CN112301013B - 复合酶及其在制备麦角硫因中的应用 - Google Patents
复合酶及其在制备麦角硫因中的应用 Download PDFInfo
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- CN112301013B CN112301013B CN202011209524.3A CN202011209524A CN112301013B CN 112301013 B CN112301013 B CN 112301013B CN 202011209524 A CN202011209524 A CN 202011209524A CN 112301013 B CN112301013 B CN 112301013B
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- histidine
- ala
- leu
- gly
- trimethylhistidine
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Abstract
本发明涉及生物工程技术领域,尤其涉及复合酶及其在制备麦角硫因中的应用。本发明提供了一种复合酶,该酶中包括L‑组氨酸甲基化酶、卤素甲基转移酶和三甲基组氨酸硫化酶。L‑组氨酸经L‑组氨酸甲基化酶、卤素甲基转移酶催化,获得三甲基组氨酸;然后经三甲基组氨酸硫化酶催化获得麦角硫因。该方法仅需两步就能实现由L‑组氨酸到麦角硫因的转化。并且,利用通过使SAM酶再生,大幅降低了SAM酶的用量。因此,该方法大幅降低了原料成本。而与此同时,该方法反应浓度高(近三十克/升)、工艺简单,具有良好的工业化生产前景。
Description
技术领域
本发明涉及生物工程技术领域,尤其涉及复合酶及其在制备麦角硫因中的应用。
背景技术
麦角硫因(L-Ergothioneine,又名thiolhistidinebetaine)是一种含硫的L-组氨酸衍生物,它广泛存在于蘑菇、黑豆、红肉和燕麦等人类日常饮食中,人体一般通过具有高度特异性的麦角硫因转运蛋白来获取并保留在体内大部分细胞和组织中。麦角硫因是一种天然抗氧化剂,能有效清除体内活性氧和氮以保护细胞免受氧化凋亡损伤;此外大量研究表明麦角硫因也可保护皮肤免受UV-辐射,可有效降低眼疾、炎症性肠病、肝纤维化等疾病;因此在日常饮食中补充麦角硫因正变成一种潜在的预防上述疾病的选择。然而高昂的价格一直极大的限制了麦角硫因的进一步推广应用,因此开发一种简易的方法能规模化生产麦角硫因变得非常重要。
麦角硫因虽然分子量不大(C9H15N3O2S,229.3),但其含有的三甲基氨以及硫化的氮杂环官能团决定了该化合物功能及制备的特殊性。现今麦角硫因制备方法包含了化学合成法、发酵法以及酶催化法:
化学合成法是以L-组氨酸甲酯为起始原料,通过多次官能团选择性保护及脱保护才能间接实现氮杂环的硫化以及氨基的三甲基化(如图2所示,参考专利号:US7767826B2),整个制备工艺非常繁琐,最终收率也低,环境成本高。
麦角硫因发酵生产研究历史悠久,如美国的Liu,pinghua通过植入Egt-1与EgtE两个麦角硫因合成基因到大肠杆菌(Escherichia coli)里,然后以L-组氨酸或三甲基组氨酸为原料发酵生产麦角硫因(参考专利:WO 2014/100752 Al);英国的Steven A.van derHoek通过改造酿酒酵母(Saccharomyces cerevisiae),用普通的酵母培养基发酵生产麦角硫因(参考文献:Steven A.van der Hoek et al,Front.Bioeng.Biotech.2019,7,262),然而由于麦角硫因发酵收率低(报道所实现的最高浓度接近克级每升),因此现今无法实现规模化生产。
麦角硫因的体外酶催化制备也有相关报道,其采用的是生物体内麦角硫因Egt系列合成酶催化(如图2所示,参考文献:Florian P.Seebeck,JACS,2010,132,6632-6633),然由于该路线较长,EgtD酶与EgtB酶转化效率低,以及腺苷蛋氨酸用量大等原因,酶合成制备麦角硫因成本居高不下。
可见,目前仍需进一步开发低成本高收率的工业化麦角硫因生产方法。
发明内容
有鉴于此,本发明要解决的技术问题在于提供复合酶及其在制备麦角硫因中的应用,该方法通过两步反应即可获得麦角硫因。
本发明还提供了一种复合酶,其包括:L-组氨酸甲基化酶、卤素甲基转移酶和三甲基组氨酸硫化酶。
本发明所述的复合酶中,所述L-组氨酸甲基化酶来自Mycobacteriumsmegmatismc或Chlorobium limicola;所述卤素甲基转移酶来自Chloracidobacteriumthermophilum或Mycobacterium smegmatis;所述三甲基组氨酸硫化酶来自Escherichiacoli或Chlorobium limicola。
在本发明实施例中,所述L-组氨酸甲基化酶具有如SEQ ID NO:1或2所示的氨基酸序列,所述卤素甲基转移酶具有如SEQ ID NO:3或4所示的氨基酸序列,所述三甲基组氨酸硫化酶具有如SEQ ID NO:5或6所示的氨基酸序列。
本发明中,来自Mycobacterium smegmatismc的L-组氨酸甲基化酶记为MsHisMT,来自Chlorobium limicola的L-组氨酸甲基化酶记为ClHisMT。来自Chloracidobacteriumthermophilum的卤素甲基转移酶记为CtHaMT,来自Mycobacterium smegmatis的卤素甲基转移酶记为MsHaMT。来自Escherichia coli的三甲基组氨酸硫化酶记为EcHerS,来自Chlorobium limicola的三甲基组氨酸硫化酶记为ClHerS。
一些实施例中,所述复合酶由MsHisMT、CtHaMT和EcHerS组成。在该实施例中,MsHisMT与CtHaMT的比例为1000U:1500U。
另一些实施例中,所述复合酶由ClHisMT、CtHaMT和ClHerS组成。在该实施例中,ClHisMT与CtHaMT的比例为800U:800U。
另一些实施例中,所述复合酶由MsHisMT、MspHaMT和ClHerS组成。在该实施例中,MsHisMT与MspHaMT的比例为500U:1000U。
本发明所述复合酶在麦角硫因酶催化制备中的应用。
本发明还提供了麦角硫因的酶催化制备方法,其包括:
L-组氨酸经L-组氨酸甲基化酶、卤素甲基转移酶催化,获得三甲基组氨酸;然后经三甲基组氨酸硫化酶催化获得麦角硫因。
