CN116515785A - 亚砜合酶及其在制备麦角硫因或其中间体中的应用 - Google Patents
亚砜合酶及其在制备麦角硫因或其中间体中的应用 Download PDFInfo
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Abstract
本发明公开了亚砜合酶及其在制备麦角硫因或其中间体中的应用。一种亚砜合酶,其氨基酸序列如SEQ ID NO:3所示或与SEQ ID NO:3具有至少99%的序列同一性。本发明首次对合成亚砜合酶蛋白的基因进行截短改造,保留了其亚砜合酶活性,并提高了其催化活性。通过基因突变等手段改造截短后的亚砜合酶蛋白,筛选得到催化活性进一步提高的突变体,且突变的亚砜合酶的麦角硫因产量可达392mg/L。
Description
技术领域
本发明属于生物工程领域,具体涉及一种亚砜合酶及其在制备麦角硫因或其中间体中的应用。
背景技术
麦角硫因(以下也简称“ERG”)是一种独特的含硫氨基酸,广泛存在于人体的多种组织和器官,但是人体不能合成麦角硫因,主要从食物中摄取。麦角硫因因其独特的化学结构,具有较高的稳定性和强的抗氧化功能,可以用作保健品,食品防腐剂以及应对多种疾病的保护剂等。目前,麦角硫因可以通过化学方法合成,也可以从蘑菇等天然产物中提取,但是这两种方法存在产量低,杂质多,成本高等缺点。随着多条麦角硫因微生物合成路径的发现,可以期望通过微生物发酵或体外酶促反应实现麦角硫因的大量生产。目前的研究主要包括(1)寻找天然合成麦角硫因的微生物(2)直接引入或组合不同来源的麦角硫因合成途径,利用各种微生物宿主菌(如大肠杆菌,米曲霉,酿酒酵母等)生产麦角硫因。如CN113186107A提供了一种麦角硫因生产菌-贝壳状革耳菌(Panus conchatus),结合发酵过程调控和工艺优化降低了发酵成本,但是产量偏低,96h发酵产量达到140.89mg/L。专利CN110358719A中克隆了不同来源的egtABCDE基因簇,分别在大肠杆菌和枯草芽孢杆菌中实现了麦角硫因的异源表达,但是egtABCDE合成途径步骤多,麦角硫因与谷胱甘肽的合成存在潜在的竞争作用,且其存在发酵时间长,组氨酸等前体氨基酸的转化率低等问题。CN112251392A通过基因改造及宿主菌改造提供了一种高产麦角硫因的基因工程菌,经30h摇瓶发酵产量达到105.7mg/L。但是该操作复杂,在大肠杆菌基因组上整合了多个外源基因,可能会对宿主菌造成一定的代谢负担。由于天然合成麦角硫因的微生物产量低,天然存在的酶的活性较低等原因,目前仍缺乏高效生产麦角硫因的菌株。天然麦角硫因合成途径存在产率低,相关酶活性不高等缺点。
发明内容
来源于Neurospora crassa的NcEgt1蛋白(即亚砜合酶)参与催化麦角硫因的形成,但其活性较低,本发明的目的是通过基因工程手段改造NcEgt1蛋白,通过筛选,获得活性提高的突变体。
为了解决egtABCDE合成途径步骤多,与谷胱甘肽合成存在竞争作用等问题,本发明以大肠杆菌为宿主菌,构建了一个包含非天然麦角硫因合成途径的基因工程菌,该途径包含三种酶——来自Mycobacterium smegmatis的EgtD(组氨酸甲基转移酶),来自Neurospora crassa的NcEgt1、和同样来自Mycobacterium smegmatis的EgtE(C-S键裂解酶),分别负责催化组氨酸三甲基化生成化合物Ⅰ,催化半胱氨酸和化合物Ⅰ生成化合物Ⅱ以及化合物Ⅱ中C-S键裂解生成麦角硫因(如图1所示)。该途径比egtABCDE途径短,仅需三步酶催化反应,且该途径中的NcEgt1酶以半胱氨酸和组氨酸甜菜碱为底物,消除了麦角硫因和谷胱甘肽合成之间的竞争作用(Hu W,Song H,Her A S,et al.Bioinformatic andbiochemical characterizations of C-S bond formation and cleavage enzymes inthe fungus Neurospora crassa ergothioneine biosynthetic pathway.[J].OrganicLetters,2014,16(20):5382-5)。
NcEgt1催化的反应是该麦角硫因合成途径中的关键步骤,但是该天然酶存在分子量大,活性低等问题,使得其催化的反应成为该途径中的限速步骤,为了提高NcEgt1蛋白的催化活性,本发明提供一种亚砜合酶及其在制备麦角硫因或其中间体中的应用。发明人通过截短,随机突变,组合突变等方法对NcEgt1蛋白进行改造,经筛选获得了活性提高的突变体。活性提高的突变体与EgtD和EgtE共同作用,进一步提高了麦角硫因的产量。
本发明第一方面提供一种亚砜合酶,其氨基酸序列如SEQ ID NO:3所示或与SEQID NO:3具有至少99%的序列同一性。
本发明中将SEQ ID NO:3的前两个氨基酸M和G的位置定义为-2,-1,第三个氨基酸M的位置定义为1。
所述氨基酸序列较佳地与SEQ ID NO:3相比包含选自以下一个或多个的氨基酸残基差异:
G-1R/S;T27S;Q34R;Q66R/H;K69R;K72I;A74V;A79T;K83D;E86G;D107Y/A;L153Q;L170P;Q195H;A201S;S215N;Q238H;D259V;N270S;G276S;Q293R;S297G;V311M;A316S;L317R;S324N/C;G330C;T368S;A395E;F424Y;V440I;L445I;P469I/T;P509S;
并具有不低于如SEQ ID NO:3的氨基酸序列所示的亚砜合酶的活性。
上述差异可以是在SEQ ID NO:3上进行突变,也可以是在其它序列上进行突变,只要最终结果体现为其氨基酸序列与SEQ ID NO:3有上述差异即可。
例如,这些差异中G-1R/S代表在-1位点处的G最终被R或S替换。
在某一较佳实施方案中,所述氨基酸序列为与SEQ ID NO:3相比包含选自以下任一组的氨基酸残基差异:
G-1S和D107A;
Q66H和S324C;或,
D107Y和V311M;或,
A79T和S297G;或,
L170P和Q195H;或,
K83D和S215N;或,
D259V和V440I;或,
T27S和A74V;或,
Q238H和Q293R;或,
K69R和T368S,P509S;或,
G276S、G330C和A395E;或,
E86G、A316S和L317R;或,
Q34R、K72I、N270S和F424Y;或,
S324N和L445I;或,
D107A和P469T;或,
Q66R和A201S;或,
L445I和P469I;或,
K83D、D107A和S215N;或,
Q66R、D107Y和V311M;或,
G-1S、D107A和P469T;或,
G-1R、T27S和A74V;或,
Q66H、E86G、A316S和L317R;或,
G276S、G330C、A395E和P469T;或,
Q66H、A79T、S297G和S324C;或,
L170P、Q195H、D259V和V440I;或,
K69R、D259V、T368S、V440I和P509S;或,
L153Q、L170P、Q195H、Q238H和Q293R;或,
T27S、Q34R、K72I、A74V、N270S和F424Y;或,
G-1S、L153Q、L170P、Q195H、Q238H和Q293R。
本发明另一方面提供一种融合蛋白,其包括如本发明所述的亚砜合酶、以及组氨酸甲基转移酶和C-S键裂解酶。
所述组氨酸甲基转移酶的氨基酸序列较佳地如SEQ ID NO:4所示,或所述C-S键裂解酶的氨基酸序列较佳地如SEQ ID NO:6所示。
