ala Ala Gly Pro Val
245 250 255
Pro Val Gly Leu Arg Ala Gly Phe Phe His Pro Val Thr Gly Tyr Ser
260 265 270
Leu Pro Tyr Ala Ala Gln Val Ala Asp Val Val Ala Gly Leu Ser Gly
275 280 285
Pro Pro Gly Thr Asp Ala Leu Arg Gly Ala Ile Arg Asp Tyr Ala Ile
290 295 300
Asp Arg Ala Arg Arg Asp Arg Phe Leu Arg Leu Leu Asn Arg Met Leu
305 310 315 320
Phe Arg Gly Cys Ala Pro Asp Arg Arg Tyr Thr Leu Leu Gln Arg Phe
325 330 335
Tyr Arg Met Pro His Gly Leu Ile Glu Arg Phe Tyr Ala Gly Arg Leu
340 345 350
Ser Val Ala Asp Gln Leu Arg Ile Val Thr Gly Lys Pro Pro Ile Pro
355 360 365
Leu Gly Thr Ala Ile Arg Cys Leu Pro Glu Arg Pro Leu Leu Lys Glu
370 375 380
Asn Ala
385
<210>5
<211>501
<212>PRT
<213>Paracoccus sp.
<400>5
Met Asn Ala His Ser Pro Ala Ala Lys Thr Ala Ile Val Ile Gly Ala
1 5 10 15
Gly Phe Gly Gly Leu Ala Leu Ala Ile Arg Leu Gln Ser Ala Gly Ile
20 25 30
Ala Thr Thr Leu Val Glu Ala Arg Asp Lys Pro Gly Gly Arg Ala Tyr
35 40 45
Val Trp His Asp Gln Gly His Leu Phe Asp Ala Gly Pro Thr Val Ile
50 55 60
Thr Asp Pro Asp Ala Leu Lys Glu Leu Trp Ala Leu Thr Gly Gln Asp
65 70 75 80
Met Ala Arg Asp Val Thr Leu Met Pro Val Ser Pro Phe Tyr Arg Leu
85 90 95
Met Trp Pro Gly Gly Lys Val Phe Asp Tyr Val Asn Glu Ala Asp Gln
100 105 110
Leu Glu Arg Gln Ile Ala Gln Phe Asn Pro Asp Asp Leu Glu Gly Tyr
115 120 125
Arg Arg Phe Arg Asp Tyr Ala Glu Glu Val Tyr Gln Glu Gly Tyr Val
130 135 140
Lys Leu Gly Thr Val Pro Phe Leu Lys Leu Gly Gln Met Leu Lys Ala
145 150 155 160
Ala Pro Ala Leu Met Lys Leu Glu Ala Tyr Lys Ser Val His Ala Lys
165 170 175
Val Ala Thr Phe Ile Lys Asp Pro Tyr Leu Arg Gln Ala Phe Ser Tyr
180 185 190
His Thr Leu Leu Val Gly Gly Asn Pro Phe Ser Thr Ser Ser Ile Tyr
195 200 205
Ala Leu Ile His Ala Leu Glu Arg Arg Gly Gly Val Trp Phe Ala Lys
210 215 220
Gly Gly Thr Asn Gln Leu Val Ala Gly Met Val Ala Leu Phe Glu Arg
225 230 235 240
Leu Gly Gly Gln Met Leu Leu Asn Ala Lys Val Ala Arg Ile Asp Thr
245 250 255
Asp Gly Pro Arg Ala Thr Gly Val Thr Leu Ala Asp Gly Arg Ala Leu
260 265 270
Thr Ala Asp Met Val Ala Ser Asn Gly Asp Val Met His Asn Tyr Arg
275 280 285
Asp Leu Leu Gly His Thr Ala Arg Gly Gln Ser Arg Ala Lys Ser Leu
290 295 300
Asn Ala Lys Arg Trp Ser Met Ser Leu Phe Val Leu His Phe Gly Leu
305 310 315 320
Arg Glu Ala Pro Lys Asp Val Ala His His Thr Ile Leu Phe Gly Pro
325 330 335
Arg Tyr Lys Glu Leu Val Asn Glu Ile Phe Lys Gly Pro Lys Leu Ala
340 345 350
Glu Asp Phe Ser Leu Tyr Leu His Ser Pro Cys Thr Thr Asp Pro Glu
355 360 365
Met Ala Pro Pro Gly Met Ser Thr His Tyr Val Leu Ala Pro Val Pro
370 375 380
His Leu Gly Arg Ala Asp Ile Asp Trp Ala Val Glu Gly Pro Arg Tyr
385 390 395 400
Ala Asp Arg Ile Leu Ala Ser Leu Glu Glu Arg Leu Ile Pro Asn Leu
405 410 415
Arg Ala Asn Leu Thr Thr Thr Arg Ile Phe Thr Pro Ser Asp Phe Ala
420 425 430
Ser Glu Leu Asn Ala His His Gly Ser Ala Phe Ser Val Glu Pro Ile
435 440 445
Leu Thr Gln Ser Ala Trp Phe Arg Pro His Asn Arg Asp Lys Thr Ile
450 455 460
Arg Asn Phe Tyr Leu Val Gly Ala Gly Thr His Pro Gly Ala Gly Ile
465 470 475 480
Pro Gly Val Val Gly Ser Ala Lys Ala Thr Ala Gln Val Met Leu Ser
485 490 495
Asp Leu Ala Ser Ala
500
<210>6
<211>304
<212>PRT
<213>Paracoccus sp.