在有L-组氨酸反应获得三甲基组氨酸的步骤中,加入卤素甲基转移酶HaMT,该酶能利用碘甲烷快速转化腺苷高半胱氨酸(SAH)成腺苷蛋氨酸(SAM)。因此该步骤采用HaMT酶与HisMT酶组合,从而利用L-组氨酸甲基化酶HisMT与卤素甲基转移酶HaMT再生腺苷蛋氨酸将原料L-组氨酸一次性转化成三甲基组氨酸。
本发明所述的方法中,三甲基组氨酸的制备方法包括:在缓冲液中加入L-组氨酸、腺苷蛋氨酸、L-组氨酸甲基化酶和卤素甲基转移酶,然后滴加碘甲烷,pH7.0~9.0搅拌反应制得三甲基组氨酸。
一些实施例中,所述缓冲液为100mmol/L pH值为8.0的磷酸缓冲液;
所述加入至反应体系中L-组氨酸浓度为100mmol/L~200mmol/L;腺苷蛋氨酸浓度为0.8mmol/L~1.2mmol/L;L-组氨酸甲基化酶的浓度为500U/L~1000U/L;卤素甲基转移酶的浓度为800U/L~1500U/L;
所述滴加碘甲烷与腺苷蛋氨酸的摩尔比为(360~720):1。
所述滴加的时间为4h,所述滴加后再维持搅拌反应4h。
在获得三甲基组氨酸后,反应液以乙酸乙酯萃取,水相经1000~5000分子量超滤,取滤液为含有三甲基组氨酸的溶液。
其中,萃取步骤去除反应液中的碘甲烷和碘;超滤步骤去除反应液中的MsHisMT酶和CtHaMT酶。所得含有三甲基组氨酸的溶液以隔膜真空泵抽真空、补充N2的方式除去反应溶液的O2,并最终用N2保护的方式封存。
本发明所述的方法中,所述三甲基组氨酸硫化酶催化获得麦角硫因包括:加入三甲基组氨酸硫化酶和聚硫化钾,N2环境反应获得麦角硫因。所述N2环境反应的时间为6h。
一些实施例中,所述加入三甲基组氨酸硫化酶至浓度为600U/L~800U/L,加入聚硫化钾的量为三甲基组氨酸的两倍当量。
反应获得的含有麦角硫因的反应液以乙醇沉淀后,取上清液,经浓缩后上样于阴离子交换柱,以水洗脱,经浓缩、干燥获得麦角硫因粗品。所述麦角硫因粗品以乙醇/水溶液结晶获得麦角硫因纯品。所述阴离子交换柱为4200,-OH型。所述乙醇沉淀步骤,去除EcHerS酶和磷酸盐。
一些实施例中,所述L-组氨酸甲基化酶的制备方法包括:将编码L-组氨酸甲基化酶的核酸转化入敲除S-腺苷同型半胱氨酸核苷水解酶mtnN基因的宿主,经诱导表达获得含有L-组氨酸甲基化酶的菌液。
所述卤素甲基转移酶的制备方法包括:将编码卤素甲基转移酶的核酸转化入敲除S-腺苷同型半胱氨酸核苷水解酶mtnN基因的宿主,经诱导表达获得含有卤素甲基转移酶的菌液。
所述三甲基组氨酸硫化酶的制备方法包括:将编码三甲基组氨酸硫化酶的核酸转化入敲除S-腺苷同型半胱氨酸核苷水解酶mtnN基因的宿主,经诱导表达获得含有三甲基组氨酸硫化酶的菌液。
宿主mtnN基因表达产生的酶会将SAH降解掉,导致无法再生成SAM,因此在构建重组宿主时选择无mtnN基因表达,或mtnN基因被敲除的宿主。一些实施例中,所述重组宿主的宿主细胞为大肠杆菌。具体的所述宿主细胞为大肠杆菌BL21-DE3。
本发明还提供了编码L-组氨酸甲基化酶的核酸,其为:
I)、具有如SEQ ID NO:7或8所示核苷酸序列的核酸;
II)、在I)所述的片段中取代、缺失或添加一个或多个核苷酸的核酸;
III)、与I)所述核酸的序列至少具有85%的同源性,且编码L-组氨酸甲基化酶的核酸;
IV)、与I)~III)中任一项部分互补或完全互补的核酸。
本发明还提供了编码卤素甲基转移酶的核酸,其为:
i)、具有如SEQ ID NO:9或10所示核苷酸序列的核酸;
ii)、在i)所述的片段中取代、缺失或添加一个或多个核苷酸的核酸;
iii)、与i)所述核酸的序列至少具有85%的同源性,且编码L-组氨酸甲基化酶的核酸;
iv)、与i)~iii)中任一项部分互补或完全互补的核酸。
本发明还提供了编码三甲基组氨酸硫化酶的核酸,其为:
a)、具有如SEQ ID NO:11或12所示核苷酸序列的核酸;
b)、在a)所述的片段中取代、缺失或添加一个或多个核苷酸的核酸;
c)、与a)所述核酸的序列至少具有85%的同源性,且编码三甲基组氨酸硫化酶的核酸;
d)、与a)~c)中任一项部分互补或完全互补的核酸。
本发明还提供了一种重组载体,其包括编码L-组氨酸甲基化酶的核酸及骨架载体。一些实施例中,所述骨架载体为pET28a。核酸片段的插入位点为Nde I/Xho I。
或所述重组载体包括编码卤素甲基转移酶的核酸及骨架载体。一些实施例中,所述骨架载体为pET28a。核酸片段的插入位点为Nde I/Xho I。
或所述重组载体包括编码卤素甲基转移酶的核酸及骨架载体。一些实施例中,所述骨架载体为pET28a。核酸片段的插入位点为Nco I/Xho I。
本发明还提供了转化或转染所述重组载体的重组宿主,所述宿主的S-腺苷同型半胱氨酸核苷水解酶mtnN基因被敲除。
本发明提供了一种复合酶,该酶中包括L-组氨酸甲基化酶、卤素甲基转移酶和三甲基组氨酸硫化酶。L-组氨酸经L-组氨酸甲基化酶、卤素甲基转移酶催化,获得三甲基组氨酸;然后经三甲基组氨酸硫化酶催化获得麦角硫因。该方法仅需两步就能实现由L-组氨酸到麦角硫因的转化。并且,利用通过使SAM酶再生,大幅降低了SAM酶的用量。因此,该方法大幅降低了原料成本。而与此同时,该方法反应浓度高(近三十克/升)、工艺简单,具有良好的工业化生产前景。
附图说明:
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示本专利麦角硫因酶制备路线图;
图2示市面上采用的麦角硫因制备路线;
图3示实施例中L-组氨酸甲基化酶HisMT,卤素甲基转移酶HaMT以及三甲基组氨酸硫化酶HerS SDS-PAGE凝胶图;
图4示最终纯化的麦角硫因在600M Varian,D2O溶液核磁1H-NMR数据。
具体实施方式
本发明提供了复合酶及其在制备麦角硫因中的应用,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
在自然界中广泛存在各种麦角硫因合成酶,生物体一般先利用L-组氨酸甲基化酶(EgtD,HisMT,EC 2.1.1.44)将L-组氨酸转化成三甲基组氨酸;随后,在大多数有氧微生物体内,三甲基组氨酸则被三甲基组氨酸氧化酶(EgtB,EC 1.14.99.50),谷氨酸水解酶(EgtC,EC 3.5.1.118)以及硫氧裂解酶(EgtE,EC 4.4.1.36)连续转化成麦角硫因。