所述融合蛋白从N端至C端较佳地依次包括所述亚砜合酶、所述组氨酸甲基转移酶以及所述C-S键裂解酶。
本发明另一方面提供一种分离的核酸,所述核酸编码如本发明所述的亚砜合酶或如本发明所述的融合蛋白。
所述核酸的核苷酸序列较佳地如SEQ ID NO:2所示。
本发明另一方面提供一种重组表达载体,其包含如本发明所述的核酸。
所述重组表达载体的骨架质粒较佳地为pETDuet-1。
编码所述组氨酸甲基转移酶的核苷酸序列较佳地如SEQ ID NO:5所示或编码所述C-S键裂解酶的核酸序列较佳地如SEQ ID NO:7所示。
本发明另一方面提供一种转化体,其包含如本发明所述的核酸或如本发明所述的重组表达载体。
所述转化体的宿主细胞较佳地为埃希氏大肠杆菌(Escherichia coli)例如E.coli BL21(DE3)。
本发明另一方面提供一种制备如本发明所述的亚砜合酶的方法,所述方法包括培养如本发明所述的转化体获得所述亚砜合酶。
本发明另一方面提供一种制备化合物II的方法,所述方法包括如下步骤:使用如本发明所述的亚砜合酶或本发明所述的转化体制备所述化合物II;
在某一较佳实施方案中,所述方法为使用发酵培养基震荡培养所述转化体,之后加入异丙基硫代半乳糖苷诱导所述化合物II的表达。
所述发酵培养基优选含有Fe2+和半胱氨酸;
在某一较佳实施方案中,所述方法为在半胱氨酸、Fe2+、氧气以及所述亚砜合酶的存在下,与组氨酸三甲基内盐进行反应,即得所述化合物II。
在某一较佳实施方案中,所述亚砜合酶以菌体存在于菌体破碎后的上清液中。
在某一较佳实施方案中,所述组氨酸三甲基内盐与所述上清液的质量体积比为3-15mg/ml,例如9.9mg/ml。
在某一较佳实施方案中,所述半胱氨酸、Fe2+、以及所述组氨酸三甲基内盐的摩尔比为(1-3):1:(1-2),例如5:2:2.5。
在某一较佳实施方案中,所述反应在转速为200-250rpm例如220rpm、温度为20℃-30℃例如25℃的条件下进行。
在某一较佳实施方案中,所述反应在pH为6-8,例如pH为7的条件下进行。
本发明另一方面提供一种麦角硫因的制备方法,其包括如本发明所述的方法制备所述化合物II的步骤,进一步还包括将所述化合物II制备为麦角硫因的步骤。
本发明另一方面提供如本发明所述的亚砜合酶或如本发明所述的转化体在制备麦角硫因或其中间体例如化合物II中的应用。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
1)首次对合成NcEgt1蛋白的基因进行截短改造,保留了其亚砜合酶活性,并提高了其催化活性。
2)通过基因突变等手段改造截短后的NcEgt1蛋白,筛选得到催化活性进一步提高的突变体,且突变的亚砜合酶在制备麦角硫因时产量可达392mg/L。
附图说明
图1显示了本发明构建的麦角硫因生物合成途径,其中,Histidine为组氨酸,Hercynine为组氨酸三甲基内盐(即(αS)-α-Carboxy-N,N,N-trimethyl-1H-imidazole-4-ethanaminium hydroxide,inner salt),Methione为甲硫氨酸,SAM为S-腺苷甲硫氨酸,Cysteine为半胱氨酸,Hercynylcysteine sulfoxide为(2S)-3-(2-{[(2R)-2-氨基-2-羧基乙基]亚磺酰}-1H-咪唑-5-基)-2-(三甲基氮烷正离子基)丙酸酯,Ergothioneine为麦角硫因。
图2显示了包含麦角硫因合成途径的质粒图谱。
图3为NcEgt1蛋白的结构域。
图4为表达截短后NcEgt1蛋白的质粒图谱。
图5为体外实验液相检测图谱(箭头所指为产物峰);其中,A为W菌体催化的体外反应液相检测图,B为W1菌体催化的体外反应液相检测图。
图6为麦角硫因液相检测图谱(箭头所指为麦角硫因);其中,A为实施例7中的ERG液相检测图谱,B为实施例8中的ERG液相检测图谱。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明所用的菌株、质粒、试剂
本发明使用的大肠杆菌DH5α和大肠杆菌BL21(DE3)均购自康为世纪公司,分别用来进行基因克隆和蛋白表达。本发明中使用的DNA胶回收纯化试剂盒和质粒提取试剂盒购自生工生物工程(上海)股份有限公司,所有限制性内切酶和DNA聚合酶都购自Takara公司,同源重组试剂盒购自Vazyme公司。
质粒构建方法:通过PCR获得目标片段,对质粒进行酶切,分别进行DNA胶回收,得到目标片段和载体片段,同源重组后,转化大肠杆菌DH5α或BL21(DE3)感受态,涂抗性板。
LB培养基(g/L):胰蛋白胨10.0,酵母提取物5.0,NaCl 10.0,去离子水1L,pH 7.0。
发酵培养基配方(g/L):酵母提取物(24.0),大豆蛋白胨(12.0),氯化钠(3.0),甘油(5.0),磷酸氢二钾(2.0),七水硫酸镁(0.5),半胱氨酸盐酸盐(1.0),组氨酸(1.0),甲硫氨酸(1.0),柠檬酸三铁胺(0.06),去离子水1L,pH 7.0。
发酵液处理方法:取2mL发酵液,100℃水浴5min,12000rpm离心5min,取上清用0.22μm滤膜过滤后进行HPLC分析。
HPLC条件:色谱柱为Ultimate Hilic Silica,5μm,4.6×250mm;流动相为水:乙腈=20:80(v/v);柱温为30℃;检测波长为254nm;流速为1.0mL/min,进样量为20μL。
体外反应HPLC检测条件:色谱柱为Cosmosil PBr column(250mm L×4.6mm ID,5μm;Nacalai Tesque,Inc.,Kyoto,Japan);流动相为0.1%甲酸水;柱温为35℃;检测波长为250nm;流速为1.0mL/min,进样量为20μL。
实施例1麦角硫因工程菌和麦角硫氨酸酶工程菌的构建
将来源于耻垢分枝杆菌Mycobacterium smegmatis的编码组氨酸甲基转移酶(EgtD)的基因,PLP依赖的C-S键裂解酶(EgtE)的基因以及来自Neurospora crassa的NcEgt1酶的编码基因委托商业化公司进行全基因合成,克隆到pETDuet-1载体中,得到质粒pETDuet-1-ncEgt1-egtD-egtE(如图2所示)。将该质粒转入大肠杆菌BL21(DE3)感受态细胞,涂布到氨苄青霉素抗性平板(50μg/mL),37℃过夜培养。挑取阳性转化单菌落,LB培养,提取质粒测序验证,获得含有麦角硫因合成途径的重组基因工程菌S。按照上述相同的流程将来源于Burkholderia sp.HME13的麦角硫氨酸酶ergothionase(accession numberBAM63550.1)的基因序列连接到载体pACYCDuet-1上,采用上述同样的方法制备麦角硫氨酸酶上清液。
实施例2 NcEgt1酶的截短改造
NcEgt1蛋白含878个氨基酸(SEQ ID NO:1),具有两个结构域——甲基转移酶结构域和C-S键合成酶结构域(如图3所示)。发明人研究发现NcEgt1蛋白催化化合物Ⅰ和半胱氨酸形成化合物Ⅱ的反应是该麦角硫因合成途径的限速步骤,为了方便后续酶改造,我们首先对其进行了截短改造。在两个结构域连接处设计引物,通过PCR得到截短的ncEgt1基因(称为TncEgt1,核苷酸序列如SEQ ID NO:2所示),用HindⅢ和NcoⅠ酶切质粒pETDuet-1,然后用同源重组的方式将ncEgt1片段以及TncEgt1基因片段分别插入到pETDuet-1载体的HindⅢ和NcoⅠ酶切位点(如图4所示),转化大肠杆菌BL21(DE3)感受态细胞,涂布到50μg/mL含氨苄青霉素的平板,37℃过夜培养。挑取阳性转化单菌落,LB培养,提取质粒测序验证,得到菌株W(含ncEgt1基因)和W1(含TncEgt1基因)。
