CN116855467A - 一种化学-酶偶联方法用于合成麦角硫因 - Google Patents
一种化学-酶偶联方法用于合成麦角硫因 Download PDFInfo
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Abstract
本发明提供了一种合成麦角硫因的化学‑酶偶联方法,具体地,本发明提供了一种组氨酸甜菜碱的大规模化学合成方法,以及将组氨酸甜菜碱用定向进化后的裂殖酵母麦角硫因合成酶SPEGT1和SPEGT2高效合成麦角硫因的策略。
Description
技术领域
本发明属于合成工艺领域,具体地,本发明提供了一种L-组氨酸甜菜碱的大规模化学合成方法,以及将L-组氨酸甜菜碱用定向进化后的裂殖酵母麦角硫因合成酶SPEGT1和SPEGT2高效合成麦角硫因的策略。
背景技术
麦角硫因(Ergothioneine,简称EGT)是一种特殊的硫代组氨酸甜菜碱的氨基酸,其独特的氧化还原特性使它成为最好的天然抗氧化剂之一。麦角硫因主要由真菌、放线菌等微生物合成,对植物和动物具有独特的生理作用。麦角硫因相当于动物稀有的维生素,对氧化应激具有良好的抵制作用。因此,麦角硫因可以作为抗氧化剂和潜在的营养食品,在食品、化妆品和医药等行业具有极大的应用前景。
目前化学合成法制备麦角硫因难以获得正确的手性,生物提取产能不足,生物发酵合成成为主流的发展方向。一方面,虽然粗糙脉孢菌、侧耳类食用菌等真菌的麦角硫因合成酶EGT1和EGT2已有报道,并在大肠杆菌中异源表达用于体外合成麦角硫因。但是,现有技术中的合成的麦角硫因产量普遍偏低,远未达到工业生产放大的潜力。另一方面,利用合成麦角硫因的真菌发酵最多达到了1.5克每升的产量,但生产成本依旧偏高,且生产周期较长。
综上所述,本领域尚缺乏一种高效率生产麦角硫因的方法。
发明内容
为了克服现有技术的缺点与不足,本发明结合了化学合成和生物合成二者各自的优势,目的在于提供一种麦角硫因的化学-酶偶联高效合成系统(如图1所示)。L-组氨酸通过使用钯碳催化的甲醛还原胺化和碘化钾亲核取代合成L-组氨酸甜菜碱,然后使用裂殖酵母(Schizosaccharomyces pombe)的麦角硫因合成酶SPEGT1(Uniprot ID:O94632)和SPEGT2(Uniprot ID:O94431)的突变体工程酶SPEGT1-tr M10和SPEGT2 M3由L-组氨酸甜菜碱和半胱氨酸合成麦角硫因。
本发明的第一方面,提供了一种裂殖酵母麦角硫因合成酶SPEGT1-tr M10,所述合成酶的氨基酸序列如SEQ ID NO:7所示。
在另一优选例中,所述合成酶的编码基因(spegt1-tr M10)核苷酸序列如SEQ IDNO:8所示。
本发明的第二方面,提供了一种裂殖酵母麦角硫因合成酶SPEGT2 M3,所述合成酶的氨基酸序列如SEQ ID NO:9所示。
在另一优选例中,所述合成酶的编码基因(spegt2 M3)核苷酸序列如SEQ ID NO:10所示。
本发明的第三方面,提供了一种裂殖酵母麦角硫因合成酶SPEGT1-tr,所述的合成酶的氨基酸序列如SEQ ID NO:5所示。
在另一优选例中,所述合成酶编码基因(spegt1-tr)的核苷酸序列如SEQ ID NO:6所示。
在另一优选例中,本发明提供了一种裂殖酵母麦角硫因合成酶SPEGT1,所述的合成酶的氨基酸序列如SEQ ID NO:1所示。
在另一优选例中,所述合成酶的编码基因(spegt1)的核苷酸序列如SEQ ID NO:2所示。
在另一优选例中,本发明提供了一种裂殖酵母麦角硫因合成酶SPEGT2,其特征在于,所述的合成酶的氨基酸序列如SEQ ID NO:3所示。
在另一优选例中,所述合成酶的编码基因(spegt2)的核苷酸序列如SEQ ID NO:4所示。
本发明的第四方面,提供了一种麦角硫因合成酶表达载体,其特征在于,所述的表达载体用于表达如本发明第一至第三方面任一所述的裂殖酵母麦角硫因合成酶。
在另一优选例中,所述的表达载体表达如本发明第一或第二方面中所述的合成酶。
本发明的第五方面,提供了一种表达盒,所述的表达盒用于表达如本发明第一至第三方面任一所述的裂殖酵母麦角硫因合成酶。
本发明的第六方面,提供了一种重组菌株,其特征在于,所述的重组菌株含有如本发明第四方面中所述的表达载体,或其基因组中整合有编码如本发明第一至第三方面任一所述的合成酶的多核苷酸序列。
在另一优选例中,所述的重组菌株基因组中整合有编码如本发明第一和/或第二方面中所述的合成酶的多核苷酸序列。
本发明的第七方面,提供了一种用于麦角硫因合成的化学-酶偶联系统,所述的化学催化系统包括:钯碳催化L-组氨酸的甲醛还原胺化双甲基化以及碘甲烷亲核取代合成三甲基取代的季铵盐组氨酸甜菜碱;
所述的催化酶系统包括:如本发明第二方面所述的合成酶SPEGT2 M3,和选自下组的合成酶:如本发明第一方面所述的合成酶SPEGT1-tr M10,或如本发明第三方面所述的合成酶SPEGT1-tr。
本发明的第九方面,提供了一种麦角硫因合成方法,所述方法包括以下步骤:
(3)在如本发明第二方面所述的合成酶SPEGT2 M3,和选自下组的合成酶:如本发明第一方面所述的合成酶SPEGT1-tr M10,或如本发明第三方面所述的合成酶SPEGT1-tr,或者如本发明第六方面所述的重组菌株存在下,用组氨酸甜菜碱和半胱氨酸反应,得到麦角硫因。
在另一优选例中,所述的化学合成步骤:
(1)用钯碳催化L-组氨酸进行甲醛还原胺化,得到二甲基组氨酸;
(2)用二甲基组氨酸与碘甲烷进行亲核取代,合成三甲基取代的季铵盐组氨酸甜菜碱。
在另一优选例中,所述的酶催化步骤在Fe2+、磷酸吡哆醛和beta巯基乙醇存在下进行。
在另一优选例中,所述的方法在pH=7-9的缓冲体系下进行。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为麦角硫因的化学-酶偶联合成方法。
图2为表达裂殖酵母麦角硫因合成酶SPEGT1、去除催化甲基化结构域后的SPEGT1-tr以及SPEGT2编码基因的大肠杆菌表达质粒pET-28a-SpEgt1、pET-28a-SpEgt1-tr、pET-28a-SpEgt2的示意图;
图3为定向进化中质粒pET-28a-SpEgt1-tr使用随机突变试剂盒进行PCR的琼脂糖凝胶电泳图(条带1、3)以及互补的载体部分进行PCR的琼脂糖凝胶电泳图(条带2、4)。还包括定向进化中质粒pET-28a-SpEgt2使用随机突变试剂盒进行PCR的琼脂糖凝胶电泳图(条带5、7)以及互补的载体部分进行PCR的琼脂糖凝胶电泳图(条带6、8)。
图4为裂殖酵母麦角硫因合成酶SPEGT1、去除催化甲基化结构域后的SPEGT1-tr、定向进化后的SPEGT1-tr M10,以及SPEGT2和定向进化后的SPEGT2 M3经过大肠杆菌表达后的SDS-PAGE图。
图5为麦角硫因标准品的HPLC鉴定图,以及没加酶的反应体系加上产物麦角硫因和内标对氨基苯甲酸后的化合物混合液的HPLC鉴定图。
图6为使用裂殖酵母麦角硫因合成酶SPEGT1-tr和SPEGT2在10mM组氨酸甜菜碱条件下合成麦角硫因的HPLC鉴定图,以及定向进化后的SPEGT1-tr M10和SPEGT2 M3在10mM组氨酸甜菜碱条件下合成麦角硫因的HPLC鉴定图。
图7为使用裂殖酵母麦角硫因合成酶SPEGT1-tr和SPEGT2在100mM组氨酸甜菜碱条件下合成麦角硫因的HPLC鉴定图,以及定向进化后的SPEGT1-tr M10和SPEGT2 M3在100mM组氨酸甜菜碱条件下合成麦角硫因的HPLC鉴定图。
具体实施方式
本发明人经过长期而深入的研究,获得了一套麦角硫因的化学-酶偶联高效合成策略。其中,主要取得了一套L-组氨酸甜菜碱的大规模化学合成方法以及一种基于裂殖酵母的麦角硫因合成酶,所述的麦角硫因合成酶在现有的SPEGT1合成酶基础上去除了催化甲基化结构域,并进行定向进化得到SPEGT1-tr M10,并在SPEGT2合成酶基础上定向进化得到SPEGT2 M3。所得到的SPEGT1-tr M10合成酶相较于现有SPEGT1合成酶,在基因工程菌发酵表达中产量提高,且其麦角硫因合成效率显著提高。基于上述发现,发明人完成了本发明。
基于裂殖酵母的麦角硫因合成酶
本发明提供一种基于裂殖酵母的麦角硫因合成酶SPEGT1和SPEGT2的应用。
所述的裂殖酵母麦角硫因合成酶SPEGT1的氨基酸序列如SEQ ID NO:1所示:
MTEIENIGALEVLFSPESIEQSLKRCQLPSTLLYDEKGLRLFDEITNLKEYYLYESELDILKKFSDSIANQLLSPDLPNTVIELGCGNMRKTKLLLDAFEKKGCDVHFYALDLNEAELQKGLQELRQTTNYQHVKVSGICGCFERLLQCLDRFRSEPNSRISMLYLGASIGNFDRKSAASFLRSFASRLNIHDNLLISFDHRNKAELVQLAYDDPYRITEKFEKNILASVNAVFGENLFDENDWEYKSVYDEDLGVHRAYLQAKNEVTVIKGPMFFQFKPSHLILIEESWKNSDQECRQIIEKGDFKLVSKYESTIADYSTYVITKQFPAMLQLPLQPCPSLAEWDALRKVWLFITNKLLNKDNMYTAWIPLRHPPIFYIGHVPVFNDIYLTKIVKNKATANKKHFWEWFQRGIDPDIEDPSKCHWHSEVPESWPSPDQLREYEKESWEYHIVKLCKAMDELSTSEKRILWLCYEHVAMHVETTLYIYVQSFQNANQTVSICGSLPEPAEKLTKAPLWVNVPETEIAVGMPLTTQYTSVGSNLQSSDLSAHENTDELFYFAWDNEKPMRKKLVSSFSIANRPISNGEYLDFINKKSKTERVYPKQWAEIDGTLYIRTMYGLLPLDDYLGWPVMTSYDDLNNYASSQGCRLPTEDELNCFYDRVLERTDEPYVSTEGKATGFQQLHPLALSDNSSNQIFTGAWEWTSTVLEKHEDFEPEELYPDYTRDFFDGKHNVVLGGSFATATRISNRRSFRNFYQAGYKYAWIGARLVKN*;