本发明利用筛选获得的的多种L-组氨酸甲基化酶HisMT、三甲基组氨酸硫化酶HerS,挑选部分大肠杆菌体里过表达、活性高的HisMT、HerS,从而有效实现了三甲基组氨酸硫化的放大制备;与此同时,通过在制备过程中引入一种卤素甲基转移酶HaMT,该酶能利用碘甲烷快速转化腺苷高半胱氨酸(SAH)成腺苷蛋氨酸(SAM)。因此采用HaMT酶与HisMT酶组合从而有效实现昂贵辅酶腺苷蛋氨酸的循环再生。
为了实现上述发明目的,本发明提供以下技术方案:利用L-组氨酸甲基化酶HisMT与卤素甲基转移酶HaMT再生腺苷蛋氨酸将原料L-组氨酸一次性转化成三甲基组氨酸;再利用三甲基组氨酸硫化酶HerS将三甲基组氨转化成麦角硫因。
在本发明的一些具体实施方案中,L-组氨酸甲基化酶(HisMT,EC 2.1.1.44)、卤素甲基转移酶(HaMT)、三甲基组氨酸硫化酶HerS,依次属于PF10017、PF05724、PF00581酶家族成员,其来源可能是Escherichia coli,Mycobacterium smegmatis,Chlorobiumlimicola,Chloracidobacterium thermophilum,Methylibium sp.等菌种。
本发明中,各种酶的氨基酸序列来自菌种,编码酶的核酸序列经过密码子优化,所述优化包括:码子使用偏好性,消除不利于表达的二级结构(如发夹结构),改变GC含量,CpG二核苷酸含量,mRNA的二级结构,隐蔽剪接位点,早期多聚腺苷化位点,内部核糖体进入位点和结合位点,负CpG岛,RNA不稳定区,重复序列(直接重复、反向重复等)和可能影响克隆的限制性位点。在本发明中,所述编码酶的核酸可以是DNA、RNA、cDNA或PNA。在本发明实施例中,所述核酸为DNA形式。所述DNA形式包括cDNA、基因组DNA或人工合成的DNA。所述DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。
本发明所述的重组载体包含一个或多个调节序列以及目标蛋白的编码序列。调节序列可以包括与核酸序列可操作地连接的启动子、增强子、转录终止信号、多腺苷酸化序列、复制起点、核酸限制性位点、和同源重组位点。载体还可包括选择性标记,例如:抗性蛋白标记、氨基酸筛选标记或绿色荧光蛋白等。
本发明采用的试材皆为普通市售品,皆可于市场购得,其中采用的引物序列及酶的氨基酸序列、核酸序列如表1~3:
表1
表2
表3
下面结合实施例,进一步阐述本发明:
实施例1MsHisMT酶液制备
①耻垢分枝杆菌(Mycobacterium smegmatismc2 155,ATCC700084)染色体DNA为模板用表1相应引物PCR扩增出MsHisMT基因片段,然后利用NEB公司购买的Nde I/Xho I进行相应的酶切,并连接到相同酶切的pET28a质粒上(购于Addgene),最后进行质粒转化(转入E coli DH5a细胞,购于擎科生物)并通过菌落PCR及基因测序验证。
②上述序列验证正确的质粒转入E.coli KO1(敲除掉S-腺苷同型半胱氨酸核苷水解酶mtnN基因的BL21-DE3细胞,母体菌株来源于擎科生物,基因敲除服务源于源井生物)菌株里,在37℃、5ml含50μM卡那霉素(Kanamycin)的LB培养液中进行小量培养,当细胞生长至OD600值为0.5~0.8加入0.5mM异丙基-β-D-硫代吡喃半乳糖苷(IPTG),37℃诱导蛋白表达3小时,最后收集细胞、冻融法进行细胞破碎、高速离心,收集到的上清液再利用十二烷基磺酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)确认蛋白表达。小量表达后,经检测MsHisMT的酶活力为90~180U/mg。
③蛋白表达正确的菌株逐级培养至5升发酵罐,在1.0mM IPTG条件下37℃诱导表达4小时,收集湿细胞30~60克;然后将细胞与适量的Tris.HCl缓冲液(25mM,pH=8.0)混合均匀后用高压破碎仪低温破碎,高速离心除去细胞壁后MsHisMT酶液保存在4℃冰箱待用。
上述步骤中,所述LB培养基构成为:1%胰蛋白胨、0.5%酵母粉、1%NaCl、1%磷酸氢二钾、1%磷酸氢二钾以及5%的甘油。
实施例2ClHisMT酶液制备
ClHisMT基因是通过公司合成(安徽通用生物)并亚克隆到pET28a质粒上。克隆方法同实施例步骤①,酶切位点为Nde I/Xho I。验证正确的质粒转入E.coli KO1,相继在5mlLB培养基内小量培养、蛋白表达验证后再放大到5升发酵罐内高密度发酵,小量培养和高密度发酵的方法同实施例步骤②、③。小量表达后,经检测ClHisMT的酶活力为30~80U/mg。大量表达后的菌体经破碎、离心去除细胞壁后,得到ClHisMT酶液。
实施例3CtHaMT酶液制备
CtHaMT基因是通过公司合成(安徽通用生物)并亚克隆到pET28a质粒上。克隆方法同实施例步骤①,酶切位点为Nde I/Xho I。验证正确的质粒转入E.coli KO1,相继在5mlLB培养基内小量培养、蛋白表达验证后再放大到5升发酵罐内高密度发酵,小量培养和高密度发酵的方法同实施例步骤②、③。小量表达后,经检测CtHaMT的酶活力为20~60U/mg。大量表达后的菌体经破碎、离心去除细胞壁后,得到CtHaMT酶液。
实施例4MspHaMT酶液制备
MspHaMT基因是通过公司合成(安徽通用生物)并亚克隆到pET28a质粒上。克隆方法同实施例步骤①,酶切位点为Nde I/Xho I。验证正确的质粒转入E.coli KO1,相继在5mlLB培养基内小量培养、蛋白表达验证后再放大到5升发酵罐内高密度发酵,小量培养和高密度发酵的方法同实施例步骤②、③。小量表达后,经检测MspHaMT的酶活力为15~35U/mg。大量表达后的菌体经破碎、离心去除细胞壁后,得到MspHaMT酶液。
实施例5EcHerS酶液制备
以ATCC购买的大肠杆菌(Escherichia coli O6:H1,ATCC 700928)染色体DNA为模板,用表1相应引物PCR扩增出EcHerS基因片段,然后利用NEB公司购买的Nco I/Xho I进行相应的酶切,并连接到相同酶切的pET28a质粒上(购于Addgene),最后进行质粒转化(转入Ecoli DH5a细胞,购于擎科生物)并通过菌落PCR及基因测序验证。
验证正确的质粒转入E.coli KO1,相继在5mlLB培养基内小量培养、蛋白表达验证后再放大到5升发酵罐内高密度发酵,小量培养和高密度发酵的方法同实施例步骤②、③。小量表达后,经检测EcHerS的酶活力为15~50U/mg。大量表达后的菌体经破碎、离心去除细胞壁后,所得EcHerS酶液需采用多次隔膜真空泵(天津津腾实验设备有限公司)抽真空、补充N2的方式除去溶液的O2,并用N2保护封存备用。
实施例6ClHerS酶液制备