实施例3体外催化反应
麦角硫因生物合成途径如图1所示。
取10μL菌株W的甘油菌接至5mL LB培养基中(含50μg/mL氨苄青霉素),37℃,220rpm培养12h。然后按1.5%的接种量将种子液转接至含100mLLB培养基的(含50μg/mL氨苄青霉素)摇瓶中,37℃,200rpm,培养3h,加入终浓度为1mM的异丙基硫代半乳糖苷(IPTG),28℃诱导蛋白表达,继续培养20h。发酵结束后,12000rpm,4℃离心获得菌体。采用相同的办法获得W1菌体。取一定量的W菌体和W1菌体,用磷酸缓冲液(pH=7.0)稀释至相同浓度,使用超声波细胞破碎仪破碎细胞,12000rpm,4℃离心获得上清液。反应体系如下:2mL反应体系,100mM HEPES(pH7.5),5mM Cys·HCl,2mM FeSO4·7H2O,2.5mM HER(Hercynine,组氨酸三甲基内盐),100μl菌体破碎上清液。25℃,220rpm,有氧条件下进行反应。反应30min后,终止反应。用0.1%甲酸水等比例稀释反应液,进行高效液相检测(如图5所示)。相同反应条件下,W1菌体催化能力是W菌体的27倍。
表1
菌株 | 序列 | 相对活性 |
W | SEQ ID NO:1 | 100% |
W1 | SEQ ID NO:3 | 2700% |
实施例4TNcEgt1酶随机突变库的构建与筛选
使用HindⅢ/NcoⅠ酶切质粒pETDuet-1-ncEgt1-egtD-egtE,获得不含ncEgt1片段的载体,通过酶连的方式将TncEgt1片段插入到质粒pETDuet-1-ncEgt1-egtD-egtE的HindⅢ/NcoⅠ酶切位点。转入大肠杆菌BL21(DE3)感受态中,在含50μg/mL氨苄青霉素的LB固体培养基上37℃培养过夜。挑取阳性克隆子,测序验证,将所得菌株命名为S1。
以TncEgt1基因为模板,利用随机点突变试剂盒(II Site-DirectedMutagenesis Kit),进行易错PCR,胶回收PCR片段。通过同源重组的方式将PCR片段插入到质粒pETDuet-1-ncEgt1-egtD-egtE的HindⅢ/NcoⅠ酶切位点,然后转入大肠杆菌BL21(DE3)感受态中,在含50μg/mL氨苄青霉素的LB固体培养基上37℃培养过夜。将突变体单菌落挑选至每孔含400μL LB液体培养基(含50μg/mL氨苄青霉素)的96孔板中,37℃,200rpm过夜培养。然后将10μL种子液转移至每孔含600μL发酵培养基(含50μg/mL氨苄青霉素)的96深孔板中,37℃,200rpm,培养3h。然后加入终浓度为1mM的异丙基硫代半乳糖苷(IPTG),降温至28℃诱导突变体表达,继续培养20h。发酵结束后,96深孔板在4℃,4000g离心30min,用0.1M磷酸缓冲液将上清稀释5倍,分别取190μL到96孔酶标板中,在311nm下检测发酵液的初始吸收值,然后加入10μL麦角硫氨酸酶上清液(含有10U麦角硫氨酸酶的0.1M磷酸缓冲液,pH 7.0,U的定义是1min内催化1mmol底物转化所需要的酶量)(该酶上清液制备方法同实施例3),室温反应10min后在311nm下检测得到一个终止值,根据标准曲线算出对应的麦角硫因含量。挑选麦角硫因含量高的突变体进行测序及摇瓶验证,筛选结果如表2所示。
表2
注:将SEQ ID NO:3的前两个氨基酸M和G的位置定义为-2,-1。
实施例5TNcEgt1酶组合突变库的构建与筛选
该实施例为在实施例4的随机突变的基础上选择相应突变位点进行组合突变。
根据随机突变的结果,设计相应的引物,以TncEgt1基因为模板,使用PrimeSTARGXL DNA Polymerase(TaKaRa,Japan)进行重叠PCR,胶回收PCR片段,通过同源重组的方式将PCR片段插入到质粒pETDuet-1-ncEgt1-egtD-egtE的HindⅢ/NcoⅠ位点,然后转入大肠杆菌BL21(DE3)中,在含50μg/mL氨苄青霉素的LB固体培养基上37℃培养过夜。挑取阳性单克隆至5mL LB中,37℃,200rpm过夜培养,测序验证,并进行摇瓶发酵,利用高效液相检测ERG含量。筛选结果如表3所示。
表3
注:将SEQ ID NO:3的前两个氨基酸M和G的位置定义为-2,-1。
实施例6利用S菌株发酵生产麦角硫因
取10μl S菌株的甘油菌接入5mL LB中(含50μg/mL氨苄青霉素),37℃,200rpm培养12h。然后按1.5%的接种量将种子液转移至含20mL发酵培养基的(含50μg/mL氨苄青霉素)摇瓶中,37℃,200rpm,培养3h,加入终浓度为1mM的异丙基硫代半乳糖苷(IPTG),28℃诱导突变体表达,继续培养20h。发酵结束后按照前面样品处理方法处理发酵液,进行高效液相检测,麦角硫因含量为40.0mg/L。
实施例7利用S1菌株发酵生产麦角硫因
取10μl甘油菌(S1菌株)接入5mL LB中(含100μg/mL氨苄青霉素),37℃,200rpm培养12h。然后按1.5%的接种量将种子液转移至含20mL发酵培养基的(含50μg/mL氨苄青霉素)摇瓶中,37℃,200rpm,培养3h,加入终浓度为1mM的异丙基硫代半乳糖苷(IPTG),28℃诱导突变体表达,继续培养20h。发酵结束后按照前面样品处理方法处理发酵液,高效液相检测含量为54.9mg/L(见图6中的A)。
实施例8利用含突变25对应基因的突变菌株发酵生产麦角硫因
取10μl甘油菌(含突变25序列的突变菌株)接入5mL LB中(含50μg/mL氨苄青霉素),37℃,200rpm培养12h。然后按1.5%的接种量将种子液转移至含20mL发酵培养基的(含50μg/mL氨苄青霉素)摇瓶中,37℃,200rpm,培养3h,加入终浓度为1mM的异丙基硫代半乳糖苷(IPTG),28℃诱导突变体表达,继续培养20h。发酵结束后按照前面样品处理方法处理发酵液,进行高效液相检测,麦角硫因含量为392mg/L(见图6中的B)。
SEQUENCE LISTING
<110> 上海医药工业研究院有限公司
中国医药工业研究总院有限公司
<120> 亚砜合酶及其在制备麦角硫因或其中间体中的应用
<130> P210110037C
<160> 7
<170> PatentIn version 3.5
<210> 1
<211> 878
<212> PRT
<213> Artificial Sequence
<220>
<223> NcEgt1氨基酸序列
<400> 1
Met Gly Met Pro Ser Ala Glu Ser Met Thr Pro Ser Ser Ala Leu Gly
1 5 10 15
Gln Leu Lys Ala Thr Gly Gln His Val Leu Ser Lys Leu Gln Gln Gln
20 25 30
Thr Ser Asn Ala Asp Ile Ile Asp Ile Arg Arg Val Ala Val Glu Ile
35 40 45
Asn Leu Lys Thr Glu Ile Thr Ser Met Phe Arg Pro Lys Asp Gly Pro
50 55 60
Arg Gln Leu Pro Thr Leu Leu Leu Tyr Asn Glu Arg Gly Leu Gln Leu
65 70 75 80
Phe Glu Arg Ile Thr Tyr Leu Glu Glu Tyr Tyr Leu Thr Asn Asp Glu
85 90 95
Ile Lys Ile Leu Thr Lys His Ala Thr Glu Met Ala Ser Phe Ile Pro