其编码基因(spegt1)的核苷酸序列如SEQ ID NO:2所示:
atgaccgaaattgagaacatcggtgccctggaagtgctgttttctccggaaagtattgaacagagtctgaaacgttgccagctgccgagtaccctgctgtatgatgagaaaggtctgcgcctgtttgatgaaatcaccaatctgaaagaatactacctgtatgaaagcgaactggatattctgaagaaattcagcgatagcattgccaatcagctgctgagtccggatctgccgaataccgttattgaactgggctgtggcaatatgcgtaagactaaactgctgctggatgcctttgagaagaaaggctgcgatgttcatttctatgccctggatctgaatgaagccgaactgcagaaaggtctgcaggaactgcgccagaccaccaactatcagcatgttaaagtgagtggtatttgcggttgtttcgaacgcctgctgcagtgtctggatcgtttccgtagcgaaccgaatagtcgtattagcatgctgtatctgggtgcaagtattggtaacttcgatcgcaaatcagccgcaagtttcctgcgtagtttcgcaagccgtctgaacatccatgataatctgctgattagtttcgatcatcgcaacaaagccgaactggttcagctggcctatgatgatccgtatcgcattaccgagaaattcgagaagaacattctggccagcgttaatgcagtgtttggcgagaatctgtttgatgagaatgattgggaatacaaatccgtttatgacgaagatctgggtgtgcatcgcgcatatctgcaggcaaagaatgaagttaccgtgatcaaaggtccgatgttctttcagttcaaaccgagtcatctgattctgattgaagaaagttggaagaatagtgatcaggaatgccgtcagatcatcgagaaaggcgatttcaaactggttagcaaatacgaaagtaccattgccgattacagcacctatgtgattaccaaacagtttccagccatgctgcagctgccgctgcagccttgtccgagcctggcagaatgggatgccctgcgcaaagtgtggctgttcattaccaacaaactgctgaataaggacaatatgtacaccgcctggattccgctgcgtcatccaccgatcttctacattggccatgtgccggtgttcaacgatatctacctgaccaagattgtgaagaataaggcaaccgccaataagaaacatttctgggaatggtttcagcgtggtattgatccggatattgaagatccgagcaaatgccattggcatagtgaagttccggaaagttggccgtctccggatcagctgcgtgaatatgagaaagaaagttgggaatatcatatcgtgaaactgtgtaaagcaatggatgaactgagtaccagtgagaaacgtattctgtggctgtgttatgaacatgttgccatgcatgtggaaaccaccctgtacatctatgtgcagagctttcagaatgcaaatcagaccgttagcatttgtggcagtctgccagaaccggcagagaaactgaccaaagcacctctgtgggtgaatgtgccggaaaccgaaattgcagttggcatgccgctgaccacccagtataccagtgtgggtagcaatctgcagagcagtgatctgagcgcacatgagaataccgatgaactgttctatttcgcatgggataatgagaaaccgatgcgtaagaaactggtgagcagctttagtattgccaatcgtccgattagtaatggtgaatatctggatttcatcaataagaaatccaagaccgaacgtgtttatccgaaacagtgggcagaaattgatggtaccctgtatatccgtaccatgtatggcctgctgccgctggatgattatctgggctggccagttatgaccagttatgatgatctgaacaattacgcaagtagccagggctgccgtctgccgaccgaagatgaactgaattgtttctatgatcgtgttctggaacgcaccgatgaaccgtatgtgagtaccgaaggcaaagccaccggctttcagcagctgcatccgctggcactgagcgataacagcagtaatcagatctttaccggtgcctgggaatggaccagtaccgttctggagaaacatgaagatttcgaaccggaagaactgtatccggattacacccgtgatttctttgatggcaaacataatgtggtgctgggtggtagctttgccaccgcaacccgtattagtaatcgtcgtagtttccgtaacttctaccaagccggttacaaatacgcctggattggtgcacgtctggtgaaaaactaa
所述的裂殖酵母麦角硫因合成酶SPEGT2的氨基酸序列如SEQ ID NO:3所示:
MAENNVYGHEMKKHFMLDPDYVNVNNGSCGTESLAVYNKHVQLLKEAQSKPDFMCNAYMPMYMEATRNEVAKLIGADSSNIVFCNSATDGISTVLLTFPWEQNDEILMLNVAYPTCTYAADFAKNQHNLRLDVIDVGVEIDEDLFLKEVEQRFLQSKPRAFICDILSSMPVILFPWEKVVKLCKKYNIVSIIDGAHAIGHIPMNLANVDPDFLFTNAHKWLNSPAACTVLYVSAKNHNLIEALPLSYGYGLREKESIAVDTLTNRFVNSFKQDLPKFIAVGEAIKFRKSIGGEEKIQQYCHEIALKGAEIISKELGTSFIKPPYPVAMVNVEVPLRNIPSIETQKVFWPKYNTFLRFMEFKGKFYTRLSGAVYLEESDFYYIAKVIKDF*;
其编码基因(spegt2)的核苷酸序列如SEQ ID NO:4所示:
atggctgagaacaacgtgtacggccacgaaatgaaaaaacatttcatgctggatcctgactatgtaaacgtgaacaacggtagctgcggtaccgaatccctggctgtttacaacaaacacgttcagctgctgaaagaagctcagtccaaaccggacttcatgtgtaacgcttacatgccgatgtacatggaagcgacccgtaatgaagtcgccaaactgatcggtgcggactcttccaacatcgtgttctgcaacagcgcaacggacggcatttctactgtcctgctgaccttcccgtgggagcagaacgatgaaatcctgatgctgaacgttgcgtatccgacctgtacctacgctgcggactttgcgaaaaaccagcataacctgcgcctggacgttatcgatgttggtgttgaaatcgatgaagatctgtttctgaaagaagttgaacagcgcttcctgcagtccaaaccgcgtgcgttcatctgcgacatcctgtcctctatgccggtcattctgtttccgtgggagaaagtggtgaagctgtgcaaaaaatacaatattgtgtccatcatcgacggtgcgcacgcgattggccacatcccgatgaatctggctaacgtggatccggattttctgttcaccaacgcgcacaaatggctgaactctccggcagcgtgcaccgtgctgtacgtttctgcaaagaaccacaacctgatcgaagcactgccactgagctacggctacggcctgcgtgaaaaagaatctattgcagttgacaccctgaccaaccgcttcgttaacagcttcaaacaagatctgccgaaattcatcgcagtcggcgaagctatcaaattccgtaagagcatcggtggcgaagaaaaaatccagcagtactgtcacgaaatcgcgctgaaaggtgcggagattatctctaaagagctgggcacctccttcatcaaaccgccgtatccagttgccatggttaacgttgaggttccgctgcgtaacattccaagcatcgaaacccagaaagttttctggccgaaatataataccttcctgcgtttcatggaattcaaaggcaaattctacacccgtctgtctggcgccgtgtatctggaagaatctgacttctactatatcgccaaagtaatcaaggacttctgttccctgtaa;