ClHerS基因片段是通过公司合成(安徽通用生物),并亚克隆到pET28a质粒上。克隆方法同实施例步骤①,酶切位点为Nco I/Xho I。验证正确的质粒转入E.coli KO1,相继在5ml LB培养基内小量培养、蛋白表达验证后再放大到5升发酵罐内高密度发酵,小量培养和高密度发酵的方法同实施例步骤②、③。小量表达后,经检测ClHerS的酶活力为8~25U/mg。大量表达后的菌体经破碎、离心去除细胞壁后,所得EcHerS酶液需采用多次隔膜真空泵(天津津腾实验设备有限公司)抽真空、补充N2的方式除去溶液的O2,并用N2保护封存备用。
实施例7:麦角硫因的制备(MsHisMT,CtHaMT,EcHerS组合)
1、利用MsHisMT与CtHaMT催化L-组氨酸到三甲基组氨酸:
在1L100mM pH 8.0的磷酸缓冲液中加入31克L-组氨酸(200mM),0.4克腺苷蛋氨酸(SAM)(1mM),1000U MsHisMT以及1500U CtHaMT,反应溶液室温轻微搅拌,然后在4小时内缓慢滴加102.2克碘甲烷(720mmole)至反应体系,滴加完成后再维持搅拌4个小时(反应过程中通过滴加低浓度的HCl及NaOH水溶液维持反应体系pH 7.0-9.0之间)。反应结束后用HPLC检测出大部分L-组氨酸已经转化成三甲基组氨酸(Shimadzu LC-20AT HPLC withPhenomenex5μm SCXLC Column100×4.6mm,液相转化率94%),然后用250ml乙酸乙酯萃取三次以除去反应液里的碘甲烷和碘,超滤(1000~5000分子量分子截留,杭州凯洁膜分离技术有限公司)除掉反应体系里内的酶(MsHisMT与CtHaMT)后用隔膜真空泵抽真空、补充N2的方式除去反应溶液的O2,并最终用N2保护的方式封存备用。(活性单位U代表30℃每分钟转化1μM底物所需要的酶量)
2、利用EcHerS转化三甲基组氨酸到麦角硫因:
往上述三甲基组氨酸反应溶液中导入800U EcHerS,并加入12.8克(两倍当量)的聚硫化钾K2SX(Sigma-Aldrich),保持反应溶液在N2环境下室温轻微搅拌6小时,利用HPLC检测(与上同)大部分三甲基组氨酸原料消耗,然后将反应液倒入3L的乙醇溶液沉淀并离心除去反应液内的EcHerS酶以及磷酸盐,溶液真空浓缩至400ml后直接上样于阴离子交换柱(4200,-OH型,Sigma-Aldrich),然后用纯水洗脱。浓缩收集的水样得浅灰色麦角硫因粗品52克,该粗品在乙醇/水溶液中进一步结晶得淡黄色固体33.1克(最终总收率72%)。
实施例8麦角硫因的制备(ClHisMT,CtHaMT,ClHerS组合):
1、利用ClHisMT与CtHaMT催化L-组氨酸到三甲基组氨酸:
在1L100mM pH 8.0的磷酸缓冲液中加入15.5克L-组氨酸(100mM),0.2克腺苷蛋氨酸(1mM),800U ClHisMT以及800U CtHaMT;室温(25℃)搅拌并缓慢滴入51.1克碘甲烷(360mmole),滴加完成后再维持搅拌5个小时,当HPLC检测大部分L-组氨酸已经转化(液相转化率81%)后用250ml乙酸乙酯萃取除去反应体系的碘甲烷及碘,超滤除掉溶液里的酶(ClHisMT与CtHaMT)后除氧并用N2封存(方法同上)4℃保存备用。
2、利用ClHerS转化三甲基组氨酸到麦角硫因:
将以上准备的三甲基组氨酸粗液加入600U ClHerS,并加入6.4克的聚硫化钾K2SX,保持反应溶液在N2环境下室温轻微搅拌6小时,利用HPLC检测(与上同)显示大部分三甲基组氨酸原料消耗后加入3L的乙醇终止反应,并沉淀ClHerS酶及磷酸盐,离心除去沉淀,清液采用旋转蒸发仪真空浓缩至150ml;浓缩的反应液用阴离子交换柱纯化,并用纯水洗脱(与上同),浓缩得麦角硫因粗品41.5克,再经乙醇/水结晶得14.2克泛白麦角硫因固体(最终收率约61%)
实施例9麦角硫因的制备(MsHisMT,MspHaMT,ClHerS组合):
1、利用MsHisMT与MspHaMT催化L-组氨酸到三甲基组氨酸:
同样在1L100mM pH 8.0的磷酸缓冲液中加入15.5克L-组氨酸(100mM),0.2克腺苷蛋氨酸(1mM),500U MsHisMT以及1000U MspHaMT;51.1克碘甲烷(360mmole)缓慢滴加到反应体系(滴加时间维持约3个小时),然后维持反应搅拌约4小时后HPLC检测大部分L-组氨酸已消耗(液相转化率为90%)。往反应液中加入250ml乙酸乙酯萃取除去反应剩余的碘甲烷及生成的碘,超滤除掉溶液里的酶(MsHisMT与MspHaMT)后除O2并用N2封存(方法同上)4℃保存备用。
2、利用ClHerS转化三甲基组氨酸到麦角硫因:
将上述三甲基组氨酸粗液同样加入600U ClHerS,并加入6.4克的聚硫化钾K2SX,保持反应溶液在N2环境下室温轻微搅拌6小时,利用HPLC检测发现三甲基组氨酸原料消耗完毕后倒入3L乙醇溶液终止反应沉淀离心除去ClHerS酶及磷酸盐,所得溶液浓缩至约150ml后用Amberjet阴离子交换柱纯化,洗脱液浓缩得麦角硫因粗品45克,进一步用乙醇/水体系结晶纯化后得17克浅黄色麦角硫因固体(最终收率约74%)。
对比例麦角硫因的制备(ClHisMT,CtHaMT,CkHerS组合)
在麦角硫因制备的第二步反应中采用的酶在整个麦角硫因的制备体系中比较重要,前期试验中验证的大多数HerS酶的活力及稳定性都比较差,例如来源于Clostridiumscindens ATCC 35704的CsHerS,来源于Citrobacter koseri ATCC BAA-895的CkHerS,来源于Mannheimia succiniciproducens的MsHerS,来源于Leptotrichia goodfellowii的LgHerS,活力及稳定性都不理想,使得制备总收率仅为10%左右。以CkHerS进行反应,具体阐述如下:
1、CkHerS酶液制备
采用与实施例6相同的方法制备CkHerS酶的酶液,载体插入位点为Nhe I/Xho I,制备的酶活力为0.5~7U/mg。
2、麦角硫因的制备
2.1利用ClHisMT与CtHaMT催化L-组氨酸到三甲基组氨酸:
在1L 100mM pH 8.0的磷酸缓冲液中加入15.5克L-组氨酸(100mM),0.2克腺苷蛋氨酸(1mM),800U ClHisMT以及800U CtHaMT;室温(25℃)搅拌并缓慢滴入51.1克碘甲烷(360mmole),滴加完成后再维持搅拌5个小时,当HPLC检测大部分L-组氨酸已经转化(液相转化率79%)后用250ml乙酸乙酯萃取除去反应体系的碘甲烷及碘,超滤除掉溶液里的酶(ClHisMT与CtHaMT)后除氧并用N2封存(方法同上)4℃保存备用。