<400>6
Met Ser Asp Leu Val Leu Thr Ser Thr Glu Ala Ile Thr Gln Gly Ser
1 5 10 15
Gln Ser Phe Ala Thr Ala Ala Lys Leu Met Pro Pro Gly Ile Arg Asp
20 25 30
Asp Thr Val Met Leu Tyr Ala Trp Cys Arg His Ala Asp Asp Val Ile
35 40 45
Asp Gly Gln Ala Leu Gly Ser Arg Pro Glu Ala Val Asn Asp Pro Gln
50 55 60
Ala Arg Leu Asp Gly Leu Arg Ala Asp Thr Leu Ala Ala Leu Gln Gly
65 70 75 80
Asp Gly Pro Val Thr Pro Pro Phe Ala Ala Leu Arg Ala Val Ala Arg
85 90 95
Arg His Asp Phe Pro Gln Ala Trp Pro Met Asp Leu Ile Glu Gly Phe
100 105 110
Ala Met Asp Val Glu Ala Arg Asp Tyr Arg Thr Leu Asp Asp Val Leu
115 120 125
Glu Tyr Ser Tyr His Val Ala Gly Ile Val Gly Val Met Met Ala Arg
130 135 140
Val Met Gly Val Arg Asp Asp Pro Val Leu Asp Arg Ala Cys Asp Leu
145 150 155 160
Gly Leu Ala Phe Gln Leu Thr Asn Ile Ala Arg Asp Val Ile Asp Asp
165 170 175
Ala Arg Ile Gly Arg Cys Tyr Leu Pro Gly Asp Trp Leu Asp Gln Ala
180 185 190
Gly Ala Arg Val Asp Gly Pro Val Pro Ser Pro Glu Leu Tyr Thr Val
195 200 205
Ile Leu Arg Leu Leu Asp Ala Ala Glu Leu Tyr Tyr Ala Ser Ala Arg
210 215 220
Val Gly Leu Ala Asp Leu Pro Pro Arg Cys Ala Trp Ser Ile Ala Ala
225 230 235 240
Ala Leu Arg Ile Tyr Arg Ala Ile Gly Leu Arg Ile Arg Lys Gly Gly
245 250 255
Pro Glu Ala Tyr Arg Gln Arg Ile Ser Thr Ser Lys Ala Ala Lys Ile
260 265 270
Gly Leu Leu Gly Ile Gly Gly Trp Asp Val Ala Arg Ser Arg Leu Pro
275 280 285
Gly Ala Gly Val Ser Arg Gln Gly Leu Trp Thr Arg Pro His His Ala
290 295 300
<210>7
<211>293
<212>PRT
<213>Paracoccus sp.
<400>7
Met Arg Arg Asp Val Asn Pro Ile His Ala Thr Leu Leu Gln Thr Arg
1 5 10 15
Leu Glu Glu Ile Ala Gln Gly Phe Gly Ala Val Ser Gln Pro Leu Gly
20 25 30
Ala Ala Met Ser His Gly Ala Leu Ser Ser Gly Lys Arg Phe Arg Gly
35 40 45
Met Leu Met Leu Leu Ala Ala Glu Ala Ser Gly Gly Val Cys Asp Thr
50 55 60
Ile Val Asp Ala Ala Cys Ala Val Glu Met Val His Ala Ala Ser Leu
65 70 75 80
Ile Phe Asp Asp Leu Pro Cys Met Asp Asp Ala Gly Leu Arg Arg Gly
85 90 95
Gln Ser Ala Thr His Val Ala His Gly Glu Ser Arg Ala Val Leu Gly
100 105 110
Gly Ile Ala Leu Ile Thr Glu Ala Met Ala Leu Leu Ala Gly Ala Arg
115 120 125
Gly Ala Ser Gly Thr Gly Arg Ala Gln Leu Val Arg Ile Leu Ser Arg
130 135 140
Ser Leu Gly Pro Gln Gly Leu Cys Ala Gly Gln Asp Leu Asp Leu His
145 150 155 160
Ala Ala Lys Asn Gly Ala Gly Val Glu Gln Glu Gln Asp Leu Lys Thr
165 170 175
Gly Val Leu Phe Ile Ala Gly Leu Glu Thr Leu Ala Val Ile Lys Glu
180 185 190
Phe Asp Ala Glu Glu Gln Thr Gln Met Ile Asp Phe Gly Arg Gln Leu
195 200 205
Gly Arg Val Phe Gln Ser Tyr Asp Asp Leu Leu Asp Val Val Gly Asp
210 215 220
Gln Ala Ala Leu Gly Lys Asp Thr Gly Arg Asp Ala Ala Ala Pro Gly
225 230 235 240
Pro Arg Arg Gly Leu Leu Ala Val Ser Asp Leu Gln Asn Val Ser Arg
245 250 255
His Tyr Glu Ala Ser Arg Ala Gln Leu Asp Ala Met Leu Arg Ser Lys
260 265 270
Arg Leu Gln Ala Pro Glu Ile Ala Ala Leu Leu Glu Arg Val Leu Pro
275 280 285
Tyr Ala Ala Arg Ala
290
<210>8
<211>5377
<212>DNA
<213>Paracoccus sp.
<400>8
gcggatccgg cgaccttgcg gcgctgcgcc gcgcgccttt gctggtgcct gggccgggtg 60
gccaatggtc gcaagcaacg gggatggaaa ccggcgatgc gggactgtag tctgcgcgga 120
tcgccggtcc gggggacaag atgagcgcac atgccctgcc caaggcagat ctgaccgcca 180
ccagcctgat cgtctcgggc ggcatcatcg ccgcttggct ggccctgcat gtgcatgcgc 240
tgtggtttct ggacgcagcg gcgcatccca tcctggcgat cgcaaatttc ctggggctga 300
cctggctgtc ggtcggattg ttcatcatcg cgcatgacgc gatgcacggg tcggtggtgc 360
cggggcgtcc gcgcgccaat gcggcgatgg gccagcttgt cctgtggctg tatgccggat 420
tttcgtggcg caagatgatc gtcaagcaca tggcccatca ccgccatgcc ggaaccgacg 480
acgaccccga tttcgaccat ggcggcccgg tccgctggta cgcccgcttc atcggcacct 540
atttcggctg gcgcgagggg ctgctgctgc ccgtcatcgt gacggtctat gcgctgatcc 600
ttggggatcg ctggatgtac gtggtcttct ggccgctgcc gtcgatcctg gcgtcgatcc 660
agctgttcgt gttcggcacc tggctgccgc accgccccgg ccacgacgcg ttcccggacc 720
gccacaatgc gcggtcgtcg cggatcagcg accccgtgtc gctgctgacc tgctttcact 780
ttggcggtta tcatcacgaa caccacctgc acccgacggt gccgtggtgg cgcctgccca 840
gcacccgcac caagggggac accgcatgac caatttcctg atcgtcgtcg ccaccgtgct 900
ggtgatggag ttgacggcct attccgtcca ccgctggatc atgcacggcc ccctgggctg 960
gggctggcac aagtcccacc acgaggaaca cgaccacgcg ctggaaaaga acgacctgta 1020
cggcctggtc tttgcggtga tcgccacggt gctgttcacg gtgggctgga tctgggcgcc 1080
ggtcctgtgg tggatcgcct tgggcatgac tgtctatggg ctgatctatt tcgtcctgca 1140
tgacgggctg gtgcatcagc gctggccgtt ccgttatatc ccgcgcaagg gctatgccag 1200
acgcctgtat caggcccacc gcctgcacca tgcggtcgag gggcgcgacc attgcgtcag 1260
cttcggcttc atctatgcgc ccccggtcga caagctgaag caggacctga agatgtcggg 1320
cgtgctgcgg gccgaggcgc aggagcgcac gtgacccatg acgtgctgct ggcaggggcg 1380
ggccttgcca acgggctgat cgccctggcg ctgcgcgcgg cgcggcccga cctgcgcgtg 1440
ctgctgctgg accatgccgc aggaccgtca gacggccaca cctggtcctg ccacgacccc 1500