所述的裂殖酵母麦角硫因合成酶SPEGT1催化甲基化结构域去除后的氨基酸序列(SPEGT1-tr)如SEQ ID NO:5所示:
PAMLQLPLQPCPSLAEWDALRKVWLFITNKLLNKDNMYTAWIPLRHPPIFYIGHVPVFNDIYLTKIVKNKATANKKHFWEWFQRGIDPDIEDPSKCHWHSEVPESWPSPDQLREYEKESWEYHIVKLCKAMDELSTSEKRILWLCYEHVAMHVETTLYIYVQSFQNANQTVSICGSLPEPAEKLTKAPLWVNVPETEIAVGMPLTTQYTSVGSNLQSSDLSAHENTDELFYFAWDNEKPMRKKLVSSFSIANRPISNGEYLDFINKKSKTERVYPKQWAEIDGTLYIRTMYGLLPLDDYLGWPVMTSYDDLNNYASSQGCRLPTEDELNCFYDRVLERTDEPYVSTEGKATGFQQLHPLALSDNSSNQIFTGAWEWTSTVLEKHEDFEPEELYPDYTRDFFDGKHNVVLGGSFATATRISNRRSFRNFYQAGYKYAWIGARLVKN*;
其编码基因(spegt1-tr)的核苷酸序列如SEQ ID NO:6所示;
ccagccatgctgcagctgccgctgcagccttgtccgagcctggcagaatgggatgccctgcgcaaagtgtggctgttcattaccaacaaactgctgaataaggacaatatgtacaccgcctggattccgctgcgtcatccaccgatcttctacattggccatgtgccggtgttcaacgatatctacctgaccaagattgtgaagaataaggcaaccgccaataagaaacatttctgggaatggtttcagcgtggtattgatccggatattgaagatccgagcaaatgccattggcatagtgaagttccggaaagttggccgtctccggatcagctgcgtgaatatgagaaagaaagttgggaatatcatatcgtgaaactgtgtaaagcaatggatgaactgagtaccagtgagaaacgtattctgtggctgtgttatgaacatgttgccatgcatgtggaaaccaccctgtacatctatgtgcagagctttcagaatgcaaatcagaccgttagcatttgtggcagtctgccagaaccggcagagaaactgaccaaagcacctctgtgggtgaatgtgccggaaaccgaaattgcagttggcatgccgctgaccacccagtataccagtgtgggtagcaatctgcagagcagtgatctgagcgcacatgagaataccgatgaactgttctatttcgcatgggataatgagaaaccgatgcgtaagaaactggtgagcagctttagtattgccaatcgtccgattagtaatggtgaatatctggatttcatcaataagaaatccaagaccgaacgtgtttatccgaaacagtgggcagaaattgatggtaccctgtatatccgtaccatgtatggcctgctgccgctggatgattatctgggctggccagttatgaccagttatgatgatctgaacaattacgcaagtagccagggctgccgtctgccgaccgaagatgaactgaattgtttctatgatcgtgttctggaacgcaccgatgaaccgtatgtgagtaccgaaggcaaagccaccggctttcagcagctgcatccgctggcactgagcgataacagcagtaatcagatctttaccggtgcctgggaatggaccagtaccgttctggagaaacatgaagatttcgaaccggaagaactgtatccggattacacccgtgatttctttgatggcaaacataatgtggtgctgggtggtagctttgccaccgcaacccgtattagtaatcgtcgtagtttccgtaacttctaccaagccggttacaaatacgcctggattggtgcacgtctggtgaaaaactaa;
所述的裂殖酵母麦角硫因合成酶SPEGT1突变体的氨基酸序列(SPEGT1-tr M10)如SEQ ID NO:7所示:
PAMLQLPLQPCPSLAEWDALRKVWLFITNKLLNKDNMYTAWIPLRHPPILFIGHVPVFNDIYLTKIVKNKATANKKHFWEWFQRGIDPDIEDPSKCNWNSEVPESWPSPDQLREYEKESWEYHIVKLCKAMDELSTSEKRILWLCYEHVALHVETTLYIYVQSFQNANQTVSICGSLPEPAEKLTKAPLWVNVPETEIAVGMPLTTQYTSVGSNLQSSDLSAHENTDELFYFAWDNEKPMRKKLVSSFSIANRPISNGEYLDFINKKSKTERVYPKQWAEIDGTLYIRTMYGLLPLDDYLGWPVMTSYDDLNNYASSQGCRLPTEDELNCFYDRVLERTDEPYVSTEGKATGFQQLHPLALSDNSSNQIFTGAWECTSTVLEKHEDFEPEELYPDYTRDFFDGKLNVVLGGSFATATRISNRRSLRNFYQAGYKSAWIGARLVKN*
其编码基因(spegt1-tr M10)的核苷酸序列如SEQ ID NO:8所示:
ccagccatgctgcagctgccgctgcagccttgtccgagcctggcagaatgggatgccctgcgcaaagtgtggctgttcattaccaacaaactgctgaataaggacaatatgtacaccgcctggattccgctgcgtcatccaccgatcctcttcattggccatgtgccggtattcaacgatatctacctgaccaagattgtgaagaataaggcaaccgccaataagaaacatttctgggaatggtttcagcgtggtattgatccggatattgaagatccgagcaaatgcaattggaacagtgaagttccggaaagttggccgtctccggatcagctgcgtgaatatgagaaagaaagttgggaatatcatatcgtgaagctgtgtaaagcaatggatgaactgagtaccagtgagaaacgtattctgtggctgtgttatgaacatgttgccctgcatgtggaaaccaccctgtacatctatgtgcagagctttcagaatgcaaatcagaccgttagcatttgtggcagtctgccagaaccggcagagaaactgaccaaagcacctctgtgggtgaatgtgccggaaaccgaaattgcagttggcatgccgctgaccacccagtataccagtgtgggtagcaatctgcagagcagtgatctgagcgcacatgagaataccgatgaactgttctatttcgcatgggataatgagaaaccgatgcgtaagaaactggtgagcagctttagtattgccaatcgtccgattagtaatggtgaatatctggatttcatcaataagaaatccaagaccgaacgtgtttatccgaaacagtgggcagaaattgatggtaccctgtatatccgtaccatgtatggcctgctgccgctggatgattatctgggctggccagttatgaccagttatgatgatctgaacaattacgcaagtagccagggctgccgtctgccgaccgaagatgaactgaattgtttctatgatcgtgttctggaacgcaccgatgaaccgtatgtgagtaccgaaggcaaagccaccggctttcagcagctgcatccgctggcactgagcgataacagcagtaatcagatctttaccggtgcctgggaatgtaccagtaccgttctggagaaacatgaagatttcgaaccggaagaactgtacccggattacacccgtgatttctttgatggcaaacttaatgtggtgctgggtggtagctttgccaccgcaacccgtattagtaatcgtcgtagtctccgtaacttctaccaagccggttacaaatccgcctggattggtgcacgtctggtgaaaaactaa
所述的裂殖酵母麦角硫因合成酶SPEGT2定向进化后的氨基酸序列(SPEGT2 M3)如SEQ ID NO:9所示:
MAENNVYGHEMKKHFMLDPDYVNVNNGPCGTESLAVYNKHVQLLKEAQSKPDFMCNAYMPMYMEATRNEVAKLIGADSSNIVFCNSATDGISTVLLTFPWEQNDEILMLNVAFPTCTYAADFAKNQHNLRLDVIDVGVEIDEDLFLKEVEQRFLQSKPRAFICDILASMPVILFPWEKVVKLCKKYNIVSIIDGAHAIGHIPMNLANVDPDFLFTNAHKWLNSPAACTVLYVSAKNHNLIEALPLSYGYGLREKESIAVDTLTNRFVNSFKQDLPKFIAVGEAIKFRKSIGGEEKIQQYCHEIALKGAEIISKELGTSFIKPPYPVAMVNVEVPLRNIPSIETQKVFWPKYNTFLRFMEFKGKFYTRLSGAVYLEESDFYYIAKVIKDFCSL*
