CN117106742A - 来源于粉防己的一个甲基转移酶及其在制备异汉防己甲素中的应用 - Google Patents
来源于粉防己的一个甲基转移酶及其在制备异汉防己甲素中的应用 Download PDFInfo
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- CN117106742A CN117106742A CN202210528066.2A CN202210528066A CN117106742A CN 117106742 A CN117106742 A CN 117106742A CN 202210528066 A CN202210528066 A CN 202210528066A CN 117106742 A CN117106742 A CN 117106742A
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Abstract
本发明公开了来源于粉防己的一个甲基转移酶及其在制备异汉防己甲素中的应用。本发明所要保护的一个技术方案是蛋白质相关的生物材料和蛋白质在作为甲基转移酶或在制备双苄基异喹啉生物碱中的应用。所述蛋白质的氨基酸序列可为序列表中序列2或序列3。实验证明,将甲基转移酶BOMT进行克隆和表达载体构建并进行表达和纯化得到重组甲基转移酶BOMT,该酶可以以AdoMet为甲基供体,催化小檗胺(Berbamine)的羟基发生甲基化,生成异汉防己甲素(Isotetrandrine)。该甲基转移酶BOMT可用于BIA工程菌的构建。
Description
技术领域
本发明涉及生物技术领域,具体涉及来源于粉防己的一个甲基转移酶及其在制备异汉防己甲素中的应用。
背景技术
次生代谢产物是药用植物生物活性成分的主要来源。近年来,组学技术的快速发展为药用植物次生代谢产物生物合成相关基因的挖掘与鉴定奠定了前期研究基础。次生代谢产物合成相关基因的克隆与功能验证为天然产物的代谢工程和合成生物学研究提供必需的生物元件,同时也为药用植物选种育种及品种改良提供参考。
粉防己(Stephania tetrandra S.Moore)为防己科千金藤属多年生藤本植物,其根部是中药防己的植物来源,具有祛风止痛,利水消肿等功效。目前,从防己中共分离鉴定出的化合物类型主要包括:生物碱类、甾体类和黄酮类。其中,生物碱类化合物含量丰富,骨架众多,药理活性显著,一直是中药防己药效物质基础研究的重要方向。对粉防己中分离得到的生物碱类化合物进行研究总结,发现其主要为双苄基异喹啉生物碱(Bisbenzylisoquinoline alkaloid,BBIQ),如汉防己甲素(Tetrandrine)、异汉防己甲素(Isotetrandrine)、防己诺林碱(Fangchinoline)、小檗胺(Berbamine)等。
研究表明,粉防己中BBIQ生物合成的上游途径与吗啡等其他苄基异喹啉类生物碱的上游途径一致,是从酪氨酸开始,经过脱羧酶、羟化酶、转氨酶、去甲乌药碱合酶、去甲乌药碱-6-O-甲基转移酶及乌药碱-N-甲基转移酶的催化形成中间体化合物N-甲基乌药碱。根据结构推测,两分子N-甲基乌药碱经过头-头和尾-尾的C-O耦合形成BBIQ的基本骨架,再经过O-甲基化形成各种化合物。因此,O-甲基转移酶(OMT)是粉防己BBIQ生物合成的关键酶。
甲基转移酶是整个苄基异喹啉生物碱(Benzylisoquinoline alkaloid,BIA)生物合成途径中数量较多的一类酶,主要包括OMT和N-甲基转移酶(NMT)。它们有些具有高度的底物特异性,有些能够同时催化多个位置的甲基化。BIA生物合成途径中的所有的OMT都不需要金属离子作为辅助因子,它们依赖S-腺苷-L-甲硫氨酸(S-adenosyl-L-methionine,AdoMet)作为甲基供体。
发明内容
本发明所要解决的技术问题是如何获得催化生成异汉防己甲素的甲基转移酶。
为了解决上述技术问题,本发明首先提供了蛋白质相关的生物材料。所述蛋白质可为如下A1)、A2)、A3)或A4)的蛋白质:
A1)氨基酸序列是序列表中序列2的蛋白质。
A2)氨基酸序列是序列表中序列3的蛋白质。
A3)在A1)或A2)所示的蛋白质的羧基端或/和氨基端融合蛋白标签得到的融合蛋白。
A4)将A1)或A2)所示的蛋白质序列经过一个或几个氨基酸残基的取代和/或缺失和/或添加得到的且具有相同功能的由A1)或A2)衍生的或与A1)或A2)所示的蛋白质具有70%以上的同一性的蛋白质。
上述蛋白质可人工合成,也可先合成其编码基因,再进行生物表达得到。
上述蛋白质中,所述蛋白标签(protein-tag)是指利用DNA体外重组技术,与目的蛋白一起融合表达的一种多肽或者蛋白,以便于目的蛋白的表达、检测、示踪和/或纯化。所述蛋白标签可为Flag标签、His标签、MBP标签、HA标签、myc标签、GST标签和/或SUMO标签等。