gacctgtcgc cggactggct ggcgcggctg aagcccctgc gccgcgccaa ctggcccgac 1560
caggaggtgc gctttccccg ccatgcccgg cggctggcca ccggttacgg gtcgctggac 1620
ggggcggcgc tggcggatgc ggtggtccgg tcgggcgccg agatccgctg ggacagcgac 1680
atcgccctgc tggatgcgca gggggcgacg ctgtcctgcg gcacccggat cgaggcgggc 1740
gcggtcctgg acgggcgggg cgcgcagccg tcgcggcatc tgaccgtggg tttccagaaa 1800
ttcgtgggtg tcgagatcga gaccgaccgc ccccacggcg tgccccgccc gatgatcatg 1860
gacgcgaccg tcacccagca ggacgggtac cgcttcatct atctgctgcc cttctctccg 1920
acgcgcatcc tgatcgagga cacgcgctat tccgatggcg gcgatctgga cgacgacgcg 1980
ctggcggcgg cgtcccacga ctatgcccgc cagcagggct ggaccggggc cgaggtccgg 2040
cgcgaacgcg gcatccttcc catcgcgctg gcccatgatg cggcgggctt ctgggccgat 2100
cacgcggcgg ggcctgttcc cgtgggactg cgcgcggggt tctttcatcc ggtcaccggc 2160
tattcgctgc cctatgcggc acaggtggcg gacgtggtgg cgggtctgtc cgggccgccc 2220
ggcaccgacg cgctgcgcgg cgccatccgc gattacgcga tcgaccgggc gcgccgcgac 2280
cgctttctgc gccttttgaa ccggatgctg ttccgcggct gcgcgcccga ccggcgctat 2340
accctgctgc agcggttcta ccgcatgccg catggactga tcgaacggtt ctatgccggc 2400
cggctgagcg tggcggatca gctgcgcatc gtgaccggca agcctcccat tccccttggc 2460
acggccatcc gctgcctgcc cgaacgtccc ctgctgaagg aaaacgcatg aacgcccatt 2520
cgcccgcggc caagaccgcc atcgtgatcg gcgcaggctt tggcgggctg gccctggcca 2580
tccgcctgca gtccgcgggc atcgccacca ccctggtcga ggcccgggac aagcccggcg 2640
ggcgcgccta tgtctggcac gatcagggcc atctcttcga cgcgggcccg accgtcatca 2700
ccgaccccga tgcgctgaaa gagctgtggg ccctgaccgg gcaggacatg gcgcgcgacg 2760
tgacgctgat gccggtctcg cccttctatc ggctgatgtg gccgggcggg aaggtcttcg 2820
attacgtgaa cgaggccgat cagctggaac gccagatcgc ccagttcaac ccggacgacc 2880
tggagggata ccgccgcttc cgtgattacg ctgaggaggt gtaccaggag ggctacgtca 2940
agctgggcac cgtgcccttc ctcaagctgg gccagatgct caaggccgcg cccgcgctga 3000
tgaagttgga ggcctacaag tcggtccatg ccaaggtcgc gaccttcatc aaggacccct 3060
atctgcggca ggcgttttcg tatcacacgc tgctggtggg cgggaatccc ttctcgacca 3120
gctcgatcta tgcgctgaac cacgcgctgg agcggcgcgg cggggtctgg ttcgccaagg 3180
gcggcaccaa ccagctggtt gcgggcatgg tcgcgctgtt cgaacggctt ggcgggcaga 3240
tgctgctaaa cgccaaggtc gcgcggatcg acacggacgg gccgcgcgcg accggcgtga 3300
ccctggccga cgggcgcgcc ttgaccgccg acatggtcgc cagcaacggc gacgtgatgc 3360
acaactatcg cgacctgctg ggccataccg cccgcgggca gagccgggcg aaatcgctga 3420
acgcgaagcg ctggtccatg tcgctcttcg tgctgcattt cggcctgcgc gaggcgccca 3480
aggacgtggc gcatcacacc atcctgttcg gcccccgcta caaggagctg gtcaacgaga 3540
tcttcaaggg cccgaagctg gccgaggatt tctcgctcta tctgcattcg ccctgcacga 3600
ccgacccgga gatggcgcct ccgggcatgt ccacgcatta cgtcctggcc ccggtgccgc 3660
atctgggccg cgcggacatt gattgggcgg tcgaggggcc gcgctatgcc gaccgcatcc 3720
tggccagcct ggaggagcgg ctgatcccga acctgcgcgc caacctgacc acgacgcgca 3780
tcttcacccc gtccgatttc gccagcgaac tgaacgccca tcatggcagc gccttctcgg 3840
tcgagccgat cctgacgcaa tccgcgtggt tccggccgca caaccgcgac aagacgatcc 3900
gcaacttcta tctggtcggc gcgggcaccc atccgggcgc ggggattccg ggcgtcgtgg 3960
gctcggccaa ggccacggcc caggtgatgc tgtccgacct ggcgagcgca tgagcgatct 4020
ggtcctgacc tcgaccgagg cgatcaccca agggtcgcaa agctttgcca cggcggccaa 4080
gctgatgccg ccgggcatcc gcgacgacac ggtgatgctc tatgcctggt gccgccacgc 4140
ggatgacgtg atcgacggtc aggccctggg cagctgcccc gaggcggtga acgacccgca 4200
ggcgcggctg gacggcctgc gcgccgacac gctggccgcg ttgcagggcg acggtccggt 4260
gaccccgccc tttgcctgcg cggtggcgcg gcggcatgat tttccgcagg cctggcccat 4320
ggacctgatc gaaggctttg cgatggatgt cgaggcgcgc gactatcgca cgctggacga 4380
cgtgctggaa tattcctatc acgtcgcggg catcgtcggc gtgatgatgg cccgtgtgat 4440
gggcgtgcgc gacgatcctg tcctggaccg tgcctgcgac ctggggctgg cgttccagct 4500
gaccaacatc gcgcgcgacg tgatcgacga cgcgcgcatc gggcggtgct atctgccagg 4560
cgactggctg gatcaggcgg gcgcgcgggt cgacgggccg gtgccgtcgc cggagctgta 4620
caccgtgatc ctgcgcctgc tggatgcggc tgaactctat tacgcgtcgg cgcgggtggg 4680
tctggcggat ctgccgccgc gctgcgcctg gtccatcgcc gccgcgttgc ggatctatcg 4740
cgccatcggg ctgcgcatcc gcaagggcgg gccggaggcc tatcgccagc ggatcagcac 4800
gtccaaggcc gccaagatcg ggctgctggg catcgggggc tgggatgtcg ccgatcacgc 4860
ctgccggggg cggcgtgtcg cgacaggcct ctggacccgg ccgcatcacg cctaggcgcg 4920
cgcggcgtag ggcagaaccc gttccagcag ggccgcgatt tccggagcct gaaggcgctt 4980
gctgcgcagc atcgcgtcca gctgggcgcg gctggcctca tagtggcggg acacgttctg 5040
caggtctgac acggccagaa ggccgcgccg cgggtcgggg gccgcggcat cgcgaccggt 5100
atccttgcca agcgccgcct ggtcgcccac gacgtccagc aggtcgtcat aggactggaa 5160
cacccggccc agctgacggc caaagtcgat catctgggtc tgctcctcgg cgtcgaactc 5220
cttgatcacg gccagcatct ccagcccggc gatgaacagc acgccggtct tcaggtcctg 5280
ttcctgttcg acccccgcgc cgttcttggc cgcgtgcagg tccaggtcct ggccggcgca 5340
caggccctgc ggccccaggg accgcgacag gatcccg 5377
<210>9
<211>1416
<212>DNA
<213>Paracoccus sp.