其编码基因(spegt2 M3)的核苷酸序列如SEQ ID NO:10所示:
atggctgagaacaacgtgtacggccacgaaatgaaaaaacatttcatgctggatcctgactatgtaaacgtgaacaacggtccctgcggtaccgaatccctggctgtttacaacaaacacgttcagctgctgaaagaagctcagtccaaaccggacttcatgtgtaacgcttacatgccgatgtacatggaagcgacccgtaatgaagtcgccaaactgatcggtgcggactcttccaacatcgtgttctgcaacagcgcaacggacggcatttctactgtcctgctgaccttcccgtgggagcagaacgatgaaatcctgatgctgaacgttgcgtttccgacctgtacctacgctgcggactttgcgaaaaaccagcataacctgcgcctggacgttatcgatgttggtgttgaaatcgatgaagatctgtttctgaaagaagttgaacagcgcttcctgcagtccaaaccgcgtgcgttcatctgcgacatcctggcctctatgccggtcattctgtttccgtgggagaaagtggtgaagctgtgcaaaaaatacaatattgtgtccatcatcgacggtgcgcacgcgattggccacatcccgatgaatctggctaacgtggatccggattttctgttcaccaacgcgcacaaatggctgaactctccggcagcgtgcaccgtgctgtacgtttctgcaaagaaccacaacctgatcgaagcactgccactgagctacggctacggcctgcgtgaaaaagaatctattgcagttgacaccctgaccaaccgcttcgttaacagcttcaaacaagatctgccgaaattcatcgcagtcggcgaagctatcaaattccgtaagagcatcggtggcgaagaaaaaatccagcagtactgtcacgaaatcgcgctgaaaggtgcggagattatctctaaagagctgggcacctccttcatcaaaccgccgtatccagttgccatggttaacgttgaggttccgctgcgtaacattccaagcatcgaaacccagaaagttttctggccgaaatataataccttcctgcgtttcatggaattcaaaggcaaattctacacccgtctgtctggcgccgtgtatctggaagaatctgacttctactatatcgccaaagtaatcaaggacttctgttccctgtaa
在一个优选的实施方式下,SEQ ID NO:7和SEQ ID NO:9所示的氨基酸序列可以存在一个或几个氨基酸残基的取代、缺失,和/或添加,前提是不影响其功能,该类功能相同的衍生蛋白也属于本发明的保护范围。
在另一个优选的实施方式下,SEQ ID NO:8和SEQ ID NO:10所示的核苷酸序列可以存在一个或几个核苷酸的取代、缺失,和/或添加,前提是不影响其功能,该类功能相同的核苷酸序列也属于本发明的保护范围。
本发明中,还提供了一种裂殖酵母麦角硫因合成酶组合,其包括裂殖酵母麦角硫因合成酶SPEGT1、SPEGT2经去催化甲基化结构域和/或定向进化后的氨基酸序列。具体地,所述的裂殖酵母麦角硫因合成酶SPEGT1为SPEGT1-tr M10,其具有SEQ ID NO:7所示的氨基酸序列,所述的裂殖酵母麦角硫因合成酶SPEGT2为SPEGT2 M3裂殖酵母麦角硫因合成酶,其具有SEQ ID NO:9所示的氨基酸序列。应理解,上述氨基酸序列可能经取代和/或缺失和/或添加一个或几个氨基酸残基,而形成功能基本相同的衍生蛋白,上述衍生蛋白同样可作为本发明的合成酶组合。
此外,含有所述编码基因的重组载体、表达盒、重组菌也属于本发明的保护范围。
一种麦角硫因合成方法
本发明中,还提供了一种麦角硫因的合成方法,所述的方法采用L-组氨酸作为原料,采用钯碳催化的甲醛还原胺化二甲基化和碘甲烷亲核取代合成L-组氨酸甜菜碱,之后采用如本发明所述的裂殖酵母麦角硫因合成酶组合进行酶催化制备,从而高产率地得到麦角硫因。
具体地,所述方法包括步骤:
在如本发明第二方面述的麦角硫因化学-酶偶联合成系统存在下,从L-组氨酸和半胱氨酸出发,得到麦角硫因。
优选地,所述的酶催化步骤在Fe2+、磷酸吡哆醛和beta巯基乙醇存在下进行。
为了获得最佳的反应结果,所述的方法在pH=7-9的缓冲体系中,在20-30℃下进行。
本发明相对于现有技术具有如下的优点及效果:
本发明使用化学方法大规模合成L-组氨酸甜菜碱,克服了麦角硫因合成酶EGT1的大肠杆菌发酵液催化甲基化效率低的问题(主要是由于大肠杆菌中S-腺苷甲硫氨酸浓度较低)。然后从裂殖酵母(Schizosaccharomyces pombe)的麦角硫因合成酶出发,从Uniprot上得到了裂殖酵母麦角硫因合成酶SPEGT1(Uniprot ID:O94632)和SPEGT2(Uniprot ID:O94431)的氨基酸序列,并使用Uniprot的信息去除SPEGT1催化甲基化结构域(M1~F328)获得SPEGT1-tr的氨基酸序列。合成上述基因并构建于pET28a载体中,在大肠杆菌中实现了异源表达。通过随机突变试剂盒对裂殖酵母麦角硫因合成编码相关基因(spegt1-tr、spegt2)进行定向进化得到相应活性显著提高的合成麦角硫因所需的酶(SPEGT1-tr M10和SPEGT2M3),用于麦角硫因的合成,相对于现有合成麦角硫因技术的产量显著提高。同时,本发明构建的基因工程大肠杆菌安全稳定,生产周期短,展示出SPEGT1-tr M10和SPEGT2 M3工程酶发酵放大并工业化生产麦角硫因的巨大潜力。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。其他使用的材料、试剂等,如无特殊说明,为从商业途径得到的试剂和材料。
实施例1
N,N-二甲基组氨酸的合成
向1L高压釜中依次加入625ml水、96g(0.5mol)L-组氨酸盐酸盐、96g(1.185mol,2.37eq)37%甲醛水溶液及10g 10%Pd-C催化剂。加毕,用氮气置换3次,再用氢气置换3次。置换完毕后,开始通氢气氢化,保持压力0.5-1.0MPa,反应温度控制10℃~30℃,反应24h。反应毕,过滤去催化剂,滤液经减压浓缩至约(100-150)ml,加入600L乙醇,重结晶得产品约85g,收率:71%。1H NMR(D2O)δ8.51(s,1H),7.26(s,1H),3.76-3.80(m,1H),3.31-3.36(m,1H),3.15-3.21(s,1H),2.83(s,6H)。
实施例2
组氨酸甜菜碱的合成
将238g(1mol)N,N-二甲基组氨酸悬浮于1500ml甲醇中,控制在15℃以下,滴加150g浓氨水/35ml水的溶液,加毕,PH=9,再滴加碘甲烷195g(1.37mol,1.37eq),滴加完毕,于15℃~25℃下反应4-5h,然后减压蒸去甲醇,然后加水稀释至约4000ml,用40g氢氧化钠/100ml水的溶液调节PH=9-11,分别经膜分离、阴离子交换树脂脱盐,将脱盐后的水溶液减压浓缩至约250ml时,加入800ml异丙醇,搅拌过夜,析出固体,过滤、干燥,得150g组氨酸甜菜碱,收率:76%。1H NMR(D2O)δ7.73(s,1H),7.04(s,1H),3.92-3.96(m,1H),3.20-3.26(m,11H)。
实施例3
麦角硫因合成质粒的构建
使用Uniprot搜索EGT1和EGT2,找到裂殖酵母(Schizosaccharomyces pombe)的麦角硫因合成酶SPEGT1(Uniprot ID:O94632)和SPEGT2(Uniprot ID:O94431),如SEQ ID No:1和3所示。因为本发明的酶催化步骤使用组氨酸甜菜碱作为原料,SPEGT1上的催化甲基化结构域无需使用,可以去除。按Uniprot上的AlphaFold结构,在两个催化结构域中间切除,获得P329到N773的组氨酸甜菜碱半胱氨酸亚砜合成酶SPEGT1-tr,如SEQ ID No.:5。上述3个蛋白序列在通用生物优化大肠杆菌表达的核苷酸序列(如SEQ ID No.:2、4、6)并合成插入载体pET28a的NdeI和XhoI之间的质粒pET-28a-SpEgt1、pET-28a-SpEgt1-tr、pET-28a-SpEgt2(如图2所示)。
实施例4
SPEGT1-tr和SPEGT2的随机突变定向进化
使用Uniprot提供的SPEGT1和SPEGT2的AlphaFold结构,对SPEGT1-tr和SPEGT2各选取了两段富含底物0.8纳米范围内残基的片段(SPEGT1-tr:P43~N236和L356~A436;SPEGT2:M1~V136和L146-I290)进行随机突变。随机突变的具体操作如下:
(1)使用Agilent GeneMorph II随机突变试剂盒对需要突变的片段进行25μL体系的PCR反应(使用的引物和退火温度见表1)。反应体系为25ng质粒(pET-28a-SpEgt1-tr、pET-28a-SpEgt2或上一轮的阳性突变体),2.5μL 10xMutazyme II reaction buffer,0.5μL 40mM dNTP,1.25μL 10μM正向引物,1.25μL 10μM反向引物,0.5μL Mutazyme II DNAPolymerase。PCR程序为95℃变性30s,退火温度30s,72℃延伸1min,30个循环。反应结束后使用1%的琼脂糖凝胶进行胶回收纯化(见图3,条带1、3、5、7分别对应SPEGT1-tr的两段片段和SPEGT2的两段片段)。SPEGT1-tr共进行10轮随机突变,奇数轮扩增P43~N236,偶数轮扩增L356~A436。SPEGT2共进行3轮随机突变,奇数轮扩增M1~V136,偶数轮扩增L146-I290。