2.2、利用CkHerS转化三甲基组氨酸到麦角硫因:
将以上准备的三甲基组氨酸粗液加入600U CkHerS,并加入6.4克的聚硫化钾K2SX,保持反应溶液在N2环境下室温轻微搅拌10小时,HPLC检测(与上同)显示大部分三甲基组氨酸残留;随后再补加600U CkHerS,室温再搅拌20个小时后加入3L的乙醇终止反应,并沉淀ClHerS酶及磷酸盐,离心除去沉淀,清液采用旋转蒸发仪真空浓缩至150ml;浓缩的反应液用阴离子交换柱纯化,并用纯水洗脱(与上同),浓缩得灰色的反应液粗品43克,而以上采用的乙醇/水结晶条件无法得到纯化的麦角硫因,最终粗品HPLC纯度5.7%,两步液相总收率10.5%。
以上仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 深圳瑞德林生物技术有限公司
<120> 复合酶及其在制备麦角硫因中的应用
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115 120 125
Ser Ile Leu Ser Asp Ala Leu Ser Glu Pro Ser Arg Leu Gln Lys Leu
130 135 140
Pro His Phe Glu Gln Leu Val Tyr Pro Gln Trp Leu His Asn Leu Gln
145 150 155 160
Gln Gly Lys Glu Val Thr Ala Lys Pro Ala Gly Asp Trp Lys Val Ile
165 170 175
Glu Ala Ala Trp Gly Ala Pro Lys Phe Tyr Leu Ile Ser His Ile Pro
180 185 190
Gly Ala Asp Tyr Ile Asp Thr Asn Glu Val Glu Ser Glu Pro Leu Trp
195 200 205
Asn Lys Val Ser Asp Glu Gln Leu Lys Ala Met Leu Ala Lys His Gly
210 215 220
Ile Arg His Asp Thr Thr Val Ile Leu Tyr Gly Arg Asp Val Tyr Ala
225 230 235 240
Ala Ala Arg Val Ala Gln Ile Met Leu Tyr Ala Gly Val Lys Asp Val
245 250 255
Arg Leu Leu Asp Gly Gly Trp Gln Thr Trp Ser Asp Ala Gly Leu Pro
260 265 270
Val Glu Arg Gly Thr Pro Pro Lys Val Lys Ala Glu Pro Asp Phe Gly
275 280 285
Val Lys Ile Pro Ala Gln Pro Gln Leu Met Leu Asp Met Glu Gln Ala
290 295 300
Arg Gly Leu Leu His Arg Gln Asp Ala Ser Leu Val Ser Ile Arg Ser
305 310 315 320
Trp Pro Glu Phe Ile Gly Thr Thr Ser Gly Tyr Ser Tyr Ile Lys Pro
325 330 335
Lys Gly Glu Ile Ala Gly Ala Arg Trp Gly His Ala Gly Ser Asp Ser
340 345 350
Thr His Met Glu Asp Phe His Asn Pro Asp Gly Thr Met Arg Ser Ala
355 360 365
Asp Asp Ile Thr Ala Met Trp Lys Ala Trp Asn Ile Lys Pro Asp Gln
370 375 380
Gln Val Ser Phe Tyr Cys Gly Thr Gly Trp Arg Ala Ser Glu Thr Phe
385 390 395 400
Met Tyr Ala Arg Ala Met Gly Trp Asn Asn Val Ser Val Tyr Asp Gly
405 410 415
Gly Trp Tyr Glu Trp Ser Ser Asp Pro Lys Asn Pro Val Ala Thr Gly
420 425 430
Glu Arg Gly Pro Asp Ser Ser Lys
435 440
<210> 7
<211> 966
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
atgacgctct cactggccaa ctacctggca gccgactcgg ccgccgaagc actgcgccgt 60
gacgtccgcg cgggcctcac cgcggcaccg aagagtctgc cgcccaagtg gttctacgac 120
gccgtcggca gtgatctgtt cgaccagatc acccggctcc ccgagtatta ccccacccgc 180
accgaggcgc agatcctgcg gacccggtcg gcggagatca tcgcggccgc gggtgccgac 240
accctggtgg aactgggcag tggtacgtcg gagaaaaccc gcatgctgct cgacgccatg 300
cgcgacgccg agttgctgcg ccgcttcatc ccgttcgacg tcgacgcggg cgtgctgcgc 360
tcggccgggg cggcaatcgg cgcggagtac cccggtatcg agatcgacgc ggtatgtggc 420
gatttcgagg aacatctggg caagatcccg catgtcggac ggcggctcgt ggtgttcctg 480
gggtcgacca tcggcaacct gacacccgcg ccccgcgcgg agttcctcag tactctcgcg 540
gacacgctgc agccgggcga cagcctgctg ctgggcaccg atctggtgaa ggacaccggc 600
cggttggtgc gcgcgtacga cgacgcggcc ggcgtcaccg cggcgttcaa ccgcaacgtg 660