100 105 110
Ser Gly Ala Met Ile Ile Glu Leu Gly Ser Gly Asn Leu Arg Lys Val
115 120 125
Asn Leu Leu Leu Glu Ala Leu Asp Asn Ala Gly Lys Ala Ile Asp Tyr
130 135 140
Tyr Ala Leu Asp Leu Ser Arg Glu Glu Leu Glu Arg Thr Leu Ala Gln
145 150 155 160
Val Pro Ser Tyr Lys His Val Lys Cys His Gly Leu Leu Gly Thr Tyr
165 170 175
Asp Asp Gly Arg Asp Trp Leu Lys Ala Pro Glu Asn Ile Asn Lys Gln
180 185 190
Lys Cys Ile Leu His Leu Gly Ser Ser Ile Gly Asn Phe Asn Arg Ser
195 200 205
Asp Ala Ala Thr Phe Leu Lys Gly Phe Thr Asp Val Leu Gly Pro Asn
210 215 220
Asp Lys Met Leu Ile Gly Val Asp Ala Cys Asn Asp Pro Ala Arg Val
225 230 235 240
Tyr His Ala Tyr Asn Asp Lys Val Gly Ile Thr His Glu Phe Ile Leu
245 250 255
Asn Gly Leu Arg Asn Ala Asn Glu Ile Ile Gly Glu Thr Ala Phe Ile
260 265 270
Glu Gly Asp Trp Arg Val Ile Gly Glu Tyr Val Tyr Asp Glu Glu Gly
275 280 285
Gly Arg His Gln Ala Phe Tyr Ala Pro Thr Arg Asp Thr Met Val Met
290 295 300
Gly Glu Leu Ile Arg Ser His Asp Arg Ile Gln Ile Glu Gln Ser Leu
305 310 315 320
Lys Tyr Ser Lys Glu Glu Ser Glu Arg Leu Trp Ser Thr Ala Gly Leu
325 330 335
Glu Gln Val Ser Glu Trp Thr Tyr Gly Asn Glu Tyr Gly Leu His Leu
340 345 350
Leu Ala Lys Ser Arg Met Ser Phe Ser Leu Ile Pro Ser Val Tyr Ala
355 360 365
Arg Ser Ala Leu Pro Thr Leu Asp Asp Trp Glu Ala Leu Trp Ala Thr
370 375 380
Trp Asp Val Val Thr Arg Gln Met Leu Pro Gln Glu Glu Leu Leu Glu
385 390 395 400
Lys Pro Ile Lys Leu Arg Asn Ala Cys Ile Phe Tyr Leu Gly His Ile
405 410 415
Pro Thr Phe Leu Asp Ile Gln Leu Thr Lys Thr Thr Lys Gln Ala Pro
420 425 430
Ser Glu Pro Ala His Phe Cys Lys Ile Phe Glu Arg Gly Ile Asp Pro
435 440 445
Asp Val Asp Asn Pro Glu Leu Cys His Ala His Ser Glu Ile Pro Asp
450 455 460
Glu Trp Pro Pro Val Glu Glu Ile Leu Thr Tyr Gln Glu Thr Val Arg
465 470 475 480
Ser Arg Leu Arg Gly Leu Tyr Ala His Gly Ile Ala Asn Ile Pro Arg
485 490 495
Asn Val Gly Arg Ala Ile Trp Val Gly Phe Glu His Glu Leu Met His
500 505 510
Ile Glu Thr Leu Leu Tyr Met Met Leu Gln Ser Asp Lys Thr Leu Ile
515 520 525
Pro Thr His Ile Pro Arg Pro Asp Phe Asp Lys Leu Ala Arg Lys Ala
530 535 540
Glu Ser Glu Arg Val Pro Asn Gln Trp Phe Lys Ile Pro Ala Gln Glu
545 550 555 560
Ile Thr Ile Gly Leu Asp Asp Pro Glu Asp Gly Ser Asp Ile Asn Lys
565 570 575
His Tyr Gly Trp Asp Asn Glu Lys Pro Pro Arg Arg Val Gln Val Ala
580 585 590
Ala Phe Gln Ala Gln Gly Arg Pro Ile Thr Asn Glu Glu Tyr Ala Gln
595 600 605
Tyr Leu Leu Glu Lys Asn Ile Asp Lys Leu Pro Ala Ser Trp Ala Arg
610 615 620
Leu Asp Asn Glu Asn Ile Ser Asn Gly Thr Thr Asn Ser Val Ser Gly
625 630 635 640
His His Ser Asn Arg Thr Ser Lys Gln Gln Leu Pro Ser Ser Phe Leu
645 650 655
Glu Lys Thr Ala Val Arg Thr Val Tyr Gly Leu Val Pro Leu Lys His
660 665 670
Ala Leu Asp Trp Pro Val Phe Ala Ser Tyr Asp Glu Leu Ala Gly Cys
675 680 685
Ala Ala Tyr Met Gly Gly Arg Ile Pro Thr Phe Glu Glu Thr Arg Ser
690 695 700
Ile Tyr Ala Tyr Ala Asp Ala Leu Lys Lys Lys Lys Glu Ala Glu Arg
705 710 715 720
Gln Leu Gly Arg Thr Val Pro Ala Val Asn Ala His Leu Thr Asn Asn
725 730 735
Gly Val Glu Ile Thr Pro Pro Ser Ser Pro Ser Ser Glu Thr Pro Ala
740 745 750
Glu Ser Ser Ser Pro Ser Asp Ser Asn Thr Thr Leu Ile Thr Thr Glu
755 760 765
Asp Leu Phe Ser Asp Leu Asp Gly Ala Asn Val Gly Phe His Asn Trp
770 775 780
