CN117210429A - 一种组氨酸三甲基化酶EgtD突变体及其应用 - Google Patents
一种组氨酸三甲基化酶EgtD突变体及其应用 Download PDFInfo
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Abstract
本发明公开了一种组氨酸三甲基化酶EgtD突变体及其应用。所述EgtD突变体与如SEQ ID NO:4所示的氨基酸序列相比,具有选自以下氨基酸残基差异的一种或多种:T027N、I050A/L/M、V083M、E091F/T、L105P、A124V、P171L、R204C、G211S、T213S、F237C、A259V、V271M、V283I、E295G和E298D。本发明还公开了所述的EgtD突变体、含其的基因工程菌及其在生产麦角硫因中的应用。本发明还公开了制备EgtD突变体的方法和生产麦角硫因的方法。本发明通过将活性提高的EgtD蛋白与麦角硫因合成途径中的其他酶组合,用于麦角硫因的生物合成,进一步提高了麦角硫因的微生物发酵水平。
Description
技术领域
本发明涉及生物工程和酶工程领域,具体涉及一种组氨酸三甲基化酶EgtD突变体及其应用。
背景技术
麦角硫因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。
麦角硫因生物合成途径的第一步是SAM(s-腺苷甲硫氨酸)依赖的组氨酸三甲基化酶催化组氨酸转化成N-α三甲基组氨酸(Hercynine,简称HER)。有研究表明,突变SAM依赖的组氨酸三甲基转移酶EgtD会导致麦角硫因的完全缺失。所有类型麦角硫因合成途径中均包括EgtD型甲基转移酶,使该酶成为EGT(ergothioneine,麦角硫因)生产过程中唯一不可或缺的组成部分。
目前已有研究报道了EgtD的晶体结构(例如PDB:4UY5、4UY7和4UY6;JEONG J H,CHA H J,HAS C,et al.Structural insights into the histidine trimethylationactivity of EgtD from Mycobacterium smegmatis[J].Biochem Biophys Res Commun,2014,452(4):1098-1103)并研究了相关的酶学性质,现有的研究发现EgtD催化组氨酸三甲基化是一个连续的过程,且其催化活性受到严格的底物调控。
发明内容
为解决现有技术中麦角硫因合成效果不佳的技术问题,本发明提供了一种组氨酸三甲基化酶EgtD突变体及其应用。
天然产麦角硫因的微生物产量低、生长周期长,无法满足工业化生产需求。麦角硫因生物合成的第一步是组氨酸三甲基化酶催化组氨酸生成N-α三甲基组氨酸甜菜碱(HER),该步骤对麦角硫因的合成起重要作用,缺少该步骤将无法合成麦角硫因。本发明的目的是通过基因工程手段改造组氨酸三甲基化酶EgtD,通过筛选,获得活性提高的突变体,并将其应用于麦角硫因的生物合成。
为了提高组氨酸三甲基化酶的催化活性,本研究对合成EgtD酶的基因egtD进行了随机突变,并将活性提高的位点进行组合,获得催化活性提高的突变体。随后,将活性提高的突变体的合成基因用于构建麦角硫因合成途径,并将该途径导入大肠杆菌BL21(DE3)中,获得合成麦角硫因的基因工程菌,通过微生物发酵合成麦角硫因。
本发明第一方面提供了一种EgtD突变体,该突变体与如SEQ ID NO:4所示的氨基酸序列相比,具有选自以下氨基酸残基差异的一种或多种:
T027N、I050A/L/M、V083M、E091F/T、L105P、A124V、P171L、R204C、G211S、T213S、F237C、A259V、V271M、V283I、E295G和E298D。
在一些优选的实施例中,所述氨基酸差异选自以下组:
(1)I50A、I50A/E91F或I50A/E91F/V271M;
(2)I50L或I50L/E91T;
(3)I50M、I50M/E91F、I50M/E91F/G211S、I50M/E91F/V283I、I50M/E91F/V271M、I50M/E91F/R204C、I50M/E91F/R204C/G211S或I50M/E91F/R211S/V283I;
(4)E91F、E91F/V271M、E91F/E295G或E91F/V283I;
(5)L105P、L105P/R204C或L105P/V283I;
(6)V271M、T27N/R204C/V271M;
(7)V283I、R204C/V283I;
(8)E91T、G211S/T213S、T213S/R204C、E298D/A259V/P171L/V83M、A124V/F237C、G211S/E295G。