ctggccgtgg tgaaccgcga actgtccgcc gatttcgacc tcgacgcgtt cgagcatgtc 720
gcgaagtgga actccgacga ggaacgcatc gagatgtggt tgcgtgcccg caccgcacag 780
catgtccgcg tcgcggcact ggacctggag gtcgacttcg ccgcgggtga ggagatgctc 840
accgaggtgt cctgcaagtt ccgtcccgag aacgtcgtcg ccgagctggc ggaagccggt 900
ctgcggcaga cgcattggtg gaccgatccg gccggggatt tcgggttgtc gctggcggtg 960
cggtga 966
<210> 8
<211> 1002
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atggcatact cgaagaccaa tctttccgaa ctgccccttg cggacataga caaccattta 60
actgagatag gcttcgacac tactatttca gagattatta ctgggttgac tgctaatgcg 120
aagtatattc agtccaagta cttttatgat aaacggggtt ctgctttatt tgagaaaatt 180
acttcattat cagagtacta cccgagtaga acagagaagg ctataatttc acaattaccg 240
ccagccttaa tagaagatct ggctgacatc gacattatcg agttgggctg cggagatcac 300
agcaagatct cactgcttat acgccggata cccgccgaat ctgtgcctgg tttgcgctat 360
ttcccaattg atatctctca aacggcttta aaacaatcaa tcgaggactt gagagactta 420
tttccagccc tgaaggttaa aggcatcctt gcagattatg ttcaccagat gcacctgttc 480
ccagaggaac gtaaacgctt gttttgtttc tttggttcta cgataggcaa tctgtcacgt 540
gaagagacac tggattttat gcagaacatg ggcacaacta tgcacccagg cgatatgtta 600
ctggtcggta tggatcgtgt aaagaatatc gcattactgg agaaggcata taatgacgat 660
caattcataa cggcaatgtt taacaaaaat atattgcgcg ttataaacgg attaataaaa 720
tctgacttca atcctgacga tttcgagcac cgtgcttttt ataatgcgga ctttaacaga 780
atcgaaatgc accttgaagc taccggtaat atctcggtga agagcgcatt catgccagaa 840
ctgatacgga ttaaaaaagg agaaactatc cacacagaga acagtcacaa atttgagaaa 900
gctgatatat tgttaatggg acagcatgca gggttagcga tcaagaacat ctattccgac 960
aagaacgaac tttttagcct ggcccattat gagaagaagt ga 1002
<210> 9
<211> 600
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atgctgggca tggacgctga tactgcgagc ttctgggaag agaaatatcg cgccgactta 60
accgcatggg atcggggcgg tgtatctccc gctctggaac attggttggc cgagggtgcg 120
ttgaaacccg gtcgcatttt gataccgggc tgcgggtatg gccacgaagt cttagcttta 180
gctcggcgcg gatttgaggt ttgggggctt gacatagcac tgacacccgt tcgtcggctt 240
caagaaaagt tggcacaggc tggtcttacg gcacacgtag tcgagggcga cgtgcgtact 300
tggcaacccg aacaaccgtt cgatgcagta tatgaacaaa catgcttatg cgcccttagc 360
cccgaagatt ggccacggta cgaagcccaa ttgtgccgtt ggcttagacc tggcggcaga 420
ttattcgcac tttggatgca gacagaccgg ccaggcggac cgccatacca ttgtgggttg 480
gaagcaatgc gtgttttatt tgcgcttgaa agatggcgtt gggtcgaacc gccccagaga 540
acagtgccac accctacagg tttcttcgag tatgccgcga tccttgaacg gttggtctga 600
<210> 10
<211> 612
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atgagtggac ccgacttaaa tttctggcag caacgttttg acaccggcca acttccgtgg 60
gaccgtggcg caccttcgcc acaactggcg gcttggttgg gtgatgggtc attagcgcca 120
ggtcgcattg ccgtaccggg gtgcggttca ggacatgaag ttgttgcgtt agcccgcggt 180
gggttctcag taacagccat tgattacgcc cccggagcag tgcgcttaac ccaaggccgc 240
ttggctgcgg cggggttagc ggcggaagtc gtgcaggctg acgtacttac gtggcagcca 300