上述蛋白质中,同一性是指氨基酸序列的同一性。可使用国际互联网上的同源性检索站点测定氨基酸序列的同一性,如NCBI主页网站的BLAST网页。例如,可在高级BLAST2.1中,通过使用blastp作为程序,将Expect值设置为10,将所有Filter设置为OFF,使用BLOSUM62作为Matrix,将Gap existence cost,Per residue gap cost和Lambda ratio分别设置为11,1和0.85(缺省值)并进行检索一对氨基酸序列的同一性进行计算,然后即可获得同一性的值(%)。
上述蛋白质中,所述70%以上的同一性可为至少71%、72%、75%、76%、78%、80%、81%、82%、85%、86%、88%、90%、91%、92%、95%、96%、98%、99%或100%的同一性。
上文所述生物材料可为下述B1)至B6)中的任一种:
B1)编码所述蛋白质的核酸分子;
B2)含有B1)所述核酸分子的表达盒;
B3)含有B1)所述核酸分子的重组载体、或含有B2)所述表达盒的重组载体;
B4)含有B1)所述核酸分子的重组微生物、或含有B2)所述表达盒的重组微生物、或含有B3)所述重组载体的重组微生物;
B5)促进或提高所述蛋白质表达的核酸分子;
B6)含有B5)所述核酸分子的表达盒、重组载体或重组微生物。
上文所述生物材料中,B1)所述核酸分子可为如下b1)b2)或b3)所示的所述蛋白质的编码基因:
b1)编码序列是序列表中序列1的第496-1602位核苷酸的cDNA分子或DNA分子。
b2)核苷酸是序列表中序列1的cDNA分子或DNA分子。
b3)与b2)限定的cDNA或DNA分子杂交且编码具有相同功能的蛋白质的cDNA分子或DNA分子。
上文所述的蛋白质也属于本发明的保护范围。
上述杂交可为在2×SSC,0.1%SDS的溶液中,在68℃下杂交并洗膜2次,每次5min,又于0.5×SSC,0.1%SDS的溶液中,在68℃下杂交并洗膜2次,每次15min;或,0.1×SSPE(或0.1×SSC)、0.1%SDS的溶液中,65℃条件下杂交并洗膜。
上述生物材料中,B2)所述的含有核酸分子的表达盒,是指能够在宿主细胞中表达上文所述蛋白质的DNA。所述表达盒还可包括表达上述任意一种蛋白的核酸分子所必需的所有调控序列的单链或双链核酸分子。所述调控序列在其相容条件下能指导编码序列在合适的宿主细胞中表达上述任一种蛋白质。所述调控序列包括,但不限于,前导序列、多聚腺苷酸化序列、前肽序列、启动子、信号序列和转录终止子。最低限度,调控序列要包括启动子以及转录和翻译的终止信号。为了导入载体的特定限制性酶位点以便将调控序列与编码蛋白质的核酸序列的编码区进行连接,可以提供带接头的调控序列。调控序列可以是合适的启动子序列,即可被表达核酸序列的宿主细胞识别的核酸序列。启动子序列含有介导蛋白质表达的转录调控序列。启动子可以是在所选宿主细胞中有转录活性的任何核酸序列,包括突变的、截短的和杂合的启动子,可以得自编码与宿主细胞同源或异源的胞外或胞内蛋白质的基因。调控序列还可以是合适的转录终止序列,即能被宿主细胞识别从而终止转录的一段序列。终止序列可操作连接在编码蛋白质的核酸序列的3’末端。在所选宿主细胞中可发挥功能的任何终止子都可以用于本发明。调控序列还可以是合适的前导序列,即对宿主细胞的翻译十分重要的mRNA非翻译区。前导序列可操作连接于编码蛋白质的核酸序列的5’末端。在所选宿主细胞中可发挥功能的任何前导序列均可用于本发明。调控序列还可以是信号肽编码区,该区编码一段连在蛋白质氨基端的氨基酸序列,能引导编码蛋白质进入细胞分泌途径。能引导表达后的蛋白质进入所用宿主细胞的分泌途径的信号肽编码区都可以用于本发明。添加能根据宿主细胞的生长情况来调节蛋白质表达的调控序列可能也是需要的。调控系统的例子是那些能对化学或物理刺激物(包括在有调控化合物的情况下)作出反应,从而开放或关闭基因表达的系统。调控序列的其他例子是那些能使基因扩增的调控序列。在这些例子中,应将编码蛋白质的核酸序列与调控序列可操作连接在一起。
为了解决上述技术问题,本发明还提供了蛋白质在作为甲基转移酶或在制备双苄基异喹啉生物碱中的应用,所述蛋白质为上文所述的蛋白质。
所述双苄基异喹啉生物碱可为异汉防己甲素(Isotetrandrine)。
为了解决上述技术问题,本发明还提供了上文所述的生物材料和/或上文所述的蛋白质相关的下述任一种产品:
P1、生产双苄基异喹啉生物碱的产品。
P2、制备异汉防己甲素的产品。
P3、制备催化小檗胺的羟基发生甲基化的产品。
P4、生产甲基转移酶BOMT的产品。
上文所述产品中,所述双苄基异喹啉生物碱可为异汉防己甲素。