His Pro Met Pro Ile Thr Ser Lys Gly Asn Thr Leu Val Gly Gln Gly
785 790 795 800
Glu Leu Gly Gly Val Trp Glu Trp Thr Ser Ser Val Leu Arg Lys Trp
805 810 815
Glu Gly Phe Glu Pro Met Glu Leu Tyr Pro Gly Tyr Thr Ala Asp Phe
820 825 830
Phe Asp Glu Lys His Asn Ile Val Leu Gly Gly Ser Trp Ala Thr His
835 840 845
Pro Arg Ile Ala Gly Arg Lys Ser Phe Val Asn Trp Tyr Gln Arg Asn
850 855 860
Tyr Pro Tyr Ala Trp Val Gly Ala Arg Val Val Arg Asp Leu
865 870 875
<210> 2
<211> 1572
<212> DNA
<213> Artificial Sequence
<220>
<223> TNcEgt1核苷酸序列
<400> 2
atgggcatga gctttagcct gattccgagc gtttatgcgc gtagcgcgct gccgaccctg 60
gatgattggg aggcgctgtg ggcgacctgg gatgtggtta cccgtcaaat gctgccgcag 120
gaagagctgc tggaaaagcc gatcaaactg cgtaacgcgt gcatcttcta tctgggccac 180
attccgacct ttctggacat ccaactgacc aagaccacca aacaagcgcc gagcgaaccg 240
gcgcacttct gcaaaatctt tgagcgtggt attgacccgg atgttgacaa cccggagctg 300
tgccacgcgc acagcgaaat tccggacgag tggccgccag tggaggaaat cctgacctac 360
caagaaaccg ttcgtagccg tctgcgtggt ctgtatgcgc acggcatcgc gaacattccg 420
cgtaacgtgg gtcgtgcgat ttgggttggc ttcgagcacg aactgatgca catcgagacc 480
ctgctgtaca tgatgctgca gagcgataag accctgatcc cgacccacat tccgcgtccg 540
gatttcgaca agctggcgcg taaagcggag agcgaacgtg tgccgaacca atggtttaaa 600
attccggcgc aggaaatcac cattggtctg gacgatccgg aggatggcag cgacatcaac 660
aagcactacg gctgggacaa cgaaaaaccg ccgcgtcgtg tgcaagttgc ggcgttccaa 720
gcgcagggtc gtccgattac caacgaggaa tacgcgcagt atctgctgga gaagaacatc 780
gataaactgc cggcgagctg ggcgcgtctg gacaacgaaa acatcagcaa cggcaccacc 840
aacagcgtta gcggccacca cagcaaccgt accagcaagc aacagctgcc gagcagcttt 900
ctggagaaaa ccgcggtgcg taccgtttat ggtctggtgc cgctgaagca tgcgctggat 960
tggccggttt tcgcgagcta cgacgaactg gcgggttgcg cggcgtatat gggtggccgt 1020
attccgacct ttgaggaaac ccgtagcatc tacgcgtatg cggatgcgct gaagaaaaag 1080
aaagaggcgg aacgccaact gggtcgtacc gtgccggcgg ttaacgcgca cctgaccaac 1140
aacggtgttg agatcacccc gccgagcagc ccgagcagcg aaaccccggc ggagagcagc 1200
agcccgagcg atagcaacac caccctgatt accaccgaag acctgttcag cgatctggac 1260
ggtgcgaacg tgggctttca caactggcac ccgatgccga tcaccagcaa gggtaacacc 1320
ctggttggtc agggcgaact gggtggcgtg tgggagtgga ccagcagcgt tctgcgtaaa 1380
tgggagggct tcgaaccgat ggagctgtac ccgggttata ccgcggattt ctttgacgag 1440
aagcacaaca ttgttctggg tggcagctgg gcgacccacc cgcgtattgc gggtcgtaag 1500
agcttcgtga actggtatca gcgtaactac ccgtatgcgt gggttggtgc gcgtgtggtt 1560
cgtgacctgt aa 1572
<210> 3
<211> 523
<212> PRT
<213> Artificial Sequence
<220>
<223> TNcEgt1氨基酸序列
<400> 3
Met Gly Met Ser Phe Ser Leu Ile Pro Ser Val Tyr Ala Arg Ser Ala
1 5 10 15
Leu Pro Thr Leu Asp Asp Trp Glu Ala Leu Trp Ala Thr Trp Asp Val
20 25 30
Val Thr Arg Gln Met Leu Pro Gln Glu Glu Leu Leu Glu Lys Pro Ile
35 40 45
Lys Leu Arg Asn Ala Cys Ile Phe Tyr Leu Gly His Ile Pro Thr Phe
50 55 60
Leu Asp Ile Gln Leu Thr Lys Thr Thr Lys Gln Ala Pro Ser Glu Pro
65 70 75 80
Ala His Phe Cys Lys Ile Phe Glu Arg Gly Ile Asp Pro Asp Val Asp
85 90 95
Asn Pro Glu Leu Cys His Ala His Ser Glu Ile Pro Asp Glu Trp Pro
100 105 110
Pro Val Glu Glu Ile Leu Thr Tyr Gln Glu Thr Val Arg Ser Arg Leu
115 120 125
Arg Gly Leu Tyr Ala His Gly Ile Ala Asn Ile Pro Arg Asn Val Gly
130 135 140
Arg Ala Ile Trp Val Gly Phe Glu His Glu Leu Met His Ile Glu Thr
145 150 155 160
Leu Leu Tyr Met Met Leu Gln Ser Asp Lys Thr Leu Ile Pro Thr His
165 170 175