本发明第二方面提供了一种酶组合,该酶组合包括如本发明第一方面提供的EgtD突变体,以及亚砜合酶TNcEgt1和/或PLP依赖的C-S键裂解酶EgtE。
在一些优选的实施例中,所述亚砜合酶TNcEgt1和C-S键裂解酶EgtE的氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2所示。
本发明第三方面提供了一种分离的核酸,该核酸包含编码如本发明第一方面提供的EgtD突变体的核苷酸序列。优选地,所述核苷酸序列如SEQ ID NO:3所示
本发明第四方面提供了一种重组表达载体,该重组表达载体包含如本发明第三方面提供的核酸。
在一些优选的实施例中,该重组表达载体还包括编码亚砜合酶TNcEgt1和/或C-S键裂解酶EgtE的核苷酸序列,所述亚砜合酶TNcEgt1和C-S键裂解酶EgtE的氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2所示。
本发明第五方面提供了一种转化体,该转化体包含本发明第三方面提供的分离的核酸,或本发明第四方面提供的重组表达载体。
本发明第六方面提供了一种基因工程菌,该基因工程菌包含本发明第三方面提供的核酸、以及第四方面中的重组表达载体,该重组表达载体还包括编码亚砜合酶TNcEgt1和/或C-S键裂解酶EgtE的核苷酸序列,亚砜合酶TNcEgt1和C-S键裂解酶EgtE的氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2所示。
本发明第七方面提供了一种制备EgtD突变体的方法,在适合本发明第五方面提供的转化体生长的条件下,培养所述转化体即得。
本发明第八方面提供了一种生产麦角硫因的方法,在适合的条件下,发酵如本发明第六方面提供的基因工程菌,即得;
在一些优选的实施例中,还包括加入IPTG进行诱导的步骤;
优选地,所述IPTG的终浓度为1mM;和/或,所述诱导的温度为28℃;和/或,所述诱导的时间为16~24小时,例如20小时。
本发明第九方面提供了一种如本发明第一方面提供的突变体、本发明第二方面提供的酶组合、本发明第三方面提供的核酸、本发明第四方面提供的重组表达载体、本发明第五方面提供的转化体、本发明第六方面提供的基因工程菌在生产麦角硫因中的应用。
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)通过基因突变等手段改造EgtD蛋白,筛选得到活性进一步提高的突变体。
(2)将活性提高的EgtD蛋白与麦角硫因合成途径中的其他酶组合,用于麦角硫因的生物合成,进一步提高了麦角硫因的微生物发酵水平。
附图说明
图1为表达三甲基化酶(EgtD)的质粒图谱;
图2为包含麦角硫因合成途径的质粒图谱;
图3A为S菌株发酵生产麦角硫因的ERG液相检测图谱,3B为S1菌株发酵生产麦角硫因的ERG液相检测图谱。
具体实施方式
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:XBridge BEH C18 XP column(150mm length×2.0mminternal diameter,2.5μm,Waters),流动相:含0.05%HFBA的7%甲醇水;柱温35℃;检测波长210nm,流速为0.3mL/min,进样量为2μL。
实施例1:麦角硫因工程菌和三甲基化酶工程菌的构建
将来源于耻垢分枝杆菌(Mycobacterium smegmatis)的编码组氨酸甲基转移酶的基因egtD(SEQ ID NO:3),委托商业化公司进行全基因合成。将egtD基因克隆到pACYCDuet-1载体中,得到质粒pACYCDuet-1-egtD(图1)将该质粒转入大肠杆菌BL21(DE3)感受态细胞,涂布到氯霉素抗性平板(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,获得表达组氨酸三甲基化酶的重组基因工程菌W(图1)。
SEQ ID NO:3:egtD的核苷酸序列(GenBank:WP_011731156)