为了解决上述技术问题,本发明还提供了上文所述的生物材料和/或上文所述的蛋白质的下述任一种应用:
Q1、上文所述的生物材料和/或上文所述的蛋白质在制备生产双苄基异喹啉生物碱的产品中的应用。
Q2、上文所述的生物材料和/或上文所述的蛋白质在制备异汉防己甲素的产品中的应用。
Q3、上文所述的生物材料和/或上文所述的蛋白质在制备催化小檗胺的羟基发生甲基化的产品中的应用。
Q4、上文所述的生物材料和/或上文所述的蛋白质在制备生产甲基转移酶BOMT中的应用。
为了解决上述技术问题,本发明还提供了一种制备上文所述蛋白质的方法。所述方法包括如下步骤:将上文所述蛋白质的编码基因在原核微生物中进行表达得到上文所述的蛋白质。
上文所述方法中,将上文所述蛋白质的编码基因在原核微生物中进行表达可包括将上文所述蛋白质的编码基因导入受体微生物,得到表达上文所述蛋白质的重组微生物,培养所述重组微生物,表达得到所述蛋白质。
上文所述方法中,所述表达可为诱导表达。
上文所述方法中,所述原核微生物可为大肠杆菌。
本发明通过基因的筛选、异源表达以及酶活性的体外检测等方法对粉防己的一个OMT进行了鉴定得到甲基转移酶(Berbamine O-Methyltransferase,BOMT),将该甲基转移酶BOMT进行克隆和表达载体构建得到重组甲基转移酶BOMT,该酶可以以AdoMet为甲基供体,催化小檗胺(Berbamine)的羟基发生甲基化,生成异汉防己甲素(Isotetrandrine)。该甲基转移酶BOMT可用于BIA工程菌的构建。
附图说明
图1为BOMT的PCR扩增电泳胶图。
图2为重组BOMT蛋白的SDS-PAGE电泳胶图。
图3为重组BOMT的酶促反应示意图。
图4为重组BOMT的酶促反应质谱图。上图为空载pET-32a(+)酶促反应质谱图;中图为重组BOMT蛋白酶促反应质谱图;下图为Berbamine标品质谱图。横坐标为时间,纵坐标为丰度。
图5为重组BOMT的酶促反应的产物鉴定图。上图为重组BOMT蛋白反应产物的二级碎片;下图为Berbamine标品二级碎片。横坐标为质荷比,纵坐标为丰度。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南,并不以任何方式构成对本发明的限制。
下述实施例中的实验方法,如无特殊说明,均为常规方法,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
本发明实施例中表达菌株来源为:
BL21(DE3)Chemically Competent Cell:北京全式金生物技术有限公司产品,货号CD601-02。
本发明实施例中表达载体来源为:
pET-32a(+)DNA:Invitrogen,货号69-015-3。
实施例一、BOMT基因克隆和载体构建
1.基因克隆
提取了粉防己根部总RNA,然后进行反转录成cDNA,采用高通量测序技术对cDNA进行转录组测序。利用BLAST的方法获得一条可能的OMT基因,根据该基因的碱基序列,设计一对引物(上游引物:5’-ATGGATTCCATTATTCGTGA-3’,下游引物:5’-TTATTTGAGAAATTCAATGA-3’),以粉防己根部cDNA为模板进行高保真PCR反应,PCR条件为:首先94℃预变性5min;然后98℃变性10sec,50℃退火15sec,72℃延伸12sec,40个循环,最后72℃延伸10min。PCR反应结束后将产物进行回收并亚克隆到克隆载体,经过测序分析,表明成功获得BOMT基因(图1)。该BOMT基因的CDS的核苷酸序列如序列表中序列1的第496-1602位所示,其编码的甲基转移酶BOMT的氨基酸序列如序列表中的序列2所示。
2.载体构建
根据BOMT基因编码序列,设计扩增完整开放阅读框的引物,并在上下游引物上分别加上限制性内切酶位点(BamHⅠ),上游引物为:5’-CATGGCTGATATCGGATCCATGGATTCCATTATTCGTGA-3’,下游引物为:5’-GGAGCTCGAATTCGGATCCTTATTTGAGAAATTCAATGA-3’。PCR反应条件为:首先94℃预变性5min;然后98℃变性10sec,50℃退火15sec,72℃延伸12sec,40个循环,最后72℃延伸10min。PCR扩增后,利用Gibson Assembly无缝拼接的方法将PCR产物连接到表达载体pET-32a(+)上得到重组载体BOMT-pET-32a,将重组载体BOMT-pET-32a转化到E.Coil Trans T1感受态细胞中,通过含有50μg/mL氨苄青霉素钠的固体LB培养基(配方:10%Tryptone,5%Yeast Extract,10%NaCl,15%Agar)筛选出阳性克隆菌株,再挑取阳性克隆菌株至含有50μg/mL氨苄青霉素钠的液体LB培养基(配方:10%Tryptone,5%YeastExtract,10%NaCl;下同。)扩大培养后提取质粒,即获得阳性重组载体BOMT-pET-32a。经测序,重组载体BOMT-pET-32a含有序列表中序列1所示的重组BOMT蛋白的编码序列,能表达序列表中序列3所示的重组BOMT蛋白(TrxA标签的氨基酸序列是序列3的第1-109位所示;His标签的氨基酸序列是序列3的第117-122位)。