<400>9
gcggatccgg cgaccttgcg gcgctgcgcc gcgcgccttt gctggtgcct gggccgggtg 60
gccaatggtc gcaagcaacg gggatggaaa ccggcgatgc gggactgtag tctgcgcgga 120
tcgccggtcc gggggacaag atgagcgcac atgccctgcc caaggcagat ctgaccgcca 180
ccagcctgat cgtctcgggc ggcatcatcg ccgcttggct ggccctgcat gtgcatgcgc 240
tgtggtttct ggacgcagcg gcgcatccca tcctggcgat cgcaaatttc ctggggctga 300
cctggctgtc ggtcggattg ttcatcatcg cgcatgacgc gatgcacggg tcggtggtgc 360
cggggcgtcc gcgcgccaat gcggcgatgg gccagcttgt cctgtggctg tatgccggat 420
tttcgtggcg caagatgatc gtcaagcaca tggcccatca ccgccatgcc ggaaccgacg 480
acgaccccga tttcgaccat ggcggcccgg tccgctggta cgcccgcttc atcggcacct 540
atttcggctg gcgcgagggg ctgctgctgc ccgtcatcgt gacggtctat gcgctgatcc 600
ttggggatcg ctggatgtac gtggtcttct ggccgctgcc gtcgatcctg gcgtcgatcc 660
agctgttcgt gttcggcacc tggctgccgc accgccccgg ccacgacgcg ttcccggacc 720
gccacaatgc gcggtcgtcg cggatcagcg accccgtgtc gctgctgacc tgctttcact 780
ttggcggtta tcatcacgaa caccacctgc acccgacggt gccgtggtgg cgcctgccca 840
gcacccgcac caagggggac accgcatgac caatttcctg atcgtcgtcg ccaccgtgct 900
ggtgatggag ttgacggcct attccgtcca ccgctggatc atgcacggcc ccctgggctg 960
gggctggcac aagtcccacc acgaggaaca cgaccacgcg ctggaaaaga acgacctgta 1020
cggcctggtc tttgcggtga tcgccacggt gctgttcacg gtgggctgga tctgggcgcc 1080
ggtcctgtgg tggatcgcct tgggcatgac tgtctatggg ctgatctatt tcgtcctgca 1140
tgacgggctg gtgcatcagc gctggccgtt ccgttatatc ccgcgcaagg gctatgccag 1200
acgcctgtat caggcccacc gcctgcacca tgcggtcgag gggcgcgacc attgcgtcag 1260
cttcggcttc atctatgcgc ccccggtcga caagctgaag caggacctga agatgtcggg 1320
cgtgctgcgg gccgaggcgc aggagcgcac gtgacccatg acgtgctgct ggcaggggcg 1380
ggccttgcca acgggctgat cgccctgcgg atcccg 1416
<210>10
<211>1210
<212>DNA
<213>Paracoccus sp.
<400>10
ctagtctaga tgcttgacaa tccgggtgac gcggccgacc tgcgccgcgc cgcgcgccgg 60
acgatcctgg ccgatcatga tgcggcgcgg gtgtttccgg ccaaggatgc ctggctgcgc 120
gcggccatcg gcgcgccggt ccactgacct tgttggacaa attgccgcgc gaccccgcgt 180
cgccgtcgaa aaggctcgca atcgggcgtg aaccgttcca acatggggac tgttgacggt 240
ggatgacggg tcacggggtg ccgccccggc ctgaccttcc cgccaggtca gaaccccagc 300
gcgagggcac tgatgagacg agacgtcaac ccgatccacg ccacccttct gcagaccaga 360
cttgaggaga tcgcccaggg attcggtgcc gtgtcgcagc cgctcggcgc ggccatgagc 420
catggcgcgc tgtcgtcggg caagcggttc cgcggcatgc tgatgctgct tgcggcagag 480
gcctcgggcg gggtctgcga cacgatcgtc gacgccgcct gcgcggtcga gatggtgcat 540
gccgcatcgc tgatcttcga cgacctgccc tgcatggacg atgccgggct gcgccgcggc 600
cagtccgcga cccatgtggc gcatggcgaa agccgcgccg tgctgggcgg catcgccctg 660
atcaccgagg cgatggccct gctggccggt gcgcgcggcg cgtcgggcac ggggcgggcg 720
cagctggtgc ggatcctgtc gcggtccctg gggccgcagg gcctgtgcgc cggccaggac 780
ctggacctgc acgcggccaa gaacggcgcg ggggtcgaac aggaacagga cctgaagacc 840
ggcgtgctgt tcatcgccgg gctggagacg ctggccgtga tcaaggagtt cgacgccgag 900
gagcagaccc agatgatcga ctttggccgt cagctgggcc gggtgttcca gtcctatgac 960
gacctgctgg acgtcgtggg cgaccaggcg gcgcttggca aggataccgg tcgcgatgcc 1020
gcggcccccg gcccgcggcg cggccttctg gccgtgtcag acctgcagaa cgtgtcccgc 1080
cactatgagg ccagccgcgc ccagctggac gcgatgctgc gcagcaagcg ccttcaggct 1140
ccggaaatcg cggccctgct ggaacgggtt ctgccctacg ccgcgcgcgc ctaggcgtga 1200
tgagctccca 1210
<210>11
<211>1086
<212>DNA
<213>Paracoccus sp.