ATGACCCTGAGCCTGGCGAACTACCTGGCGGCGGATAGCGCGGCGGAGGCGCTGCGTCGTGATGTGCGTGCGGGTCTGACCGCGGCGCCGAAGAGCCTGCCGCCGAAATGGTTCTATGATGCGGTTGGCAGCGACCTGTTCGACCAGATCACCCGTCTGCCGGAGTACTATCCGACCCGTACCGAAGCGCAAATTCTGCGTACCCGTAGCGCGGAGATCATTGCGGCGGCGGGTGCGGACACCCTGGTGGAGCTGGGTAGCGGCACCAGCGAAAAGACCCGTATGCTGCTGGATGCGATGCGTGACGCGGAACTGCTGCGTCGTTTCATCCCGTTTGACGTGGATGCGGGTGTTCTGCGTAGCGCGGGTGCGGCGATTGGTGCGGAGTACCCGGGTATCGAAATTGATGCGGTGTGCGGCGACTTCGAGGAACACCTGGGCAAGATCCCGCACGTTGGCCGTCGTCTGGTGGTTTTCCTGGGTAGCACCATTGGTAACCTGACCCCGGCGCCGCGTGCGGAATTTCTGAGCACCCTGGCGGATACCCTGCAACCGGGTGACAGCCTGCTGCTGGGCACCGATCTGGTGAAAGACACCGGTCGTCTGGTTCGTGCGTATGACGATGCGGCGGGCGTGACCGCGGCGTTTAACCGTAACGTTCTGGCGGTGGTTAACCGTGAGCTGAGCGCGGACTTCGATCTGGACGCGTTTGAACACGTGGCGAAGTGGAACAGCGACGAGGAACGTATCGAGATGTGGCTGCGTGCGCGTACCGCGCAGCATGTGCGTGTTGCGGCGCTGGATCTGGAAGTGGACTTCGCGGCGGGCGAGGAAATGCTGACCGAGGTTTCTTGCAAATTTCGTCCGGAAAACGTTGTTGCGGAGCTGGCGGAAGCGGGTCTGCGTCAAACCCACTGGTGGACCGATCCGGCGGGTGACTTTGGTCTGAGCCTGGCGGTTCGTTAA
实施例2:EgtD酶突变库的构建与筛选
以egtD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pACYCDuet-1的HindⅢ/NcoⅠ酶切位点,然后转入大肠杆菌BL21(DE3)感受态中,在含34μg/mL氯霉素的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34μg/mL氯霉素)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34μg/mL氯霉素)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,弃上清,保留菌体,加入1mL100mMTris-HCl(pH7.6)的缓冲液(含2000U的溶菌酶)。28℃震荡30min,4000g离心30min。
在酶标板中加入190μL的反应液Ⅰ,加入10μL的酶上清液,利用酶标仪在265nm下检测1min。挑选表现较好的突变体进行摇瓶发酵,并进行体外反应,通过HPLC检测三甲基组氨酸的含量。
反应液Ⅰ:100mM Tris-HCl(pH7.6),100mM NaCl,0.5mM MnSO4,100μM SAM,5μg的S-腺苷-L-同型半胱氨酸核苷酶和10μg腺嘌呤脱氨酶,10mM的组氨酸溶液。
实施例3:体外催化反应
取10μL W菌株的甘油菌接至5mL LB培养基中(含34μg/mL氯霉素),37℃,220rpm培养12h。然后按1.5%的接种量将种子液转接至含20mL LB培养基的(含34μg/mL氯霉素)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突变株的菌体。取一定量W菌体和突变株菌体,用100mM Tris-HCl(pH7.6)的缓冲液稀释至相同浓度,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,100mMTris-HCl(pH7.6),100μM SAM,10mM的组氨酸溶液,100μL菌体破碎上清液。25℃,220rpm,反应30min后,取200μL加入1.8mL流动相中,反应液终止反应。12000rpm离心10min,取上清,0.22μm滤膜过滤,HPLC进行检测。
野生型酶及筛选得到的活性较高的突变体为:
表1
EgtD或突变体编号 | 与SEQ ID NO:4的残基差异 | 相对酶活 |
SEQ ID NO:4 | - | 100% |
1 | A124V,F237C | 166.3% |
2 | G211S,E295G | 176.2% |
3 | I50M | 167.3% |
4 | I50L | 162.5% |
5 | I50A | 171.1% |
6 | E91T | 183.3% |
7 | L105P | 161.2% |
8 | T213S,R204C | 169.7% |
9 | E298D,A259V,P171L,V83M | 160.0% |