Ile Pro Arg Pro Asp Phe Asp Lys Leu Ala Arg Lys Ala Glu Ser Glu
180 185 190
Arg Val Pro Asn Gln Trp Phe Lys Ile Pro Ala Gln Glu Ile Thr Ile
195 200 205
Gly Leu Asp Asp Pro Glu Asp Gly Ser Asp Ile Asn Lys His Tyr Gly
210 215 220
Trp Asp Asn Glu Lys Pro Pro Arg Arg Val Gln Val Ala Ala Phe Gln
225 230 235 240
Ala Gln Gly Arg Pro Ile Thr Asn Glu Glu Tyr Ala Gln Tyr Leu Leu
245 250 255
Glu Lys Asn Ile Asp Lys Leu Pro Ala Ser Trp Ala Arg Leu Asp Asn
260 265 270
Glu Asn Ile Ser Asn Gly Thr Thr Asn Ser Val Ser Gly His His Ser
275 280 285
Asn Arg Thr Ser Lys Gln Gln Leu Pro Ser Ser Phe Leu Glu Lys Thr
290 295 300
Ala Val Arg Thr Val Tyr Gly Leu Val Pro Leu Lys His Ala Leu Asp
305 310 315 320
Trp Pro Val Phe Ala Ser Tyr Asp Glu Leu Ala Gly Cys Ala Ala Tyr
325 330 335
Met Gly Gly Arg Ile Pro Thr Phe Glu Glu Thr Arg Ser Ile Tyr Ala
340 345 350
Tyr Ala Asp Ala Leu Lys Lys Lys Lys Glu Ala Glu Arg Gln Leu Gly
355 360 365
Arg Thr Val Pro Ala Val Asn Ala His Leu Thr Asn Asn Gly Val Glu
370 375 380
Ile Thr Pro Pro Ser Ser Pro Ser Ser Glu Thr Pro Ala Glu Ser Ser
385 390 395 400
Ser Pro Ser Asp Ser Asn Thr Thr Leu Ile Thr Thr Glu Asp Leu Phe
405 410 415
Ser Asp Leu Asp Gly Ala Asn Val Gly Phe His Asn Trp His Pro Met
420 425 430
Pro Ile Thr Ser Lys Gly Asn Thr Leu Val Gly Gln Gly Glu Leu Gly
435 440 445
Gly Val Trp Glu Trp Thr Ser Ser Val Leu Arg Lys Trp Glu Gly Phe
450 455 460
Glu Pro Met Glu Leu Tyr Pro Gly Tyr Thr Ala Asp Phe Phe Asp Glu
465 470 475 480
Lys His Asn Ile Val Leu Gly Gly Ser Trp Ala Thr His Pro Arg Ile
485 490 495
Ala Gly Arg Lys Ser Phe Val Asn Trp Tyr Gln Arg Asn Tyr Pro Tyr
500 505 510
Ala Trp Val Gly Ala Arg Val Val Arg Asp Leu
515 520
<210> 4
<211> 321
<212> PRT
<213> Artificial Sequence
<220>
<223> EgtD氨基酸序列
<400> 4
Met Thr Leu Ser Leu Ala Asn Tyr Leu Ala Ala Asp Ser Ala Ala Glu
1 5 10 15
Ala Leu Arg Arg Asp Val Arg Ala Gly Leu Thr Ala Ala Pro Lys Ser
20 25 30
Leu Pro Pro Lys Trp Phe Tyr Asp Ala Val Gly Ser Asp Leu Phe Asp
35 40 45
Gln Ile Thr Arg Leu Pro Glu Tyr Tyr Pro Thr Arg Thr Glu Ala Gln
50 55 60
Ile Leu Arg Thr Arg Ser Ala Glu Ile Ile Ala Ala Ala Gly Ala Asp
65 70 75 80
Thr Leu Val Glu Leu Gly Ser Gly Thr Ser Glu Lys Thr Arg Met Leu
85 90 95
Leu Asp Ala Met Arg Asp Ala Glu Leu Leu Arg Arg Phe Ile Pro Phe
100 105 110
Asp Val Asp Ala Gly Val Leu Arg Ser Ala Gly Ala Ala Ile Gly Ala
115 120 125
Glu Tyr Pro Gly Ile Glu Ile Asp Ala Val Cys Gly Asp Phe Glu Glu
130 135 140
His Leu Gly Lys Ile Pro His Val Gly Arg Arg Leu Val Val Phe Leu
145 150 155 160
Gly Ser Thr Ile Gly Asn Leu Thr Pro Ala Pro Arg Ala Glu Phe Leu
165 170 175
Ser Thr Leu Ala Asp Thr Leu Gln Pro Gly Asp Ser Leu Leu Leu Gly
180 185 190
Thr Asp Leu Val Lys Asp Thr Gly Arg Leu Val Arg Ala Tyr Asp Asp
195 200 205
Ala Ala Gly Val Thr Ala Ala Phe Asn Arg Asn Val Leu Ala Val Val
210 215 220
Asn Arg Glu Leu Ser Ala Asp Phe Asp Leu Asp Ala Phe Glu His Val
225 230 235 240
Ala Lys Trp Asn Ser Asp Glu Glu Arg Ile Glu Met Trp Leu Arg Ala
245 250 255
Arg Thr Ala Gln His Val Arg Val Ala Ala Leu Asp Leu Glu Val Asp
260 265 270
Phe Ala Ala Gly Glu Glu Met Leu Thr Glu Val Ser Cys Lys Phe Arg
275 280 285
Pro Glu Asn Val Val Ala Glu Leu Ala Glu Ala Gly Leu Arg Gln Thr
290 295 300
His Trp Trp Thr Asp Pro Ala Gly Asp Phe Gly Leu Ser Leu Ala Val
305 310 315 320
Arg
<210> 5
<211> 966
<212> DNA