(2)使用NEB的Q5对随机突变片段对应的载体进行50μL体系的PCR反应(使用的引物和退火温度见表1)。反应体系为1ng质粒(随机突变相同质粒),10μL 5xQ5 reactionbuffer,1μL 10mM dNTP,2.5μL 10μM正向引物,2.5μL 10μM反向引物,0.5μL Q5 High-Fidelity DNA Polymerase。PCR程序为98℃变性10s,退火温度30s,72℃延伸4min,30个循环。反应结束后使用1%的琼脂糖凝胶进行胶回收纯化(见图3,条带2、4、6、8对应上述随机突变片段对应的载体部分)。
(3)随机突变片段和载体进行10μL无缝连接反应。反应体系为125ng载体,25ng随机突变片段,5μL Seamless Cloning Kit混合液(碧云天)。无缝连接程序为50℃1h。
无缝连接产物使用唯地生物的BL21 star(DE3)感受态进行转化。具体为100μL感受态细胞,加上述10μL无缝连接产物,混合均匀,冰浴静置25min。40℃水浴热激30s,再冰浴静置3min。加入1ml没有抗生素的LB培养基,37℃,220rpm摇床培养1h。每200μL均匀涂布于卡那霉素(K+)的LB固体培养基平板(共5块)上。37℃烘箱培养12h。一般每块平板会含有200~500个克隆。
每块平板各挑选92个克隆至含有300μL LB培养基的96孔深孔板中,另外4孔使用质粒(pET-28a-SpEgt1-tr、pET-28a-SpEgt2或上一轮的阳性突变体)转化的克隆。37℃,600rpm摇床培养16h。按5%(v/v)的接种量接种到新的含500μLTB培养基的96孔深孔板中,37℃,600rpm摇床培养2h。加入终浓度为0.3mM的IPTG,20℃诱导表达24h。
96孔深孔板中的细菌离心除去培养基,加入50μL BugBuster ProteinExtraction Reagent(Merck),室温450rpm 30min。离心取上层清液获得细菌裂解液,然后进行下述的10mM反应体系反应并使用下述的HPLC方法检测反应产率,获得这一轮的最佳阳性突变体。
SPEGT1-tr经过10轮随机突变,获得突变体SPEGT1-tr M10(F50L-Y51F-H97N-H99N-M151L-W376C-H405L-F425L-Y435S),其蛋白序列和核苷酸序列见SEQ ID No.:7、8。SPEGT2经过3轮随机突变,获得突变体SPEGT2 M3(S28P-Y113F-S167A),其蛋白序列和核苷酸序列见SEQ ID No.:9、10。
表1.裂殖酵母麦角硫因合成酶SPEGT1、SPEGT2随机突变引物
实施例5
SPEGT1和SPEGT2的摇瓶表达
按照1%(v/v)的接种量将构建成功的工程菌液接种到1L TB液体培养基中,37℃,220rpm培养至OD600=0.8左右,加入浓度为0.3mM的IPTG,在20℃条件下诱导表达24h。利用pH8.0的10mM Tris洗涤工程菌株后,离心收集菌体,SPEGT1获得15.5g菌体,SPEGT1-tr获得15.8g菌体,SPEGT1-tr M10获得16.5g菌体;SPEGT2获得3.8g菌体,SPEGT2 M3获得8.5g菌体。分别将每种酶的1g菌体取出,加入5ml 10mM Tris(pH=8)涡旋分散,探头超声(50%功率,10s on-10s off;累计超声3000J)裂解菌液。菌液裂解后离心取上层清夜进行12%SDS-PAGE分析表达。结果如图4所示,从图中可以看出,表达的重组蛋白分别与预期条带大小差不多(SPEGT1为92kDa,SPEGT1-tr和SPEGT1-tr M10为54kDa,SPEGT2和SPEGT2 M3为47kDa),说明构建的表达载体能够有效以重组蛋白形式分别表达裂殖酵母麦角硫因合成酶及其突变体。SPEGT1除去催化甲基化结构域后表达量提高5倍以上。
实施例6
10mM组氨酸甜菜碱反应体系验证
上述随机突变定向进化和摇瓶表达的工程菌均使用100μL反应体系进行验证。反应体系为10mM组氨酸甜菜碱,15mM半胱氨酸,100mM Tris(pH8.0),10mM Fe2+,1mM磷酸吡哆醛(PLP),10mM beta巯基乙醇,1%(v/v)SPEGT1-tr(或SPEGT1-tr M10)裂解液,1%(v/v)SPEGT2(或SPEGT2 M3)裂解液。反应程序为25℃,500rpm摇床反应2h。反应结束后,加入终浓度为10mM的内标对氨基苯甲酸,加入0.3mL 0.1%(v/v)三氟乙酸的乙腈溶液,离心取上清进行HPLC分析。HPLC条件为C18分析柱;相A:50mM醋酸铵,相B:100%乙腈;色谱条件:0%~70%相B 3.5min,70%~0%相B1min,0%相B 0.5min;检测波长254nm,流速为1mL/min。麦角硫因标准品的谱图见图5上;反应试剂混合液外加10mM麦角硫因和10mM内标的化合物混合液见图5下。10mM组氨酸甜菜碱反应体系见图6,其中SPEGT1-tr和SPEGT2催化的反应见图6上,最终突变体SPEGT1-tr M10和SPEGT2 M3催化的反应见图6下。反应产率从0.7%提高到80.9%,提高了116倍。
实施例7
100mM组氨酸甜菜碱反应体系
摇瓶表达的工程菌同样使用高浓度的50mL反应体系进行验证。反应体系为100mM组氨酸甜菜碱,100mM半胱氨酸,100mM Tris(pH8.0),10mM Fe2+,1mM PLP,100mM beta巯基乙醇,10%(v/v)SPEGT1-tr(或SPEGT1-tr M10)裂解液,10%(v/v)SPEGT2(或SPEGT2 M3)裂解液。反应程序为25℃,220rpm摇床反应2h。反应后,加入终浓度为100mM的内标对氨基苯甲酸,取0.1mL混合液加入0.3mL的0.1%三氟乙酸的乙腈溶液,离心取上清进行HPLC分析。HPLC分析条件同上所述。100mM组氨酸甜菜碱反应体系见图7,其中SPEGT1-tr和SPEGT2催化的反应见图7上,最终突变体SPEGT1-tr M10和SPEGT2 M3催化的反应见图7下。反应产率从0.1%提高到39.3%。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 中国科学院上海有机化学研究所
<120> 一种化学-酶偶联方法用于合成麦角硫因
<130> P2022-0556
<160> 26
<170> PatentIn version 3.5
<210> 1
<211> 773
<212> PRT
<213> Artificial Sequence
<220>
<223> SPEGT1
<400> 1
Met Thr Glu Ile Glu Asn Ile Gly Ala Leu Glu Val Leu Phe Ser Pro
1 5 10 15
Glu Ser Ile Glu Gln Ser Leu Lys Arg Cys Gln Leu Pro Ser Thr Leu
20 25 30
Leu Tyr Asp Glu Lys Gly Leu Arg Leu Phe Asp Glu Ile Thr Asn Leu
35 40 45
Lys Glu Tyr Tyr Leu Tyr Glu Ser Glu Leu Asp Ile Leu Lys Lys Phe
50 55 60
Ser Asp Ser Ile Ala Asn Gln Leu Leu Ser Pro Asp Leu Pro Asn Thr
65 70 75 80
Val Ile Glu Leu Gly Cys Gly Asn Met Arg Lys Thr Lys Leu Leu Leu
85 90 95
Asp Ala Phe Glu Lys Lys Gly Cys Asp Val His Phe Tyr Ala Leu Asp
100 105 110
Leu Asn Glu Ala Glu Leu Gln Lys Gly Leu Gln Glu Leu Arg Gln Thr
115 120 125
Thr Asn Tyr Gln His Val Lys Val Ser Gly Ile Cys Gly Cys Phe Glu
130 135 140
Arg Leu Leu Gln Cys Leu Asp Arg Phe Arg Ser Glu Pro Asn Ser Arg
145 150 155 160
Ile Ser Met Leu Tyr Leu Gly Ala Ser Ile Gly Asn Phe Asp Arg Lys
165 170 175
Ser Ala Ala Ser Phe Leu Arg Ser Phe Ala Ser Arg Leu Asn Ile His
180 185 190
Asp Asn Leu Leu Ile Ser Phe Asp His Arg Asn Lys Ala Glu Leu Val
195 200 205
Gln Leu Ala Tyr Asp Asp Pro Tyr Arg Ile Thr Glu Lys Phe Glu Lys
210 215 220
Asn Ile Leu Ala Ser Val Asn Ala Val Phe Gly Glu Asn Leu Phe Asp
225 230 235 240