10 | V283I | 134.9% |
11 | V271M | 154.0% |
12 | E91F | 124.0% |
实施例4:EgtD酶组合突变库的构建与筛选
实施例2、3中筛选到的表现较好的突变株送样测序,选择多个突变位点,进行组合突变。设计相应的引物,以egtD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pACYCDuet-1的HindⅢ/NcoⅠ位点,然后转入大肠杆菌BL21(DE3)中,在含34μg/mL氯霉素的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,体外活性检测。筛选结果如表2所示。
表2
EgtD或突变体编号 | 与SEQ ID NO:4的残基差异 | 相对酶活 |
SEQ ID NO:4 | - | |
13 | G211S,T213S | 122.8% |
14 | E91F,V271M | 124.7% |
15 | E91F,E295G | 143.8% |
16 | E91F,V283I | 127.8% |
17 | L105P,R204C | 125.9% |
18 | L105P,V283I | 122.2% |
19 | I50M,E91F | 109.6% |
20 | I50A,E91F | 128.0% |
21 | I50L,E91T | 159.9% |
22 | I50M,E91F,G211S | 115.4% |
23 | R204C,V283I | 120.3% |
24 | T27N,R204C,V271M | 122.8% |
25 | I50A,E91F,V271M | 133.5% |
26 | I50M,E91F,V283I | 156.6% |
27 | I50M,E91F,V271M | 164.9% |
28 | I50M,E91F,R204C | 173.3% |
实施例5:构建麦角硫因生产菌株
将来源于耻垢分枝杆菌(Mycobacterium smegmatis)的编码组氨酸甲基转移酶(SEQ ID NO:4)的基因egtD(SEQ ID NO:3)、PLP依赖的C-S键裂解酶(SEQ ID NO:2)的基因egtE(SEQ ID NO:5)以及改造后的来自粗糙脉孢菌(Neurospora crassa)的亚砜合酶(SEQID NO:1)的编码基因TncEgt1(SEQ ID NO:6)克隆到pETDuet-1载体中,得到质粒pETDuet-1-egtD-egtE-TncEgt1(图1)。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工程菌S菌株。
SEQ ID NO:1 TNcEgt1氨基酸序列
MGMSFSLIPSVYARSALPTLDDWEALWATWDVVTRQMLPQEELLEKPIKLRNACIFYLGHIPTFLDIQLTKTTKQAPSEPAHFCKIFERGIDPDVDNPELCHAHSEIPDEWPPVEEILTYQETVRSRLRGLYAHGIANIPRNVGRAIWVGFEHELMHIETLLYMMLQSDKTLIPTHIPRPDFDKLARKAESERVPNQWFKIPAQEITIGLDDPEDGSDINKHYGWDNEKPPRRVQVAAFQAQGRPITNEEYAQYLLEKNIDKLPASWARLDNENISNGTTNSVSGHHSNRTSKQQLPSSFLEKTAVRTVYGLVPLKHALDWPVFASYDELAGCAAYMGGRIPTFEETRSIYAYADALKKKKEAERQLGRTVPAVNAHLTNNGVEITPPSSPSSETPAESSSPSDSNTTLITTEDLFSDLDGANVGFHNWHPMPITSKGNTLVGQGELGGVWEWTSSVLRKWEGFEPMELYPGYTADFFDEKHNIVLGGSWATHPRIAGRKSFVNWYQRNYPYAWVGARVVRDL
SEQ ID NO:2 EgtE氨基酸序列
MVMLAQQWRDARPKVAGLHLDSGACSRQSFAVIDATTAHARHEAEVGGYVAAEAATPALDAGRAAVASLIGFAASDVVYTSGSNHAIDLLLSSWPGKRTLACLPGEYGPNLSAMAANGFQVRALPVDDDGRVLVDEASHELSAHPVALVHLTALASHRGIAQPAAELVEACHNAGIPVVIDAAQALGHLDCNVGADAVYSSSRKWLAGPRGVGVLAVRPELAERLQPRIPPSDWPIPMSVLEKLELGEHNAAARVGFSVAVGEHLAAGPTAVRERLAEVGRLSRQVLAEVDGWRVVEPVDQPTAITTLESTDGADPASVRSWLIAERGIVTTACELARAPFEMRTPVLRISPHVDVTVDELEQFAAALREAP