<400>11
ctagtctaga gccggtccac tgaccttgtt ggacaaattg ccgcgcgacc ccgcgtcgcc 60
gtcgaaaagg ctcgcaatcg ggcgtgaacc gttccaacat ggggactgtt gacggtggat 120
gacgggtcac ggggtgccgc cccggcctga ccttcccgcc aggtcagaac cccagcgcga 180
gggcactgat gagacgagac gtcaacccga tccacgccac ccttctgcag accagacttg 240
aggagatcgc ccagggattc ggtgccgtgt cgcagccgct cggcgcggcc atgagccatg 300
gcgcgctgtc gtcgggcaag cggttccgcg gcatgctgat gctgcttgcg gcagaggcct 360
cgggcggggt ctgcgacacg atcgtcgacg ccgcctgcgc ggtcgagatg gtgcatgccg 420
catcgctgat cttcgacgac ctgccctgca tggacgatgc cgggctgcgc cgcggccagt 480
ccgcgaccca tgtggcgcat ggcgaaagcc gcgccgtgct gggcggcatc gccctgatca 540
ccgaggcgat ggccctgctg gccggtgcgc gcggcgcgtc gggcacgggg cgggcgcagc 600
tggtgcggat cctgtcgcgg tccctggggc cgcagggcct gtgcgccggc caggacctgg 660
acctgcacgc ggccaagaac ggcgcggggg tcgaacagga acaggacctg aagaccggcg 720
tgctgttcat cgccgggctg gagacgctgg ccgtgatcaa ggagttcgac gccgaggagc 780
agacccagat gatcgacttt ggccgtcagc tgggccgggt gttccagtcc tatgacgacc 840
tgctggacgt cgtgggcgac caggcggcgc ttggcaagga taccggtcgc gatgccgcgg 900
cccccggccc gcggcgcggc cttctggccg tgtcagacct gcagaacgtg tcccgccact 960
atgaggccag ccgcgcccag ctggacgcga tgctgcgcag caagcgcctt caggctccgg 1020
aaatcgcggc cctgctggaa cgggttctgc cctacgccgc gcgcgcctag gcgtgatgag 1080
ctccca 1086
<210>12
<211>6572
<212>DNA
<213>Paracoccus sp.
<400>12
ctgtcgcggt ccctggggcc gcagggcctg tgcgccggcc aggacctgga cctgcacgcg 60
gccaagaacg gcgcgggggt cgaacaggaa caggacctga agaccggcgt gctgttcatc 120
gccgggctgg agatgctggc cgtgatcaag gagttcgacg ccgaggagca gacccagatg 180
atcgactttg gccgtcagct gggccgggtg ttccagtcct atgacgacct gctggacgtc 240
gtgggcgacc aggcggcgct tggcaaggat accggtcgcg atgccgcggc ccccgacccg 300
cggcgcggcc ttctggccgt gtcagacctg cagaacgtgt cccgccacta tgaggccagc 360
cgcgcccagc tggacgcgat gctgcgcagc aagcgccttc aggctccgga aatcgcggcc 420
ctgctggaac gggttctgcc ctacgccgcg cgcgcctagg cgtgatgcgg ccgggtccag 480
aggcctgtcg cgacacgccg cccccggcag gcgtgatcgg cgacatccca gcccccgatg 540
cccagcagcc cgatcttggc ggccttggac gtgctgatcc gctggcgata ggcctccggc 600
ccgcccttgc ggatgcgcag cccgatggcg cgatagatcc gcaacgcggc ggcgatggac 660
caggcgcagc gcggcggcag atccgccaga cccacccgcg ccgacgcgta atagagttca 720
gccgcatcca gcaggcgcag gatcacggtg tacagctccg gcgacggcac cggcccgtcg 780
acccgcgcgc ccgcctgatc cagccagtcg cctggcagat agcaccgccc gatgcgcgcg 840
tcgtcgatca cgtcgcgcgc gatgttggtc agctggaacg ccagccccag gtcgcaggca 900
cggtccagga caggatcgtc gcgcacgccc atcacacggg ccatcatcac gccgacgatg 960
cccgcgacgt gataggaata ttccagcacg tcgtccagcg tgcgatagtc gcgcgcctcg 1020
acatccatcg caaagccttc gatcaggtcc atgggccagg cctgcggaaa atcatgccgc 1080
cgcgccaccg cgcaggcaaa gggcggggtc accggaccgt cgccctgcaa cgcggccagc 1140
gtgtcggcgc gcaggccgtc cagccgcgcc tgcgggtcgt tcaccgcctc ggggcagctg 1200
cccagggcct gaccgtcgat cacgtcatcc gcgtggcggc accaggcata gagcatcacc 1260
gtgtcgtcgc ggatgcccgg cggcatcagc ttggccgccg tggcaaagct ttgcgaccct 1320
tgggtgatcg cctcggtcga ggtcaggacc agatcgctca tgcgctcgcc aggtcggaca 1380
gcatcacctg ggccgtggcc ttggccgagc ccacgacgcc cggaatcccc gcgcccggat 1440
gggtgcccgc gccgaccaga tagaagttgc ggatcgtctt gtcgcggttg tgcggccgga 1500
accacgcgga ttgcgtcagg atcggctcga ccgagaaggc gctgccatga tgggcgttca 1560
gttcgctggc gaaatcggac ggggtgaaga tgcgcgtcgt ggtcaggttg gcgcgcaggt 1620
tcgggatcag ccgctcctcc aggctggcca ggatgcggtc ggcatagcgc ggcccctcga 1680
ccgcccaatc aatgtccgcg cggcccagat gcggcaccgg ggccaggacg taatgcgtgg 1740
acatgcccgg aggcgccatc tccgggtcgg tcgtgcaggg cgaatgcaga tagagcgaga 1800
aatcctcggc cagcttcggg cccttgaaga tctcgttgac cagctccttg tagcgggggc 1860
cgaacaggat ggtgtgatgc gccacgtcct tgggcgcctc gcgcaggccg aaatgcagca 1920
cgaagagcga catggaccag cgcttcgcgt tcagcgattt cgcccggctc tgcccgcggg 1980