<213> Artificial Sequence
<220>
<223> EgtD核苷酸序列
<400> 5
atgaccctga gcctggcgaa ctacctggcg gcggatagcg cggcggaggc gctgcgtcgt 60
gatgtgcgtg cgggtctgac cgcggcgccg aagagcctgc cgccgaaatg gttctatgat 120
gcggttggca gcgacctgtt cgaccagatc acccgtctgc cggagtacta tccgacccgt 180
accgaagcgc aaattctgcg tacccgtagc gcggagatca ttgcggcggc gggtgcggac 240
accctggtgg agctgggtag cggcaccagc gaaaagaccc gtatgctgct ggatgcgatg 300
cgtgacgcgg aactgctgcg tcgtttcatc ccgtttgacg tggatgcggg tgttctgcgt 360
agcgcgggtg cggcgattgg tgcggagtac ccgggtatcg aaattgatgc ggtgtgcggc 420
gacttcgagg aacacctggg caagatcccg cacgttggcc gtcgtctggt ggttttcctg 480
ggtagcacca ttggtaacct gaccccggcg ccgcgtgcgg aatttctgag caccctggcg 540
gataccctgc aaccgggtga cagcctgctg ctgggcaccg atctggtgaa agacaccggt 600
cgtctggttc gtgcgtatga cgatgcggcg ggcgtgaccg cggcgtttaa ccgtaacgtt 660
ctggcggtgg ttaaccgtga gctgagcgcg gacttcgatc tggacgcgtt tgaacacgtg 720
gcgaagtgga acagcgacga ggaacgtatc gagatgtggc tgcgtgcgcg taccgcgcag 780
catgtgcgtg ttgcggcgct ggatctggaa gtggacttcg cggcgggcga ggaaatgctg 840
accgaggttt cttgcaaatt tcgtccggaa aacgttgttg cggagctggc ggaagcgggt 900
ctgcgtcaaa cccactggtg gaccgatccg gcgggtgact ttggtctgag cctggcggtt 960
cgttaa 966
<210> 6
<211> 372
<212> PRT
<213> Artificial Sequence
<220>
<223> EgtE氨基酸序列
<400> 6
Met Val Met Leu Ala Gln Gln Trp Arg Asp Ala Arg Pro Lys Val Ala
1 5 10 15
Gly Leu His Leu Asp Ser Gly Ala Cys Ser Arg Gln Ser Phe Ala Val
20 25 30
Ile Asp Ala Thr Thr Ala His Ala Arg His Glu Ala Glu Val Gly Gly
35 40 45
Tyr Val Ala Ala Glu Ala Ala Thr Pro Ala Leu Asp Ala Gly Arg Ala
50 55 60
Ala Val Ala Ser Leu Ile Gly Phe Ala Ala Ser Asp Val Val Tyr Thr
65 70 75 80
Ser Gly Ser Asn His Ala Ile Asp Leu Leu Leu Ser Ser Trp Pro Gly
85 90 95
Lys Arg Thr Leu Ala Cys Leu Pro Gly Glu Tyr Gly Pro Asn Leu Ser
100 105 110
Ala Met Ala Ala Asn Gly Phe Gln Val Arg Ala Leu Pro Val Asp Asp
115 120 125
Asp Gly Arg Val Leu Val Asp Glu Ala Ser His Glu Leu Ser Ala His
130 135 140
Pro Val Ala Leu Val His Leu Thr Ala Leu Ala Ser His Arg Gly Ile
145 150 155 160
Ala Gln Pro Ala Ala Glu Leu Val Glu Ala Cys His Asn Ala Gly Ile
165 170 175
Pro Val Val Ile Asp Ala Ala Gln Ala Leu Gly His Leu Asp Cys Asn
180 185 190
Val Gly Ala Asp Ala Val Tyr Ser Ser Ser Arg Lys Trp Leu Ala Gly
195 200 205
Pro Arg Gly Val Gly Val Leu Ala Val Arg Pro Glu Leu Ala Glu Arg
210 215 220
Leu Gln Pro Arg Ile Pro Pro Ser Asp Trp Pro Ile Pro Met Ser Val
225 230 235 240
Leu Glu Lys Leu Glu Leu Gly Glu His Asn Ala Ala Ala Arg Val Gly
245 250 255
Phe Ser Val Ala Val Gly Glu His Leu Ala Ala Gly Pro Thr Ala Val
260 265 270
Arg Glu Arg Leu Ala Glu Val Gly Arg Leu Ser Arg Gln Val Leu Ala
275 280 285
Glu Val Asp Gly Trp Arg Val Val Glu Pro Val Asp Gln Pro Thr Ala
290 295 300
Ile Thr Thr Leu Glu Ser Thr Asp Gly Ala Asp Pro Ala Ser Val Arg
305 310 315 320
Ser Trp Leu Ile Ala Glu Arg Gly Ile Val Thr Thr Ala Cys Glu Leu
325 330 335
Ala Arg Ala Pro Phe Glu Met Arg Thr Pro Val Leu Arg Ile Ser Pro
340 345 350
His Val Asp Val Thr Val Asp Glu Leu Glu Gln Phe Ala Ala Ala Leu
355 360 365
Arg Glu Ala Pro
370
<210> 7
<211> 1119
<212> DNA
<213> Artificial Sequence
<220>
<223> EgtE核苷酸序列
<400> 7
atggttatgc tggcgcagca atggcgtgat gcgcgtccga aagtggcggg tctgcatctg 60
gacagcggtg cgtgcagccg tcagagcttc gcggttatcg atgcgaccac cgcgcatgcg 120