实施例二、重组蛋白的获得及酶促反应分析
1.蛋白诱导及提取
将重组载体BOMT-pET-32a转化到BL21(DE3)Chemically Competent Cell,获得重组大肠杆菌BL21(DE3)/BOMT-pET-32a。同时将pET-32a空载质粒转化BL21(DE3)ChemicallyCompetent Cell,得到空载对照重组大肠杆菌BL21(DE3)/pET-32a。
将重组大肠杆菌BL21(DE3)/BOMT-pET-32a和空载对照重组大肠杆菌BL21(DE3)/pET-32a在1mL含有50μg/mL氨苄青霉素钠的液体LB培养基中于37℃,200rpm振荡培养7h,取1mL菌液转入100mL含50μg/mL氨苄青霉素钠的液体LB培养基中,于37℃,200rpm振荡培养3h至菌液OD600nm值达到0.6-0.8之间后取出菌液,降温至16℃,加入IPTG至终浓度为0.5mM,置16℃,200rpm摇床中振荡培养,诱导表达16h收集发酵液,将重组大肠杆菌BL21(DE3)/BOMT-pET-32a诱导表达得到的发酵液命名为诱导BOMT-pET-32a全菌液,将重组大肠杆菌BL21(DE3)/pET-32a诱导表达得到的发酵液命名为诱导空载全菌液。
将诱导BOMT-pET-32a全菌液8000rpm离心20min,得到的沉淀即为含有重组BOMT蛋白的菌体细胞。用预冷的5mL Tris-HCl(100mM,pH 7.5)重悬菌体沉淀后进行超声破碎(功率60%,超声5s,停5s,总时间20min),然后在4℃,10000rpm离心20min,上清液即为重组BOMT粗蛋白。将上清液转入1ml镍柱(康为世纪,北京)进行亲和层析,用10mM的咪唑缓冲液洗至考马斯亮蓝不变蓝,弃去洗脱液,再用75mM咪唑缓冲液洗至考马斯亮蓝不变蓝,收集洗脱液,即为纯化的重组BOMT蛋白(氨基酸为序列表中序列3),SDS-PAGE电泳结果如图2所示,可见目标重组BOMT蛋白蛋白大小在55-70kDa之间,符合预期。
将空载全菌液用同样的方法处理,得到空载对照的纯化蛋白。
2.酶促反应及产物提取
取适量步骤1得到的纯化的重组BOMT蛋白,以小檗胺(Berbamine)(赫澎生物,上海)为底物,以S-腺苷甲硫氨酸(AdoMet)(美国Sigma公司)为甲基供体进行酶促反应,催化小檗胺的羟基发生甲基化,反应过程如图3所示。以步骤1得到的空载对照的粗蛋白为对照。酶促反应体系如下:重组BOMT粗蛋白200μL,Berbamine(10mM)1μL,AdoMet(10mM)10μL,磷酸钾(100mM,pH 7)加至500μL。反应体系配制完成后置于30℃,200rpm振荡反应3h。然后加入500μL乙酸乙酯(北京化工厂),超声提取30min,置于离心机中以12000g离心20min,取上层有机相溶液,置于氮吹仪中吹干,加入150μL甲醇(美国Merck公司)复溶,12000g离心20min,取100μL上清注入UPLC-QTOF-MS(Waters Technologies,Milford,MA,USA)进行检测。
3.反应产物检测
利用UPLC-QTOF-MS对酶促反应产物进行检测,所得结果表明以AdoMet作为甲基供体,底物Berbamine可以在重组BOMT蛋白的催化下生成异汉防己甲素(Isotetrandrine)。重组BOMT蛋白酶促反应产物(图4的中间图)及空载对照(图4的上图)检测色谱图如图4所示,目标反应产物Isotetrandrine及Isotetrandrine标准品(成都瑞芬思生物科技有限公司,DFZY-5mg)质谱图如图5所示。
色谱条件如下:色谱柱为T3柱(2.1mm×100mm,2.7μm);流动相为乙腈(A,美国Merck公司)和0.1%甲酸-水(B,美国Thermo Fisher公司),梯度洗脱条件如下:0-6.0min:5%-30%A,6.0-12.0min:30%-60%A,12.0-13.5min:60%-90%A,13.5-15.0min:90%-5%A,15.0-18.0min:5%-5%A;进样体积为4μL,柱温为40℃,流动相流速为0.4mL/min。