cggtatggcc cagcaggtcg cgatagttgt gcatcacgtc gccgttgctg gcgaccatgt 2040
cggcggtcaa ggcgcgcccg tcggccaggg tcacgccggt cgcgcgcggc ccgtccgtgt 2100
cgatccgcgc gaccttggcg tttagcagca tctgcccgcc aagccgttcg aacagcgcga 2160
ccatgcccgc aaccagctgg ttggtgccgc ccttggcgaa ccagaccccg ccgcgccgct 2220
ccagcgcgtg gttcagcgca tagatcgagc tggtcgagaa gggattcccg cccaccagca 2280
gcgtgtgata cgaaaacgcc tgccgcagat aggggtcctt gatgaaggtc gcgaccttgg 2340
catggaccga cttgtaggcc tccaacttca tcagcgcggg cgcggccttg agcatctggc 2400
ccagcttgag gaagggcacg gtgcccagct tgacgtagcc ctcctggtac acctcctcag 2460
cgtaatcacg gaagcggcgg tatccctcca ggtcgtccgg gttgaactgg gcgatctggc 2520
gttccagctg atcggcctcg ttcacgtaat cgaagacctt cccgcccggc cacatcagcc 2580
gatagaaggg cgagaccggc atcagcgtca cgtcgcgcgc catgtcctgc ccggtcaggg 2640
cccacagctc tttcagcgca tcggggtcgg tgatgacggt cgggcccgcg tcgaagagat 2700
ggccctgatc gtgccagaca taggcgcgcc cgccgggctt gtcccgggcc tcgaccaggg 2760
tggtggcgat gcccgcggac tgcaggcgga tggccagggc cagcccgcca aagcctgcgc 2820
cgatcacgat ggcggtcttg gccgcgggcg aatgggcgtt catgcgtttt ccttcagcag 2880
gggacgttcg ggcaggcagc ggatggccgt gccaagggga atgggaggct tgccggtcac 2940
gatgcgcagc tgatccgcca cgctcagccg gccggcatag aaccgttcga tcagtccatg 3000
cggcatgcgg tagaaccgct gcagcagggt atagcgccgg tcgggcgcgc agccgcggaa 3060
cagcatccgg ttcaaaaggc gcagaaagcg gtcgcggcgc gcccggtcga tcgcgtaatc 3120
gcggatggcg ccgcgcagcg cgtcggtgcc gggcggcccg gacagacccg ccaccacgtc 3180
cgccacctgt gccgcatagg gcagcgaata gccggtgacc ggatgaaaga accccgcgcg 3240
cagtcccacg ggaacaggcc ccgccgcgtg atcggcccag aagcccgccg catcatgggc 3300
cagcgcgatg ggaaggatgc cgcgttcgcg ccggacctcg gccccggtcc agccctgctg 3360
gcgggcatag tcgtgggacg ccgccgccag cgcgtcgtcg tccagatcgc cgccatcgga 3420
atagcgcgtg tcctcgatca ggatgcgcgt cggagagaag ggcagcagat agatgaagcg 3480
gtacccgtcc tgctgggtga cggtcgcgtc catgatcatc gggcggggca cgccgtgggg 3540
gcggtcggtc tcgatctcga cacccacgaa tttctggaaa cccacggtca gatgccgcga 3600
cggctgcgcg ccccgcccgt ccaggaccgc gcccgcctcg atccgggtgc cgcaggacag 3660
cgtcgccccc tgcgcatcca gcagggcgat gtcgctgtcc cagcggatct cggcgcccga 3720
ccggaccacc gcatccgcca gcgccgcccc gtccagcgac ccgtaaccgg tggccagccg 3780
ccgggcatgg cggggaaagc gcacctcctg gtcgggccag ttggcgcggc gcaggggctt 3840
cagccgcgcc agccagtccg gcgacaggtc ggggtcgtgg caggaccagg tgtggccgtc 3900
tgacggtcct gcggcatggt ccagcagcag cacgcgcagg tcgggccgcg ccgcgcgcag 3960
cgccagggcg atcagcccgt tggcaaggcc cgcccctgcc agcagcacgt catgggtcac 4020
gtgcgctcct gcgcctcggc ccgcagcacg cccgacatct tcaggtcctg cttcagcttg 4080
tcgaccgggg gcgcatagat gaagccgaag ctgacgcaat ggtcgcgccc ctcgaccgca 4140
tggtgcaggc ggtgggcctg atacaggcgt ctggcatagc ccttgcgcgg gatataacgg 4200
aacggccagc gctgatgcac cagcccgtca tgcaggacga aatagatcag cccatagaca 4260
gtcatgccca aggcgatcca ccacaggacc ggcgcccaga tccagcccac cgtgaacagc 4320
accgtggcga tcaccgcaaa gaccaggccg tacaggtcgt tcttttccag cgcgtggtcg 4380
tgttcctcgt ggtgggactt gtgccagccc cagcccaggg ggccgtgcat gatccagcgg 4440
tggacggaat aggccgtcaa ctccatcacc agcacggtgg cgacgacgat caggaaattg 4500
gtcatgcggt gtcccccttg gtgcgggtgc tgggcaggcg ccaccacggc accgtcgggt 4560
gcaggtggtg ttcgtgatga taaccgccaa agtgaaagca ggtcagcagc gacacggggt 4620
cgctgatccg cgacgaccgc gcattgtggc ggtccgggaa cgcgtcgtgg ccggggcggt 4680
gcggcagcca ggtgccgaac acgaacagct ggatcgacgc caggatcgac ggcagcggcc 4740
agaagaccac gtacatccag cgatccccaa ggatcagcgc atagaccgtc acgatgacgg 4800
gcagcagcag cccctcgcgc cagccgaaat aggtgccgat gaagcgggcg taccagcgga 4860
ccgggccgcc atggtcgaaa tcggggtcgt cgtcggttcc ggcatggcgg tgatgggcca 4920
tgtgcttgac gatcatcttg cgccacgaaa atccggcata cagccacagg acaagctggc 4980
ccatcgccgc attggcgcgc ggacgccccg gcaccaccga cccgtgcatc gcgtcatgcg 5040