cgtcatgagg cggaagttgg tggctacgtg gcggcggaag cggcgacccc ggcgctggat 180
gcgggtcgtg cggcggtggc gagcctgatc ggttttgcgg cgagcgatgt ggtttacacc 240
agcggcagca accacgcgat tgacctgctg ctgagcagct ggccgggtaa acgtaccctg 300
gcgtgcctgc cgggcgagta tggtccgaac ctgagcgcga tggcggcgaa cggcttccaa 360
gttcgtgcgc tgccggtgga cgatgacggt cgtgtgctgg ttgatgaagc gagccatgag 420
ctgagcgcgc acccggttgc gctggtgcac ctgaccgcgc tggcgagcca tcgtggtatt 480
gcgcaaccgg cggcggagct ggttgaagcg tgccacaacg cgggtatccc ggtggttatt 540
gatgcggcgc aagcgctggg tcacctggat tgcaacgttg gtgcggacgc ggtgtacagc 600
agcagccgta aatggctggc gggtccgcgt ggtgtgggcg ttctggcggt tcgtccggag 660
ctggcggaac gtctgcaacc gcgtatcccg ccgagcgatt ggccgattcc gatgagcgtt 720
ctggagaaac tggaactggg cgagcacaac gcggcggcgc gtgtgggttt tagcgtggcg 780
gttggtgaac acctggcggc gggtccgacc gcggttcgtg aacgtctggc ggaagtgggc 840
cgtctgagcc gtcaggttct ggcggaagtg gatggttggc gtgtggttga gccggttgac 900
caaccgaccg cgatcaccac cctggaaagc accgatggtg cggacccggc gagcgttcgt 960
agctggctga tcgcggagcg tggtattgtt accaccgcgt gcgaactggc gcgtgcgccg 1020
tttgagatgc gtaccccggt gctgcgtatt agcccgcacg tggatgttac cgtggacgag 1080
ctggaacagt tcgcggcggc gctgcgtgag gcgccgtaa 1119
Claims (11)
1.一种亚砜合酶,其氨基酸序列如SEQ ID NO:3所示或与SEQ ID NO:3具有至少99%的序列同一性。
2.如权利要求1所述的亚砜合酶,其特征在于,所述氨基酸序列与SEQ ID NO:3相比包含选自以下一个或多个的氨基酸残基差异:
G-1R/S;T27S;Q34R;Q66R/H;K69R;K72I;A74V;A79T;K83D;E86G;D107Y/A;L153Q;L170P;Q195H;A201S;S215N;Q238H;D259V;N270S;G276S;Q293R;S297G;V311M;A316S;L317R;S324N/C;G330C;T368S;A395E;F424Y;V440I;L445I;P469I/T;P509S;
并具有不低于如SEQ ID NO:3的氨基酸序列所示的亚砜合酶的活性。
3.如权利要求2所述的亚砜合酶,其特征在于,所述氨基酸序列为与SEQ ID NO:3相比包含选自以下任一组的氨基酸残基差异:
G-1S和D107A;或,
Q66H和S324C;或,
D107Y和V311M;或,
A79T和S297G;或,
L170P和Q195H;或,
K83D和S215N;或,
D259V和V440I;或,
T27S和A74V;或,
Q238H和Q293R;或,
K69R和T368S,P509S;或,
G276S、G330C和A395E;或,
E86G、A316S和L317R;或,
Q34R、K72I、N270S和F424Y;或,
S324N和L445I;或,
D107A和P469T;或,
Q66R和A201S;或,
L445I和P469I;或,
K83D、D107A和S215N;或,
Q66R、D107Y和V311M;或,
G-1S、D107A和P469T;或,
G-1R、T27S和A74V;或,
Q66H、E86G、A316S和L317R;或,
G276S、G330C、A395E和P469T;或,
Q66H、A79T、S297G和S324C;或,
L170P、Q195H、D259V和V440I;或,
K69R、D259V、T368S、V440I和P509S;或,
L153Q、L170P、Q195H、Q238H和Q293R;或,
T27S、Q34R、K72I、A74V、N270S和F424Y;或,
G-1S、L153Q、L170P、Q195H、Q238H和Q293R。
4.一种融合蛋白,其包括如权利要求1-3任一项所述的亚砜合酶、以及组氨酸甲基转移酶和C-S键裂解酶;
较佳地,所述组氨酸甲基转移酶的氨基酸序列如SEQ ID NO:4所示,或所述C-S键裂解酶的氨基酸序列如SEQ ID NO:6所示;和/或,
所述融合蛋白从N端至C端依次包括所述亚砜合酶、所述组氨酸甲基转移酶以及所述C-S键裂解酶。
5.一种分离的核酸,其特征在于,所述核酸编码如权利要求1-3任一项所述的亚砜合酶或如权利要求4所述的融合蛋白;
较佳地,所述核酸的核苷酸序列如SEQ ID NO:2所示。
6.一种重组表达载体,其包含如权利要求5所述的核酸;较佳地,所述重组表达载体的骨架质粒为pETDuet-1,和/或,编码所述组氨酸甲基转移酶的核苷酸序列如SEQ ID NO:5所示或编码所述C-S键裂解酶的核酸序列如SEQ ID NO:7所示。
7.一种转化体,其包含如权利要求5所述的核酸或如权利要求6所述的重组表达载体;较佳地,所述转化体的宿主细胞为埃希氏大肠杆菌(Escherichia coli)例如E.coliBL21(DE3)。
8.一种制备如权利要求1-3任一项所述的亚砜合酶的方法,其特征在于,所述方法包括培养如权利要求7所述的转化体获得所述亚砜合酶。
9.一种制备化合物II的方法,其特征在于,所述方法包括如下步骤:使用如权利要求1-3任一项所述的亚砜合酶或权利要求7所述的转化体制备所述化合物II,所述方法优选满足以下任意一组:
(1)使用发酵培养基震荡培养所述转化体,之后加入异丙基硫代半乳糖苷诱导所述化合物II的表达;所述发酵培养基优选含有Fe2+和半胱氨酸;
(2)在半胱氨酸、Fe2+、氧气以及所述亚砜合酶的存在下,与组氨酸三甲基内盐进行反应,即得所述化合物II;
较佳地,所述反应中:
所述亚砜合酶存在于菌体破碎后的上清液中;
和/或,所述组氨酸三甲基内盐与所述上清液的质量体积比为3-15mg/ml;
和/或,所述半胱氨酸、Fe2+、以及所述组氨酸三甲基内盐的摩尔比为(1-3):1:(1-2);
和/或,所述反应在转速为200-250rpm、温度为20℃-30℃的条件下进行;
和/或,所述反应在pH为6-8的条件下进行;
10.一种麦角硫因的制备方法,其包括如权利要求9所述的方法制备所述化合物II的步骤,进一步还包括将所述化合物II制备为麦角硫因的步骤。
11.如权利要求1-3任一项所述的亚砜合酶或如权利要求7所述的转化体在制备麦角硫因或其中间体例如化合物II中的应用。
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