Glu Asn Asp Trp Glu Tyr Lys Ser Val Tyr Asp Glu Asp Leu Gly Val
245 250 255
His Arg Ala Tyr Leu Gln Ala Lys Asn Glu Val Thr Val Ile Lys Gly
260 265 270
Pro Met Phe Phe Gln Phe Lys Pro Ser His Leu Ile Leu Ile Glu Glu
275 280 285
Ser Trp Lys Asn Ser Asp Gln Glu Cys Arg Gln Ile Ile Glu Lys Gly
290 295 300
Asp Phe Lys Leu Val Ser Lys Tyr Glu Ser Thr Ile Ala Asp Tyr Ser
305 310 315 320
Thr Tyr Val Ile Thr Lys Gln Phe Pro Ala Met Leu Gln Leu Pro Leu
325 330 335
Gln Pro Cys Pro Ser Leu Ala Glu Trp Asp Ala Leu Arg Lys Val Trp
340 345 350
Leu Phe Ile Thr Asn Lys Leu Leu Asn Lys Asp Asn Met Tyr Thr Ala
355 360 365
Trp Ile Pro Leu Arg His Pro Pro Ile Phe Tyr Ile Gly His Val Pro
370 375 380
Val Phe Asn Asp Ile Tyr Leu Thr Lys Ile Val Lys Asn Lys Ala Thr
385 390 395 400
Ala Asn Lys Lys His Phe Trp Glu Trp Phe Gln Arg Gly Ile Asp Pro
405 410 415
Asp Ile Glu Asp Pro Ser Lys Cys His Trp His Ser Glu Val Pro Glu
420 425 430
Ser Trp Pro Ser Pro Asp Gln Leu Arg Glu Tyr Glu Lys Glu Ser Trp
435 440 445
Glu Tyr His Ile Val Lys Leu Cys Lys Ala Met Asp Glu Leu Ser Thr
450 455 460
Ser Glu Lys Arg Ile Leu Trp Leu Cys Tyr Glu His Val Ala Met His
465 470 475 480
Val Glu Thr Thr Leu Tyr Ile Tyr Val Gln Ser Phe Gln Asn Ala Asn
485 490 495
Gln Thr Val Ser Ile Cys Gly Ser Leu Pro Glu Pro Ala Glu Lys Leu
500 505 510
Thr Lys Ala Pro Leu Trp Val Asn Val Pro Glu Thr Glu Ile Ala Val
515 520 525
Gly Met Pro Leu Thr Thr Gln Tyr Thr Ser Val Gly Ser Asn Leu Gln
530 535 540
Ser Ser Asp Leu Ser Ala His Glu Asn Thr Asp Glu Leu Phe Tyr Phe
545 550 555 560
Ala Trp Asp Asn Glu Lys Pro Met Arg Lys Lys Leu Val Ser Ser Phe
565 570 575
Ser Ile Ala Asn Arg Pro Ile Ser Asn Gly Glu Tyr Leu Asp Phe Ile
580 585 590
Asn Lys Lys Ser Lys Thr Glu Arg Val Tyr Pro Lys Gln Trp Ala Glu
595 600 605
Ile Asp Gly Thr Leu Tyr Ile Arg Thr Met Tyr Gly Leu Leu Pro Leu
610 615 620
Asp Asp Tyr Leu Gly Trp Pro Val Met Thr Ser Tyr Asp Asp Leu Asn
625 630 635 640
Asn Tyr Ala Ser Ser Gln Gly Cys Arg Leu Pro Thr Glu Asp Glu Leu
645 650 655
Asn Cys Phe Tyr Asp Arg Val Leu Glu Arg Thr Asp Glu Pro Tyr Val
660 665 670
Ser Thr Glu Gly Lys Ala Thr Gly Phe Gln Gln Leu His Pro Leu Ala
675 680 685
Leu Ser Asp Asn Ser Ser Asn Gln Ile Phe Thr Gly Ala Trp Glu Trp
690 695 700
Thr Ser Thr Val Leu Glu Lys His Glu Asp Phe Glu Pro Glu Glu Leu
705 710 715 720
Tyr Pro Asp Tyr Thr Arg Asp Phe Phe Asp Gly Lys His Asn Val Val
725 730 735
Leu Gly Gly Ser Phe Ala Thr Ala Thr Arg Ile Ser Asn Arg Arg Ser
740 745 750
Phe Arg Asn Phe Tyr Gln Ala Gly Tyr Lys Tyr Ala Trp Ile Gly Ala
755 760 765
Arg Leu Val Lys Asn
770
<210> 2
<211> 2322
<212> DNA
<213> Artificial Sequence
<220>
<223> spegt1
<400> 2
atgaccgaaa ttgagaacat cggtgccctg gaagtgctgt tttctccgga aagtattgaa 60
cagagtctga aacgttgcca gctgccgagt accctgctgt atgatgagaa aggtctgcgc 120
ctgtttgatg aaatcaccaa tctgaaagaa tactacctgt atgaaagcga actggatatt 180
ctgaagaaat tcagcgatag cattgccaat cagctgctga gtccggatct gccgaatacc 240
gttattgaac tgggctgtgg caatatgcgt aagactaaac tgctgctgga tgcctttgag 300
aagaaaggct gcgatgttca tttctatgcc ctggatctga atgaagccga actgcagaaa 360
ggtctgcagg aactgcgcca gaccaccaac tatcagcatg ttaaagtgag tggtatttgc 420
ggttgtttcg aacgcctgct gcagtgtctg gatcgtttcc gtagcgaacc gaatagtcgt 480
attagcatgc tgtatctggg tgcaagtatt ggtaacttcg atcgcaaatc agccgcaagt 540
ttcctgcgta gtttcgcaag ccgtctgaac atccatgata atctgctgat tagtttcgat 600
catcgcaaca aagccgaact ggttcagctg gcctatgatg atccgtatcg cattaccgag 660
aaattcgaga agaacattct ggccagcgtt aatgcagtgt ttggcgagaa tctgtttgat 720
gagaatgatt gggaatacaa atccgtttat gacgaagatc tgggtgtgca tcgcgcatat 780
ctgcaggcaa agaatgaagt taccgtgatc aaaggtccga tgttctttca gttcaaaccg 840
agtcatctga ttctgattga agaaagttgg aagaatagtg atcaggaatg ccgtcagatc 900
atcgagaaag gcgatttcaa actggttagc aaatacgaaa gtaccattgc cgattacagc 960
acctatgtga ttaccaaaca gtttccagcc atgctgcagc tgccgctgca gccttgtccg 1020
agcctggcag aatgggatgc cctgcgcaaa gtgtggctgt tcattaccaa caaactgctg 1080
aataaggaca atatgtacac cgcctggatt ccgctgcgtc atccaccgat cttctacatt 1140
ggccatgtgc cggtgttcaa cgatatctac ctgaccaaga ttgtgaagaa taaggcaacc 1200
gccaataaga aacatttctg ggaatggttt cagcgtggta ttgatccgga tattgaagat 1260
ccgagcaaat gccattggca tagtgaagtt ccggaaagtt ggccgtctcc ggatcagctg 1320