质谱条件如下:电喷雾离子源,正离子模式,扫描检测范围为m/z 50-1500;毛细管电压为0.5kV;样品锥电压为40V;离子源温度为100℃;脱溶温度为300℃;脱溶气体流量为800L/h;低能函数的陷阱碰撞能量设置为6eV;高能函数的斜坡陷阱碰撞能量设置为30-50eV,使用MassLynx软件进行数据采集和处理。
综上,重组BOMT蛋白是甲基转移酶,该酶可以以AdoMet为甲基供体,催化小檗胺(Berbamine)的羟基发生甲基化,生成异汉防己甲素(Isotetrandrine)。该基因可用于BIA工程菌的构建。
以上对本发明进行了详述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
序列表
<110> 中国中医科学院中药研究所
<120> 来源于粉防己的一个甲基转移酶及其在制备异汉防己甲素中的应用
<130> GNCSQ212694
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 1602
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
atgagcgata aaattattca cctgactgac gacagttttg acacggatgt actcaaagcg 60
gacggggcga tcctcgtcga tttctgggca gagtggtgcg gtccgtgcaa aatgatcgcc 120
ccgattctgg atgaaatcgc tgacgaatat cagggcaaac tgaccgttgc aaaactgaac 180
atcgatcaaa accctggcac tgcgccgaaa tatggcatcc gtggtatccc gactctgctg 240
ctgttcaaaa acggtgaagt ggcggcaacc aaagtgggtg cactgtctaa aggtcagttg 300
aaagagttcc tcgacgctaa cctggccggt tctggttctg gccatatgca ccatcatcat 360
catcattctt ctggtctggt gccacgcggt tctggtatga aagaaaccgc tgctgctaaa 420
ttcgaacgcc agcacatgga cagcccagat ctgggtaccg acgacgacga caaggccatg 480
gctgatatcg gatccatgga ttccattatt cgtgatctaa gtagcaatgg caatggagac 540
gtccgcgacg caggttactt gttcgcgaag ggactggtga atgcatgcct tctaccaatg 600
gtgatgcgag ctgctatcaa gctcaatgtg tttgagatca tgaacaacgc atcgaaaact 660
catctctcac cctctcacat tgcctctcaa ctccctaata acaaaaaccc aaatgcgcag 720
ttcgtcctcg atcgaatgct tcgctttctc gctagtcatt cagttctcac ttgcaccaca 780
aaagagagtg ttaacaatag taacaatggt gaagtcgaaa ggttgtacgg cttgactcca 840
gcttccaagt acttcatcaa aaatgaagat ggagcctcac ttgctgcttc cctcttggct 900
tctacagaca agttgatgtt ggaaacctgt tattacttgg atggtgttgt tctcgaacca 960
gatttttcag tcgatgagaa ggtttttgga atgagtgcct accaatattt tgcccaagac 1020
ccagaattga acgagttgtg caacaaaacc atgtccgacg aaactgcaat caccatgaag 1080
aggattcttg acaagtacaa agggtttgat ggtctcaaag ttgtggttga tgtgggtggt 1140
gggattggaa ctaacattaa cttaattgtt tccaagtacc ctactattaa aggcatcaat 1200
ttcgattctc ctcatgtggt tgaaaccgca ccgtcctacc caggtgttga acatgtcgga 1260
ggggacatgt ttgttagtgt tccaaaagga gatgccattt tcatgaagtg ggtacttcac 1320
aattggaaag atgagcagtg cttgacattg ttgaagaagt gtcatgaagc tctaccgaag 1380