cgatgatgaa caatccgacc gacagccagg tcagccccag gaaatttgcg atcgccagga 5100
tgggatgcgc cgctgcgtcc agaaaccaca gcgcatgcac atgcagggcc agccaagcgg 5160
cgatgatgcc gcccgagacg atcaggctgg tggcggtcag atctgccttg ggcagggcat 5220
gtgcgctcat cttgtccccc ggaccggcga tccgcgcaga ctacagtccc gcatcgccgg 5280
tttccatccc cgttgcttgc gaccattggc cacccggccc aggcaccagc aaaggcgcgc 5340
ggcgcagcgc cgcaaggtcg ccggatccta gatgcttgac aatccgggtg acgcggccga 5400
cctgcgccgc gccgcgcgcc ggacgatcct ggccgatcat gatgcggcgc gggtgtttcc 5460
ggccaaggat gcctggctgc gcgcggccat cggcgcgccg gtccactgac cttgttggac 5520
aaattgccgc gcgaccccgc gtcgccgtcg aaaaggctcg caatcgggcg tgaaccgttc 5580
caacatgggg actgttgacg gtggatgacg ggtcacgggg tgccgccccg gcctgacctt 5640
cccgccaggt cagaacccca gcgcgagggc actgatgaga cgagacgtca acccgatcca 5700
cgccaccctt ctgcagacca gacttgagga gatcgcccag ggattcggtg ccgtgtcgca 5760
gccgctcggc gcggccatga gccatggcgc gctgtcgtcg ggcaagcggt tccgcggcat 5820
gctgatgctg cttgcggcag aggcctcggg cggggtctgc gacacgatcg tcgacgccgc 5880
ctgcgcggtc gagatggtgc atgccgcatc gctgatcttc gacgacctgc cctgcatgga 5940
cgatgccggg ctgcgccgcg gccagtccgc gacccatgtg gcgcatggcg aaagccgcgc 6000
cgtgctgggc ggcatcgccc tgatcaccga ggcgatggcc ctgctggccg gtgcgcgcgg 6060
cgcgtcgggc acggggcggg cgcagctggt gcggatcctg tcgcggtccc tggggccgca 6120
gggcctgtgc gccggccagg acctggacct gcacgcggcc aagaacggcg cgggggtcga 6180
acaggaacag gacctgaaga ccggcgtgct gttcatcgcc gggctggaga cgctggccgt 6240
gatcaaggag ttcgacgccg aggagcagac ccagatgatc gactttggcc gtcagctggg 6300
ccgggtgttc cagtcctatg acgacctgct ggacgtcgtg ggcgaccagg cggcgcttgg 6360
caaggatacc ggtcgcgatg ccgcggcccc cggcccgcgg cgcggccttc tggccgtgtc 6420
agacctgcag aacgtgtccc gccactatga ggccagccgc gcccagctgg acgcgatgct 6480
gcgcagcaag cgccttcagg ctccggaaat cgcggccctg ctggaacggg ttctgcccta 6540
cgccgcgcgc gcctaggcgt gatgagctcc ca 6572
<210>13
<211>26
<212>DNA
<213>Artificial sequence
<220>
<223>primer
<400>13
gcggatccgg cgaccttgcg gcgctg 26
<210>14
<211>25
<212>DNA
<213>Artificial Sequence
<220>
<223>primer
<400>14
cgggatcctg tcgcggtccc tgggg 25
<210>15
<211>32
<212>DNA
<213>Artificial Sequence
<220>
<223>primer
<400>15
cggaattcag ggcgatcagc ccgttggcaa gg 32
<210>16
<211>33
<212>DNA
<213>Artificial Sequence
<220>
<223>primer
<400>16
ctagtcagat gcttgacaat ccgggtgacg cgg 33
<210>17
<211>35
<212>DNA
<213>Artificial Sequence
<220>
<223>primer
<400>17
tgggagctca tcacgcctag gcgcgcgcgg cgtag 35
<210>18
<211>33
<212>DNA
<213>Artificial Sequence
<220>
<223>primer
<400>18
ctagtcagag ccggtccact gacctggttg gac 33
<210>19
<211>138
<212>DNA
<213>Paracoccus sp.
<400>19
ggatccggcg accttgcggc gctgcgccgc gcgcctttgc tggtgcctgg gccgggtggc 60
caatggtcgc aagcaacggg gatggaaacc ggcgatgcgg gactgtagtc tgcgcggatc 120
gccggtccgg gggacaag 138
<210>20
<211>302
<212>DNA
<213>Paracoccus sp.
<400>20
tgcttgacaa tccgggtgac gcggccgacc tgcgccgcgc cgcgcgccgg acgatcctgg 60
ccgatcatga tgcggcgcgg gtgtttccgg ccaaggatgc ctggctgcgc gcggccatcg 120
gcgcgccggt ccactgacct tgttggacaa attgccgcgc gaccccgcgt cgccgtcgaa 180
aaggctcgca atcgggcgtg aaccgttcca acatggggac tgttgacggt ggatgacggg 240
tcacggggtg ccgccccggc ctgaccttcc cgccaggtca gaaccccagc gcgagggcac 300
tg 302
<210>21
<211>178
<212>DNA
<213>Paracoccus sp.
<400>21
gccggtccac tgaccttgtt ggacaaattg ccgcgcgacc ccgcgtcgcc gtcgaaaagg 60
ctcgcaatcg ggcgtgaacc gttccaacat ggggactgtt gacggtggat gacgggtcac 120
ggggtgccgc cccggcctga ccttcccgcc aggtcagaac cccagcgcga gggcactg 178
<210>22
<211>34
<212>DNA
<213>Artificial Sequence
<220>
<223>synnthetic construct
<400>22
tcatctagag gtaccatatg aagcttgagc tcct 34
<210>23
<211>29
<212>DNA
<213>Artificial Sequence
<220>
<223>synthetic construct
<400>23
gagctcaagc ttcatatggt acctctaga 29
<210>24
<211>1360
<212>DNA
<213>Paracoccus sp.