acggctccgc ttgacgctgt gtacgagcaa acttgtctgt gtgcattgca tcccgaccat 360
tgggtggcat acgcagctag attacacgct tggcttagac caggaggtac tttggcattg 420
ttggcaatgc aggcactgcg tgagggcgct ggacagggct tgatagaagg gcctccttac 480
catgttgacg ttaacgctct tcgcgcgctg ctgccggggg accgttggga ctggccacgt 540
ccaccgtatg cgcgcgttcc tcacccctct tctacatggg ccgagttggc aatagtcctg 600
actcggcgtt ga 612
<210> 11
<211> 1374
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
atgcagaata agaattttcg tgcaccccag tcagaggcca taggcatctt gtataaactt 60
attgaaactg gatcgaagca caaaaacatg tacgaccaca cagagatcac aacagacagt 120
ctgttggcac ttttgggttc ggaaaaggtg aagataattg acgttcgctc ggctgacgcg 180
tataacggtt ggcggatgcg tggtgaagta cgtggaggcc acatcaaagg tgcaaagtcg 240
ttgccagcga agtggctgac agatccggaa tggcttaaca ttgttcgttt caaacagata 300
cgtcccgagg acgccatcgt cctttatggt tatacgcccg aggagtgcga acaaactgcc 360
actagattca aagagaatgg ttataataat gtgagcgtat ttcacagatt ccacccggac 420
tggactggga acgatgcttt cccaatggat agactggagc aatataatag acttgtaccc 480
gccgaatggg ttaacggttt gataagcggg gaagagatcc cagagtacga caatgacacc 540
ttcatcgtgt gtcatgcaca ttatcggaac agagatgcgt atcttagcgg ccacattccg 600
ggtgctactg acatggatac tttggcgtta gaatcgccag agacctggaa tcgtcggact 660
ccagaagaat taaagaaagc tttagaagag catgggataa cggcttcgac gactgtcgtt 720
ctttatggga aatttatgca tcccgataac gcagatgaat ttcctggatc cgcagctggc 780
catatcgggg cgattcgctt ggctttcatt atgatgtacg cgggggttga ggacgttcgg 840
gtcctgaatg gcgggtatca atcatggacc gatgcgggat ttgctatttc caaagatgac 900
gtgccaaaga cgactgtccc agagttcggc gcacccattc cttcccgtcc ggaattcgct 960
gtagatatcg acgaagccaa ggaaatgctt caatcagagg attcagatct ggtgtgcgtg 1020
cgctcgtacc cggagtatat cggcgaggtc agcggctata attacataaa aaaaaagggc 1080
agaatcccgg gggctatatt tgctgagtgc gggtcggatg cctatcacat ggaaaactat 1140
agaaatcatg accacaccac gcgcgaatat catgaaatag aagatatatg ggcaaaaagc 1200
gggatcatcc cgaagaaaca cttggctttt tattgcggta ctggatggcg tggttctgag 1260
gcttggttca acgcgttgct gatgggttgg ccgcgcgttt ccgtttatga cggcggttgg 1320
tttgagtgga gcaacgaccc cgaaaaccca tacgagacgg gagttccgaa gtga 1374
<210> 12
<211> 1323
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgtcgggat tttcgatgaa acgtgtttct caaatgaccg cgctggcaat ggctttaggg 60
ctggcttgcg cttcttcgtg ggccgctgaa ctggcgaagc ctcttacact tgaccagctt 120
caacaacaaa atggcaaagc gattgatact cgccccagcg cgttttataa cggctggcca 180
caaaccttaa atggcccttc cggtcatgaa cctgccgcct taaacctctc tgctagctgg 240
ctcgacaaaa tgagcaccga acagctcaac gagtggatca agcaacataa cctgaaagcc 300
gatgccccgg tggcgctgta cggtaatgac aaagatgtcg acgccgtcaa aacgcgactg 360
caaaaagcag gttttacgca tatctccatc ctgagtgacg cgctaagcga accttcccgt 420
ctgcaaaaac tgccgcactt tgaacagctg gtatatccgc agtggctgca taacctgcaa 480
caaggtaaag aggttacggc gaaacctgcc ggtgactgga aagtcattga agcggcctgg 540
ggcgctccaa aattttacct tatcagccat attcccggcg ctgactacat cgacaccaac 600
gaagtggaaa gcgaaccgct gtggaacaaa gtttctgatg aacaactgaa agcgatgctg 660