ggaggaaagg tgattgtcgt agaggggtta cttccagaag ttcctacgcc tgacaacgct 1440
acgaaagata tgtgcgcgtt agatataatt atgacaatgt ccttcggtgc aatggagaga 1500
actgaaaaag agtttgagac cttggcgaaa gtgtctggat ttgctgacat taggttggta 1560
tgcaatgctt gtaatctgtg ggtcattgaa tttctcaaat aa 1602
<210> 2
<211> 368
<212> PRT
<213> 粉防己(Stephania tetrandra S. Moore)
<400> 2
Met Asp Ser Ile Ile Arg Asp Leu Ser Ser Asn Gly Asn Gly Asp Val
1 5 10 15
Arg Asp Ala Gly Tyr Leu Phe Ala Lys Gly Leu Val Asn Ala Cys Leu
20 25 30
Leu Pro Met Val Met Arg Ala Ala Ile Lys Leu Asn Val Phe Glu Ile
35 40 45
Met Asn Asn Ala Ser Lys Thr His Leu Ser Pro Ser His Ile Ala Ser
50 55 60
Gln Leu Pro Asn Asn Lys Asn Pro Asn Ala Gln Phe Val Leu Asp Arg
65 70 75 80
Met Leu Arg Phe Leu Ala Ser His Ser Val Leu Thr Cys Thr Thr Lys
85 90 95
Glu Ser Val Asn Asn Ser Asn Asn Gly Glu Val Glu Arg Leu Tyr Gly
100 105 110
Leu Thr Pro Ala Ser Lys Tyr Phe Ile Lys Asn Glu Asp Gly Ala Ser
115 120 125
Leu Ala Ala Ser Leu Leu Ala Ser Thr Asp Lys Leu Met Leu Glu Thr
130 135 140
Cys Tyr Tyr Leu Asp Gly Val Val Leu Glu Pro Asp Phe Ser Val Asp
145 150 155 160
Glu Lys Val Phe Gly Met Ser Ala Tyr Gln Tyr Phe Ala Gln Asp Pro
165 170 175
Glu Leu Asn Glu Leu Cys Asn Lys Thr Met Ser Asp Glu Thr Ala Ile
180 185 190
Thr Met Lys Arg Ile Leu Asp Lys Tyr Lys Gly Phe Asp Gly Leu Lys
195 200 205
Val Val Val Asp Val Gly Gly Gly Ile Gly Thr Asn Ile Asn Leu Ile
210 215 220
Val Ser Lys Tyr Pro Thr Ile Lys Gly Ile Asn Phe Asp Ser Pro His
225 230 235 240
Val Val Glu Thr Ala Pro Ser Tyr Pro Gly Val Glu His Val Gly Gly
245 250 255
Asp Met Phe Val Ser Val Pro Lys Gly Asp Ala Ile Phe Met Lys Trp
260 265 270
Val Leu His Asn Trp Lys Asp Glu Gln Cys Leu Thr Leu Leu Lys Lys
275 280 285
Cys His Glu Ala Leu Pro Lys Gly Gly Lys Val Ile Val Val Glu Gly
290 295 300
Leu Leu Pro Glu Val Pro Thr Pro Asp Asn Ala Thr Lys Asp Met Cys
305 310 315 320
Ala Leu Asp Ile Ile Met Thr Met Ser Phe Gly Ala Met Glu Arg Thr
325 330 335
Glu Lys Glu Phe Glu Thr Leu Ala Lys Val Ser Gly Phe Ala Asp Ile
340 345 350