<400>24
cgagcgagac cttcgggtct agcggcggac gggtgagtaa cgcgtgggaa cgtgcccttc 60
tctacggaat agccccggga aactgggagt aataccgtat acgccctttg ggggaaagat 120
ttatcggaga aggatcggcc cgcgttggat taggtagttg gtggggtaat ggcccaccaa 180
gccgacgatc catagctggt ttgagaggat gatcagccac actgggactg agacacggcc 240
cagactccta cgggaggcag cagtggggaa tcttagacaa tgggggcaac cctgatctag 300
ccatgccgcg tgagtgatga aggccttagg gttgtaaagc tctttcagct gggaagataa 360
tgacggtacc agcagaagaa gccccggcta actccgtgcc agcagccgcg gtaatacgga 420
gggggctagc gttgttcgga attactgggc gtaaagcgca cgtaggcgga ctggaaagtc 480
agaggtgaaa tcccagggct caaccttgga actgcctttg aaactatcag tctggagttc 540
gagagaggtg agtggaattc cgagtgtaga ggtgaaattc gtagatattc ggaggaacac 600
cagtggcgaa ggcggctcac tggctcgata ctgacgctga ggtgcgaaag cgtggggagc 660
aaacaggat tagataccctg gtagtccacg ccgtaaacga tgaatgccag acgtcggcaa 720
gcatgcttgt cggtgtcaca cctaacggat taagcattcc gcctggggag tacggtcgca 780
agattaaaac tcaaaggaat tgacgggggc ccgcacaagc ggtggagcat gtggtttaat 840
tcgaagcaac gcgcagaacc ttaccaaccc ttgacatggc aggaccgctg gagagattca 900
gctttctcgt aagagacctg cacacaggtg ctgcatggct gtcgtcagct cgtgtcgtga 960
gatgttcggt taagtccggc aacgagcgca acccacgtcc ctagttgcca gcattcagtt 1020
gggcactcta tggaaactgc cgatgataag tcggaggaag gtgtggatga cgtcaagtcc 1080
tcatggccct tacgggttgg gctacacacg tgctacaatg gtggtgacag tgggttaatc 1140
cccaaaagcc atctcagttc ggattgtcct ctgcaactcg agggcatgaa gttggaatcg 1200
ctagtaatcg cggaacagca tgccgcggtg aatacgttcc cgggccttgt acacaccgcc 1260
cgtcacacca tgggagttgg ttctacccga cgacgctgcg ctaaccttcg gggggcaggc 1320
ggccacggta ggatcagcga ctggggtgaa gtcgtaacaa 1360
Claims (5)
1.连续的寡核苷酸,特征在于所述寡核苷酸由编码SEQ ID NO:2所示、具有副球菌(Paracoccus sp.)菌株MBIC1143的将β-芷香酮环4位的亚甲基转化为酮基的酶活性的多肽的DNA链crtW和SEQ ID NO:19所示的在海洋细菌中具有启动子活性的DNA链组成。
2.质粒载体,其包含根据权利要求1所述的寡核苷酸。
3.经权利要求2所述的质粒载体转化的细胞。
4.制备类胡萝卜素的方法,特征在于:
在能够表达由权利要求2所述质粒载体的DNA链序列编码的多肽的条件下培养权利要求3的细胞。
5.根据权利要求4的方法,特征在于所述类胡萝卜素是虾青素。
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JP5706056B2 (ja) * | 2006-10-17 | 2015-04-22 | Jx日鉱日石エネルギー株式会社 | サケ類の肉色改善方法 |
JP5645840B2 (ja) | 2008-12-02 | 2014-12-24 | 株式会社Wave Life Sciences Japan | リン原子修飾核酸の合成方法 |
CN101768593B (zh) * | 2009-01-06 | 2013-01-30 | 上海市农业科学院 | 副球菌虾青素合成操纵子及其表达载体与应用 |
CN102596204B (zh) | 2009-07-06 | 2016-11-23 | 波涛生命科学有限公司 | 新的核酸前药及其使用方法 |
EP2620428B1 (en) | 2010-09-24 | 2019-05-22 | Wave Life Sciences Ltd. | Asymmetric auxiliary group |
JP6128529B2 (ja) | 2011-07-19 | 2017-05-17 | ウェイブ ライフ サイエンシズ リミテッドWave Life Sciences Ltd. | 官能化核酸の合成のための方法 |
WO2014012081A2 (en) | 2012-07-13 | 2014-01-16 | Ontorii, Inc. | Chiral control |
AU2013287630B2 (en) | 2012-07-13 | 2017-05-25 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
PL2872485T3 (pl) | 2012-07-13 | 2021-05-31 | Wave Life Sciences Ltd. | Asymetryczna grupa pomocnicza |
CN103087972B (zh) * | 2013-02-01 | 2014-11-05 | 中国科学院天津工业生物技术研究所 | 生产萜类化合物的重组微生物及构建方法 |
EP3095460A4 (en) | 2014-01-15 | 2017-08-23 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent |
WO2015108047A1 (ja) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤 |
JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
US10160969B2 (en) | 2014-01-16 | 2018-12-25 | Wave Life Sciences Ltd. | Chiral design |
CN103805623B (zh) * | 2014-01-17 | 2016-02-03 | 河北大学 | 一种虾青素合成基因重组质粒及其制备方法和用途 |
PL231220B1 (pl) * | 2014-03-12 | 2019-02-28 | Univ Warszawski | Plazmid będący pochodnym plazmidu pAMI2 z Paracoccus aminophilus JCM 7686 obejmujący funkcjonalne geny crt z Paracoccus marcusii OS22, zapewniające zdolność do wytwarzania karotenoidów i sekwencję przedstawioną na SEKW NR ID: 1, nowe szczepy bakteryjne, ich zastosowania, sposoby wytwarzania nowych szczepów bakteryjnych zdolnych do syntezy karotenoidów oraz sposoby wytwarzania karotenoidów |
WO2016154314A1 (en) * | 2015-03-23 | 2016-09-29 | Arch Innotek, Llc | Compositions and methods of biosynthesizing carotenoids and their derivatives |
KR20170068304A (ko) * | 2015-12-09 | 2017-06-19 | 삼성전자주식회사 | 대장균 및 코마가타에이박터 속 세포에서 복제가능한 벡터, 그를 포함한 세포, 및 그를 이용하는 방법 |
CN111032855A (zh) * | 2017-06-01 | 2020-04-17 | 尼普生物股份有限公司 | 微生物体中异源类胡萝卜素的产生 |
CN107418968A (zh) * | 2017-06-02 | 2017-12-01 | 湖北大学 | 一种利用烟草质体高效生产虾青素的方法 |
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EP1942185A1 (en) | 2008-07-09 |
CN101466834A (zh) | 2009-06-24 |
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EP1942185A4 (en) | 2009-11-25 |
NO20081833L (no) | 2008-07-23 |
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