gcaaaacacg gcattcgcca tgacaccacg gtcattctgt acgggcgtga cgtatacgct 720
gcagcgcgtg tggcgcaaat tatgctttat gccggcgtga aagatgtgcg cctgctggac 780
ggaggctggc aaacctggtc cgacgcgggt ctgcccgttg agcgcggaac gccaccgaaa 840
gtgaaagcgg aaccggattt cggcgtgaag atcccggcac aaccgcaact gatgcttgat 900
atggaacaag cgcgtggact gctgcatcgc caggatgcat cgctggtgag cattcgttcg 960
tggccagaat ttatcggtac gaccagcggt tacagctata ttaaaccaaa aggtgaaata 1020
gccggagcac gttggggaca cgcaggtagc gactcgacgc atatggaaga tttccataac 1080
ccggatggca ccatgcgcag cgccgatgat ataaccgcta tgtggaaagc atggaatatc 1140
aaaccagatc agcaagtttc attctactgc ggcactggct ggcgcgcgtc agaaaccttt 1200
atgtacgcac gcgcaatggg ctggaataac gtctccgttt acgacggtgg ctggtacgaa 1260
tggagcagcg atccaaaaaa tccggtagca accggtgaac gcggcccgga cagcagtaaa 1320
taa 1323
<210> 13
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gtgaaaggac gccatatgac gctctcactg 30
<210> 14
<211> 31
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
cactgctgct cgagcatcac cgcaccgcca g 31
<210> 15
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
ctcaaaacta ccatggcggg attttcgatg 30
<210> 16
<211> 31
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
gacgctgaag tcgctcgagc gtcagtaatt g 31
Claims (8)
1.复合酶,其由:L-组氨酸甲基化酶、卤素甲基转移酶和三甲基组氨酸硫化酶组成,
所述L-组氨酸甲基化酶的氨基酸序列如SEQ ID NO:1或2所示,
所述卤素甲基转移酶的氨基酸序列如SEQ ID NO:3或4所示,
所述三甲基组氨酸硫化酶的氨基酸序列如SEQ ID NO:5或6所示。
2.权利要求1所述的复合酶在麦角硫因酶催化制备中的应用。
3.麦角硫因的酶催化制备方法,其特征在于,包括:
L-组氨酸经L-组氨酸甲基化酶、卤素甲基转移酶催化,获得三甲基组氨酸;然后经三甲基组氨酸硫化酶催化获得麦角硫因;
所述L-组氨酸甲基化酶的氨基酸序列如SEQ ID NO:1或2所示,
所述卤素甲基转移酶的氨基酸序列如SEQ ID NO:3或4所示,
所述三甲基组氨酸硫化酶的氨基酸序列如SEQ ID NO:5或6所示。
4.根据权利要求3所述的酶催化制备方法,其特征在于,其中三甲基组氨酸的制备方法包括:
在缓冲液中加入L-组氨酸、腺苷蛋氨酸、L-组氨酸甲基化酶和卤素甲基转移酶,然后滴加碘甲烷,pH7.0~9.0搅拌反应制得三甲基组氨酸。
5.根据权利要求4所述的酶催化制备方法,其特征在于,
所述缓冲液为100mmol/L pH值为8.0的磷酸缓冲液;
所述加入至L-组氨酸浓度为100 mmol/L ~200mmol/L;腺苷蛋氨酸浓度为0.8 mmol/L~1.2 mmol/L;L-组氨酸甲基化酶的浓度为500 U/L ~1000U/L;卤素甲基转移酶的浓度为800 U/L ~1500U/L;
所述滴加碘甲烷与腺苷蛋氨酸的摩尔比为(360~720):1。
6.根据权利要求3所述的酶催化制备方法,其特征在于,所述三甲基组氨酸硫化酶催化获得麦角硫因包括:加入三甲基组氨酸硫化酶和聚硫化钾,N2环境反应获得麦角硫因。
7.根据权利要求6所述的酶催化制备方法,其特征在于,所述加入三甲基组氨酸硫化酶至浓度为600 U/L ~800 U/L,加入聚硫化钾的量为三甲基组氨酸的两倍当量。
8.根据权利要求3~7任一项所述的酶催化制备方法,其特征在于,
所述L-组氨酸甲基化酶的制备方法包括:将编码L-组氨酸甲基化酶的核酸转化入敲除S-腺苷同型半胱氨酸核苷水解酶mtnN基因的宿主,经诱导表达获得含有L-组氨酸甲基化酶的菌液;
所述卤素甲基转移酶的制备方法包括:将编码卤素甲基转移酶的核酸转化入敲除S-腺苷同型半胱氨酸核苷水解酶mtnN基因的宿主,经诱导表达获得含有卤素甲基转移酶的菌液;
所述三甲基组氨酸硫化酶的制备方法包括:将编码三甲基组氨酸硫化酶的核酸转化入敲除S-腺苷同型半胱氨酸核苷水解酶mtnN基因的宿主,经诱导表达获得含有三甲基组氨酸硫化酶的菌液。
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S-腺苷甲硫氨酸的研究进展;汤亚杰等;《生物技术通报》;20070426(第02期);79-84 * |
TPMT Chloracidobacterium thermophilum;GenBank:AEP12557.1;《GenBank:AEP12557.1》;20160323;1-2 * |
TPMT methylibium sp.T29;GenBank:EWS55296.1;《GenBank:EWS55296.1》;20140220;1-2 * |
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CN112301013A (zh) | 2021-02-02 |
WO2022095591A1 (zh) | 2022-05-12 |
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