Arg Leu Val Cys Asn Ala Cys Asn Leu Trp Val Ile Glu Phe Leu Lys
355 360 365
<210> 3
<211> 533
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Ser Asp Lys Ile Ile His Leu Thr Asp Asp Ser Phe Asp Thr Asp
1 5 10 15
Val Leu Lys Ala Asp Gly Ala Ile Leu Val Asp Phe Trp Ala Glu Trp
20 25 30
Cys Gly Pro Cys Lys Met Ile Ala Pro Ile Leu Asp Glu Ile Ala Asp
35 40 45
Glu Tyr Gln Gly Lys Leu Thr Val Ala Lys Leu Asn Ile Asp Gln Asn
50 55 60
Pro Gly Thr Ala Pro Lys Tyr Gly Ile Arg Gly Ile Pro Thr Leu Leu
65 70 75 80
Leu Phe Lys Asn Gly Glu Val Ala Ala Thr Lys Val Gly Ala Leu Ser
85 90 95
Lys Gly Gln Leu Lys Glu Phe Leu Asp Ala Asn Leu Ala Gly Ser Gly
100 105 110
Ser Gly His Met His His His His His His Ser Ser Gly Leu Val Pro
115 120 125
Arg Gly Ser Gly Met Lys Glu Thr Ala Ala Ala Lys Phe Glu Arg Gln
130 135 140
His Met Asp Ser Pro Asp Leu Gly Thr Asp Asp Asp Asp Lys Ala Met
145 150 155 160
Ala Asp Ile Gly Ser Met Asp Ser Ile Ile Arg Asp Leu Ser Ser Asn
165 170 175
Gly Asn Gly Asp Val Arg Asp Ala Gly Tyr Leu Phe Ala Lys Gly Leu
180 185 190
Val Asn Ala Cys Leu Leu Pro Met Val Met Arg Ala Ala Ile Lys Leu
195 200 205
Asn Val Phe Glu Ile Met Asn Asn Ala Ser Lys Thr His Leu Ser Pro
210 215 220
Ser His Ile Ala Ser Gln Leu Pro Asn Asn Lys Asn Pro Asn Ala Gln
225 230 235 240
Phe Val Leu Asp Arg Met Leu Arg Phe Leu Ala Ser His Ser Val Leu
245 250 255
Thr Cys Thr Thr Lys Glu Ser Val Asn Asn Ser Asn Asn Gly Glu Val
260 265 270
Glu Arg Leu Tyr Gly Leu Thr Pro Ala Ser Lys Tyr Phe Ile Lys Asn
275 280 285
Glu Asp Gly Ala Ser Leu Ala Ala Ser Leu Leu Ala Ser Thr Asp Lys
290 295 300
Leu Met Leu Glu Thr Cys Tyr Tyr Leu Asp Gly Val Val Leu Glu Pro
305 310 315 320
Asp Phe Ser Val Asp Glu Lys Val Phe Gly Met Ser Ala Tyr Gln Tyr
325 330 335
Phe Ala Gln Asp Pro Glu Leu Asn Glu Leu Cys Asn Lys Thr Met Ser
340 345 350
Asp Glu Thr Ala Ile Thr Met Lys Arg Ile Leu Asp Lys Tyr Lys Gly
355 360 365
Phe Asp Gly Leu Lys Val Val Val Asp Val Gly Gly Gly Ile Gly Thr
370 375 380
Asn Ile Asn Leu Ile Val Ser Lys Tyr Pro Thr Ile Lys Gly Ile Asn
385 390 395 400