cgtgaatatg agaaagaaag ttgggaatat catatcgtga aactgtgtaa agcaatggat 1380
gaactgagta ccagtgagaa acgtattctg tggctgtgtt atgaacatgt tgccatgcat 1440
gtggaaacca ccctgtacat ctatgtgcag agctttcaga atgcaaatca gaccgttagc 1500
atttgtggca gtctgccaga accggcagag aaactgacca aagcacctct gtgggtgaat 1560
gtgccggaaa ccgaaattgc agttggcatg ccgctgacca cccagtatac cagtgtgggt 1620
agcaatctgc agagcagtga tctgagcgca catgagaata ccgatgaact gttctatttc 1680
gcatgggata atgagaaacc gatgcgtaag aaactggtga gcagctttag tattgccaat 1740
cgtccgatta gtaatggtga atatctggat ttcatcaata agaaatccaa gaccgaacgt 1800
gtttatccga aacagtgggc agaaattgat ggtaccctgt atatccgtac catgtatggc 1860
ctgctgccgc tggatgatta tctgggctgg ccagttatga ccagttatga tgatctgaac 1920
aattacgcaa gtagccaggg ctgccgtctg ccgaccgaag atgaactgaa ttgtttctat 1980
gatcgtgttc tggaacgcac cgatgaaccg tatgtgagta ccgaaggcaa agccaccggc 2040
tttcagcagc tgcatccgct ggcactgagc gataacagca gtaatcagat ctttaccggt 2100
gcctgggaat ggaccagtac cgttctggag aaacatgaag atttcgaacc ggaagaactg 2160
tatccggatt acacccgtga tttctttgat ggcaaacata atgtggtgct gggtggtagc 2220
tttgccaccg caacccgtat tagtaatcgt cgtagtttcc gtaacttcta ccaagccggt 2280
tacaaatacg cctggattgg tgcacgtctg gtgaaaaact aa 2322
<210> 3
<211> 389
<212> PRT
<213> Artificial Sequence
<220>
<223> SPEGT2
<400> 3
Met Ala Glu Asn Asn Val Tyr Gly His Glu Met Lys Lys His Phe Met
1 5 10 15
Leu Asp Pro Asp Tyr Val Asn Val Asn Asn Gly Ser Cys Gly Thr Glu
20 25 30
Ser Leu Ala Val Tyr Asn Lys His Val Gln Leu Leu Lys Glu Ala Gln
35 40 45
Ser Lys Pro Asp Phe Met Cys Asn Ala Tyr Met Pro Met Tyr Met Glu
50 55 60
Ala Thr Arg Asn Glu Val Ala Lys Leu Ile Gly Ala Asp Ser Ser Asn
65 70 75 80
Ile Val Phe Cys Asn Ser Ala Thr Asp Gly Ile Ser Thr Val Leu Leu
85 90 95
Thr Phe Pro Trp Glu Gln Asn Asp Glu Ile Leu Met Leu Asn Val Ala
100 105 110
Tyr Pro Thr Cys Thr Tyr Ala Ala Asp Phe Ala Lys Asn Gln His Asn
115 120 125
Leu Arg Leu Asp Val Ile Asp Val Gly Val Glu Ile Asp Glu Asp Leu
130 135 140
Phe Leu Lys Glu Val Glu Gln Arg Phe Leu Gln Ser Lys Pro Arg Ala
145 150 155 160
Phe Ile Cys Asp Ile Leu Ser Ser Met Pro Val Ile Leu Phe Pro Trp
165 170 175
Glu Lys Val Val Lys Leu Cys Lys Lys Tyr Asn Ile Val Ser Ile Ile
180 185 190
Asp Gly Ala His Ala Ile Gly His Ile Pro Met Asn Leu Ala Asn Val
195 200 205
Asp Pro Asp Phe Leu Phe Thr Asn Ala His Lys Trp Leu Asn Ser Pro
210 215 220
Ala Ala Cys Thr Val Leu Tyr Val Ser Ala Lys Asn His Asn Leu Ile
225 230 235 240
Glu Ala Leu Pro Leu Ser Tyr Gly Tyr Gly Leu Arg Glu Lys Glu Ser
245 250 255
Ile Ala Val Asp Thr Leu Thr Asn Arg Phe Val Asn Ser Phe Lys Gln
260 265 270
Asp Leu Pro Lys Phe Ile Ala Val Gly Glu Ala Ile Lys Phe Arg Lys
275 280 285
Ser Ile Gly Gly Glu Glu Lys Ile Gln Gln Tyr Cys His Glu Ile Ala
290 295 300
Leu Lys Gly Ala Glu Ile Ile Ser Lys Glu Leu Gly Thr Ser Phe Ile
305 310 315 320
Lys Pro Pro Tyr Pro Val Ala Met Val Asn Val Glu Val Pro Leu Arg
325 330 335
Asn Ile Pro Ser Ile Glu Thr Gln Lys Val Phe Trp Pro Lys Tyr Asn
340 345 350
Thr Phe Leu Arg Phe Met Glu Phe Lys Gly Lys Phe Tyr Thr Arg Leu
355 360 365
Ser Gly Ala Val Tyr Leu Glu Glu Ser Asp Phe Tyr Tyr Ile Ala Lys
370 375 380
Val Ile Lys Asp Phe
385
<210> 4
<211> 1179
<212> DNA
<213> Artificial Sequence
<220>
<223> SPEGT2
<400> 4
atggctgaga acaacgtgta cggccacgaa atgaaaaaac atttcatgct ggatcctgac 60
tatgtaaacg tgaacaacgg tagctgcggt accgaatccc tggctgttta caacaaacac 120
gttcagctgc tgaaagaagc tcagtccaaa ccggacttca tgtgtaacgc ttacatgccg 180
atgtacatgg aagcgacccg taatgaagtc gccaaactga tcggtgcgga ctcttccaac 240
atcgtgttct gcaacagcgc aacggacggc atttctactg tcctgctgac cttcccgtgg 300
gagcagaacg atgaaatcct gatgctgaac gttgcgtatc cgacctgtac ctacgctgcg 360
gactttgcga aaaaccagca taacctgcgc ctggacgtta tcgatgttgg tgttgaaatc 420
gatgaagatc tgtttctgaa agaagttgaa cagcgcttcc tgcagtccaa accgcgtgcg 480
ttcatctgcg acatcctgtc ctctatgccg gtcattctgt ttccgtggga gaaagtggtg 540
aagctgtgca aaaaatacaa tattgtgtcc atcatcgacg gtgcgcacgc gattggccac 600
atcccgatga atctggctaa cgtggatccg gattttctgt tcaccaacgc gcacaaatgg 660
ctgaactctc cggcagcgtg caccgtgctg tacgtttctg caaagaacca caacctgatc 720
gaagcactgc cactgagcta cggctacggc ctgcgtgaaa aagaatctat tgcagttgac 780
accctgacca accgcttcgt taacagcttc aaacaagatc tgccgaaatt catcgcagtc 840
ggcgaagcta tcaaattccg taagagcatc ggtggcgaag aaaaaatcca gcagtactgt 900