SEQ ID NO:4 EgtD氨基酸序列
MTLSLANYLAADSAAEALRRDVRAGLTAAPKSLPPKWFYDAVGSDLFDQITRLPEYYPTRTEAQILRTRSAEIIAAAGADTLVELGSGTSEKTRMLLDAMRDAELLRRFIPFDVDAGVLRSAGAAIGAEYPGIEIDAVCGDFEEHLGKIPHVGRRLVVFLGSTIGNLTPAPRAEFLSTLADTLQPGDSLLLGTDLVKDTGRLVRAYDDAAGVTAAFNRNVLAVVNRELSADFDLDAFEHVAKWNSDEERIEMWLRARTAQHVRVAALDLEVDFAAGEEMLTEVSCKFRPENVVAELAEAGLRQTHWWTDPAGDFGLSLAVR
SEQ ID NO:5 egtE核苷酸序列(GenBank:ABK70212.1)
ATGGTTATGCTGGCGCAGCAATGGCGTGATGCGCGTCCGAAAGTGGCGGGTCTGCATCTGGACAGCGGTGCGTGCAGCCGTCAGAGCTTCGCGGTTATCGATGCGACCACCGCGCATGCGCGTCATGAGGCGGAAGTTGGTGGCTACGTGGCGGCGGAAGCGGCGACCCCGGCGCTGGATGCGGGTCGTGCGGCGGTGGCGAGCCTGATCGGTTTTGCGGCGAGCGATGTGGTTTACACCAGCGGCAGCAACCACGCGATTGACCTGCTGCTGAGCAGCTGGCCGGGTAAACGTACCCTGGCGTGCCTGCCGGGCGAGTATGGTCCGAACCTGAGCGCGATGGCGGCGAACGGCTTCCAAGTTCGTGCGCTGCCGGTGGACGATGACGGTCGTGTGCTGGTTGATGAAGCGAGCCATGAGCTGAGCGCGCACCCGGTTGCGCTGGTGCACCTGACCGCGCTGGCGAGCCATCGTGGTATTGCGCAACCGGCGGCGGAGCTGGTTGAAGCGTGCCACAACGCGGGTATCCCGGTGGTTATTGATGCGGCGCAAGCGCTGGGTCACCTGGATTGCAACGTTGGTGCGGACGCGGTGTACAGCAGCAGCCGTAAATGGCTGGCGGGTCCGCGTGGTGTGGGCGTTCTGGCGGTTCGTCCGGAGCTGGCGGAACGTCTGCAACCGCGTATCCCGCCGAGCGATTGGCCGATTCCGATGAGCGTTCTGGAGAAACTGGAACTGGGCGAGCACAACGCGGCGGCGCGTGTGGGTTTTAGCGTGGCGGTTGGTGAACACCTGGCGGCGGGTCCGACCGCGGTTCGTGAACGTCTGGCGGAAGTGGGCCGTCTGAGCCGTCAGGTTCTGGCGGAAGTGGATGGTTGGCGTGTGGTTGAGCCGGTTGACCAACCGACCGCGATCACCACCCTGGAAAGCACCGATGGTGCGGACCCGGCGAGCGTTCGTAGCTGGCTGATCGCGGAGCGTGGTATTGTTACCACCGCGTGCGAACTGGCGCGTGCGCCGTTTGAGATGCGTACCCCGGTGCTGCGTATTAGCCCGCACGTGGATGTTACCGTGGACGAGCTGGAACAGTTCGCGGCGGCGCTGCGTGAGGCGCCGTAA
SEQ ID NO:6 TncEgt1核苷酸序列
ATGGGCATGAGCTTTAGCCTGATTCCGAGCGTTTATGCGCGTAGCGCGCTGCCGACCCTGGATGATTGGGAGGCGCTGTGGGCGACCTGGGATGTGGTTACCCGTCAAATGCTGCCGCAGGAAGAGCTGCTGGAAAAGCCGATCAAACTGCGTAACGCGTGCATCTTCTATCTGGGCCACATTCCGACCTTTCTGGACATCCAACTGACCAAGACCACCAAACAAGCGCCGAGCGAACCGGCGCACTTCTGCAAAATCTTTGAGCGTGGTATTGACCCGGATGTTGACAACCCGGAGCTGTGCCACGCGCACAGCGAAATTCCGGACGAGTGGCCGCCAGTGGAGGAAATCCTGACCTACCAAGAAACCGTTCGTAGCCGTCTGCGTGGTCTGTATGCGCACGGCATCGCGAACATTCCGCGTAACGTGGGTCGTGCGATTTGGGTTGGCTTCGAGCACGAACTGATGCACATCGAGACCCTGCTGTACATGATGCTGCAGAGCGATAAGACCCTGATCCCGACCCACATTCCGCGTCCGGATTTCGACAAGCTGGCGCGTAAAGCGGAGAGCGAACGTGTGCCGAACCAATGGTTTAAAATTCCGGCGCAGGAAATCACCATTGGTCTGGACGATCCGGAGGATGGCAGCGACATCAACAAGCACTACGGCTGGGACAACGAAAAACCGCCGCGTCGTGTGCAAGTTGCGGCGTTCCAAGCGCAGGGTCGTCCGATTACCAACGAGGAATACGCGCAGTATCTGCTGGAGAAGAACATCGATAAACTGCCGGCGAGCTGGGCGCGTCTGGACAACGAAAACATCAGCAACGGCACCACCAACAGCGTTAGCGGCCACCACAGCAACCGTACCAGCAAGCAACAGCTGCCGAGCAGCTTTCTGGAGAAAACCGCGGTGCGTACCGTTTATGGTCTGGTGCCGCTGAAGCATGCGCTGGATTGGCCGGTTTTCGCGAGCTACGACGAACTGGCGGGTTGCGCGGCGTATATGGGTGGCCGTATTCCGACCTTTGAGGAAACCCGTAGCATCTACGCGTATGCGGATGCGCTGAAGAAAAAGAAAGAGGCGGAACGCCAACTGGGTCGTACCGTGCCGGCGGTTAACGCGCACCTGACCAACAACGGTGTTGAGATCACCCCGCCGAGCAGCCCGAGCAGCGAAACCCCGGCGGAGAGCAGCAGCCCGAGCGATAGCAACACCACCCTGATTACCACCGAAGACCTGTTCAGCGATCTGGACGGTGCGAACGTGGGCTTTCACAACTGGCACCCGATGCCGATCACCAGCAAGGGTAACACCCTGGTTGGTCAGGGCGAACTGGGTGGCGTGTGGGAGTGGACCAGCAGCGTTCTGCGTAAATGGGAGGGCTTCGAACCGATGGAGCTGTACCCGGGTTATACCGCGGATTTCTTTGACGAGAAGCACAACATTGTTCTGGGTGGCAGCTGGGCGACCCACCCGCGTATTGCGGGTCGTAAGAGCTTCGTGAACTGGTATCAGCGTAACTACCCGTATGCGTGGGTTGGTGCGCGTGTGGTTCGTGACCTGTAA
本实施例以I50A为例,阐述了包含突变体的菌株S1的构建流程:PCR获得与SEQ IDNO:4的氨基酸序列相比具有I50A(I密码子为ATC,A的密码子为GCG)突变的egtD基因片段,通过同源重组连接目的基因和酶切载体pETDuet-1-egtE-TncEgt1(HindⅢ/NotⅠ),将重组质粒转化至大肠杆菌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(含50μg/mL氨苄青霉素),37℃,200rpm培养12h,提取质粒测序验证。本领域技术人员根据本实施例,利用本领域常规技术手段可以获得其它包含突变体的菌株。
实施例6:利用S菌株发酵生产麦角硫因
取10μL甘油菌(S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170mg/L(见图3A)。
实施例7:利用S菌株发酵生产麦角硫因
取10μl甘油菌(S1菌株)接入5mLLB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311mg/L(见图3B)。
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> 一种组氨酸三甲基化酶EgtD突变体及其应用
<130> P22012819C
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 523
<212> PRT
<213> Artificial Sequence
<220>
<223> TNcEgt1
<400> 1
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> 2
<211> 372
<212> PRT
<213> Artificial Sequence
<220>
<223> EgtE