Phe Asp Ser Pro His Val Val Glu Thr Ala Pro Ser Tyr Pro Gly Val
405 410 415
Glu His Val Gly Gly Asp Met Phe Val Ser Val Pro Lys Gly Asp Ala
420 425 430
Ile Phe Met Lys Trp Val Leu His Asn Trp Lys Asp Glu Gln Cys Leu
435 440 445
Thr Leu Leu Lys Lys Cys His Glu Ala Leu Pro Lys Gly Gly Lys Val
450 455 460
Ile Val Val Glu Gly Leu Leu Pro Glu Val Pro Thr Pro Asp Asn Ala
465 470 475 480
Thr Lys Asp Met Cys Ala Leu Asp Ile Ile Met Thr Met Ser Phe Gly
485 490 495
Ala Met Glu Arg Thr Glu Lys Glu Phe Glu Thr Leu Ala Lys Val Ser
500 505 510
Gly Phe Ala Asp Ile Arg Leu Val Cys Asn Ala Cys Asn Leu Trp Val
515 520 525
Ile Glu Phe Leu Lys
530
Claims (10)
1.蛋白质相关的生物材料,其特征在于:所述蛋白质是如下A1)、A2)、A3)或A4)的蛋白质:
A1)氨基酸序列是序列表中序列2的蛋白质;
A2)氨基酸序列是序列表中序列3的蛋白质;
A3)在A1)或A2)所示的蛋白质的羧基端或/和氨基端融合蛋白标签得到的融合蛋白;
A4)将A1)或A2)所示的蛋白质的氨基酸序列经过一个或几个氨基酸残基的取代和/或缺失和/或添加得到的且具有相同功能的由A1)或A2)衍生的或与A1)或A2)所示的蛋白质具有70%以上的同一性的蛋白质;
所述生物材料为下述B1)至B6)中的任一种:
B1)编码所述蛋白质的核酸分子;
B2)含有B1)所述核酸分子的表达盒;
B3)含有B1)所述核酸分子的重组载体、或含有B2)所述表达盒的重组载体;
B4)含有B1)所述核酸分子的重组微生物、或含有B2)所述表达盒的重组微生物、或含有B3)所述重组载体的重组微生物;
B5)促进或提高所述蛋白质表达的核酸分子;
B6)含有B5)所述核酸分子的表达盒、重组载体或重组微生物。
2.根据权利要求1所述的生物材料,其特征在于:B1)所述核酸分子为如下b1)b2)或b3)所示的所述蛋白质的编码基因:
b1)编码序列是序列表中序列1的第496-1602位核苷酸的cDNA分子或DNA分子;
b2)核苷酸是序列表中序列1的cDNA分子或DNA分子;
b3)与b2)限定的cDNA或DNA分子杂交且编码具有相同功能的蛋白质的cDNA分子或DNA分子。
3.权利要求1中所述的蛋白质。
4.蛋白质在作为甲基转移酶或在制备双苄基异喹啉生物碱中的应用,所述蛋白质为权利要求1中所述的蛋白质。
5.权利要求1或2所述的生物材料和/或权利要求3所述的蛋白质相关的下述任一种产品:
P1、生产双苄基异喹啉生物碱的产品;
P2、制备异汉防己甲素的产品;
P3、制备催化小檗胺的羟基发生甲基化的产品;
P4、生产甲基转移酶BOMT的产品。
6.根据权利要求5所述的产品,其特征在于:所述双苄基异喹啉生物碱为异汉防己甲素。
7.权利要求1或2所述的生物材料和/或权利要求3所述的蛋白质的下述任一种应用:
Q1、权利要求1或2所述的生物材料和/或权利要求3所述的蛋白质在制备生产双苄基异喹啉生物碱的产品中的应用;
Q2、权利要求1或2所述的生物材料和/或权利要求3所述的蛋白质在制备异汉防己甲素的产品中的应用;
Q3、权利要求1或2所述的生物材料和/或权利要求3所述的蛋白质在制备催化小檗胺的羟基发生甲基化的产品中的应用;
Q4、权利要求1或2所述的生物材料和/或权利要求3所述的蛋白质在制备生产甲基转移酶BOMT中的应用。
8.一种制备权利要求3所述蛋白质的方法,包括如下步骤:将权利要求1或2中所述蛋白质的编码基因在原核微生物中进行表达得到权利要求3所述的蛋白质。
9.根据权利要求8所述的方法,其特征在于:将权利要求1或2中所述蛋白质的编码基因在原核微生物中进行表达包括将权利要求1或2中所述蛋白质的编码基因导入受体微生物,得到表达权利要求3所述蛋白质的重组微生物,培养所述重组微生物,表达得到所述蛋白质。
10.根据权利要求8或9所述的方法,其特征在于:所述表达为诱导表达。
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