<400> 2
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> 3
<211> 966
<212> DNA
<213> Artificial Sequence
<220>
<223> egtD
<400> 3
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> 4
<211> 321
<212> PRT
<213> Artificial Sequence
<220>
<223> EgtD
<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> 1119
<212> DNA
<213> Artificial Sequence
<220>
<223> egtE
<400> 5
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
<210> 6
<211> 1572
<212> DNA
<213> Artificial Sequence
<220>
<223> TncEgt1
<400> 6
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
Claims (11)
1.一种EgtD突变体,其特征在于,其与如SEQ ID NO:4所示的氨基酸序列相比,具有选自以下氨基酸残基差异的一种或多种:
T027N、I050A/L/M、V083M、E091F/T、L105P、A124V、P171L、R204C、G211S、T213S、F237C、A259V、V271M、V283I、E295G和E298D。
2.如权利要求1所述的EgtD突变体,其特征在于,所述氨基酸差异选自以下组:
(1)I50A、I50A/E91F或I50A/E91F/V271M;
(2)I50L或I50L/E91T;
(3)I50M、I50M/E91F、I50M/E91F/G211S、I50M/E91F/V283I、I50M/E91F/V271M、I50M/E91F/R204C、I50M/E91F/R204C/G211S或I50M/E91F/R211S/V283I;
(4)E91F、E91F/V271M、E91F/E295G或E91F/V283I;
(5)L105P、L105P/R204C或L105P/V283I;
(6)V271M、T27N/R204C/V271M;
(7)V283I、R204C/V283I;
(8)E91T、G211S/T213S、T213S/R204C、E298D/A259V/P171L/V83M、A124V/F237C、G211S/E295G。
3.一种酶组合,其特征在于,所述酶组合包括如权利要求1所述的EgtD突变体,以及亚砜合酶TNcEgt1和/或PLP依赖的C-S键裂解酶EgtE;
优选地,所述亚砜合酶TNcEgt1和C-S键裂解酶EgtE的氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2所示。
4.一种分离的核酸,其特征在于,其包含编码如权利要求1或2所述的EgtD突变体的核苷酸序列;优选地,所述核苷酸序列如SEQ ID NO:3所示。
5.一种重组表达载体,其特征在于,其包含如权利要求4所述的核酸。
6.如权利要求5所述的重组表达载体,其特征在于,所述重组表达载体还包括编码亚砜合酶TNcEgt1和/或C-S键裂解酶EgtE的核苷酸序列,所述亚砜合酶TNcEgt1和C-S键裂解酶EgtE的氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2所示。
7.一种转化体,其特征在于,其包含如权利要求4所述的分离的核酸,或如权利要求5所述的重组表达载体。
8.一种基因工程菌,其特征在于,其包含如权利要求6所述的重组表达载体。
9.一种制备EgtD突变体的方法,其特征在于,在适合如权利要求7所述的转化体生长的条件下,培养所述转化体即得。
10.一种生产麦角硫因的方法,其特征在于,在适合的条件下,发酵如权利要求8所述的基因工程菌,即得;
优选地,还包括加入IPTG进行诱导的步骤;
更优选地,所述IPTG的终浓度为1mM;和/或,所述诱导的温度为28℃;和/或,所述诱导的时间为16~24小时,例如20小时。
11.如权利要求1或2所述的EgtD突变体、权利要求3所述的酶组合、权利要求4所述的核酸、权利要求5或6所述的重组表达载体、权利要求7所述的转化体、权利要求8所述的基因工程菌在生产麦角硫因中的应用。
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