cacgaaatcg cgctgaaagg tgcggagatt atctctaaag agctgggcac ctccttcatc 960
aaaccgccgt atccagttgc catggttaac gttgaggttc cgctgcgtaa cattccaagc 1020
atcgaaaccc agaaagtttt ctggccgaaa tataatacct tcctgcgttt catggaattc 1080
aaaggcaaat tctacacccg tctgtctggc gccgtgtatc tggaagaatc tgacttctac 1140
tatatcgcca aagtaatcaa ggacttctgt tccctgtaa 1179
<210> 5
<211> 445
<212> PRT
<213> Artificial Sequence
<220>
<223> SPEGT1-tr
<400> 5
Pro Ala Met Leu Gln Leu Pro Leu Gln Pro Cys Pro Ser Leu Ala Glu
1 5 10 15
Trp Asp Ala Leu Arg Lys Val Trp Leu Phe Ile Thr Asn Lys Leu Leu
20 25 30
Asn Lys Asp Asn Met Tyr Thr Ala Trp Ile Pro Leu Arg His Pro Pro
35 40 45
Ile Phe Tyr Ile Gly His Val Pro Val Phe Asn Asp Ile Tyr Leu Thr
50 55 60
Lys Ile Val Lys Asn Lys Ala Thr Ala Asn Lys Lys His Phe Trp Glu
65 70 75 80
Trp Phe Gln Arg Gly Ile Asp Pro Asp Ile Glu Asp Pro Ser Lys Cys
85 90 95
His Trp His Ser Glu Val Pro Glu Ser Trp Pro Ser Pro Asp Gln Leu
100 105 110
Arg Glu Tyr Glu Lys Glu Ser Trp Glu Tyr His Ile Val Lys Leu Cys
115 120 125
Lys Ala Met Asp Glu Leu Ser Thr Ser Glu Lys Arg Ile Leu Trp Leu
130 135 140
Cys Tyr Glu His Val Ala Met His Val Glu Thr Thr Leu Tyr Ile Tyr
145 150 155 160
Val Gln Ser Phe Gln Asn Ala Asn Gln Thr Val Ser Ile Cys Gly Ser
165 170 175
Leu Pro Glu Pro Ala Glu Lys Leu Thr Lys Ala Pro Leu Trp Val Asn
180 185 190
Val Pro Glu Thr Glu Ile Ala Val Gly Met Pro Leu Thr Thr Gln Tyr
195 200 205
Thr Ser Val Gly Ser Asn Leu Gln Ser Ser Asp Leu Ser Ala His Glu
210 215 220
Asn Thr Asp Glu Leu Phe Tyr Phe Ala Trp Asp Asn Glu Lys Pro Met
225 230 235 240
Arg Lys Lys Leu Val Ser Ser Phe Ser Ile Ala Asn Arg Pro Ile Ser
245 250 255
Asn Gly Glu Tyr Leu Asp Phe Ile Asn Lys Lys Ser Lys Thr Glu Arg
260 265 270
Val Tyr Pro Lys Gln Trp Ala Glu Ile Asp Gly Thr Leu Tyr Ile Arg
275 280 285
Thr Met Tyr Gly Leu Leu Pro Leu Asp Asp Tyr Leu Gly Trp Pro Val
290 295 300
Met Thr Ser Tyr Asp Asp Leu Asn Asn Tyr Ala Ser Ser Gln Gly Cys
305 310 315 320
Arg Leu Pro Thr Glu Asp Glu Leu Asn Cys Phe Tyr Asp Arg Val Leu
325 330 335
Glu Arg Thr Asp Glu Pro Tyr Val Ser Thr Glu Gly Lys Ala Thr Gly
340 345 350
Phe Gln Gln Leu His Pro Leu Ala Leu Ser Asp Asn Ser Ser Asn Gln
355 360 365
Ile Phe Thr Gly Ala Trp Glu Trp Thr Ser Thr Val Leu Glu Lys His
370 375 380
Glu Asp Phe Glu Pro Glu Glu Leu Tyr Pro Asp Tyr Thr Arg Asp Phe
385 390 395 400
Phe Asp Gly Lys His Asn Val Val Leu Gly Gly Ser Phe Ala Thr Ala
405 410 415
Thr Arg Ile Ser Asn Arg Arg Ser Phe Arg Asn Phe Tyr Gln Ala Gly
420 425 430
Tyr Lys Tyr Ala Trp Ile Gly Ala Arg Leu Val Lys Asn
435 440 445
<210> 6
<211> 1338
<212> DNA
<213> Artificial Sequence
<220>
<223> spegt1-tr
<400> 6
ccagccatgc tgcagctgcc gctgcagcct tgtccgagcc tggcagaatg ggatgccctg 60
cgcaaagtgt ggctgttcat taccaacaaa ctgctgaata aggacaatat gtacaccgcc 120
tggattccgc tgcgtcatcc accgatcttc tacattggcc atgtgccggt gttcaacgat 180
atctacctga ccaagattgt gaagaataag gcaaccgcca ataagaaaca tttctgggaa 240
tggtttcagc gtggtattga tccggatatt gaagatccga gcaaatgcca ttggcatagt 300
gaagttccgg aaagttggcc gtctccggat cagctgcgtg aatatgagaa agaaagttgg 360
gaatatcata tcgtgaaact gtgtaaagca atggatgaac tgagtaccag tgagaaacgt 420
attctgtggc tgtgttatga acatgttgcc atgcatgtgg aaaccaccct gtacatctat 480
gtgcagagct ttcagaatgc aaatcagacc gttagcattt gtggcagtct gccagaaccg 540
gcagagaaac tgaccaaagc acctctgtgg gtgaatgtgc cggaaaccga aattgcagtt 600
ggcatgccgc tgaccaccca gtataccagt gtgggtagca atctgcagag cagtgatctg 660
agcgcacatg agaataccga tgaactgttc tatttcgcat gggataatga gaaaccgatg 720
cgtaagaaac tggtgagcag ctttagtatt gccaatcgtc cgattagtaa tggtgaatat 780
ctggatttca tcaataagaa atccaagacc gaacgtgttt atccgaaaca gtgggcagaa 840
attgatggta ccctgtatat ccgtaccatg tatggcctgc tgccgctgga tgattatctg 900
ggctggccag ttatgaccag ttatgatgat ctgaacaatt acgcaagtag ccagggctgc 960
cgtctgccga ccgaagatga actgaattgt ttctatgatc gtgttctgga acgcaccgat 1020
gaaccgtatg tgagtaccga aggcaaagcc accggctttc agcagctgca tccgctggca 1080
ctgagcgata acagcagtaa tcagatcttt accggtgcct gggaatggac cagtaccgtt 1140
ctggagaaac atgaagattt cgaaccggaa gaactgtatc cggattacac ccgtgatttc 1200
tttgatggca aacataatgt ggtgctgggt ggtagctttg ccaccgcaac ccgtattagt 1260
aatcgtcgta gtttccgtaa cttctaccaa gccggttaca aatacgcctg gattggtgca 1320
cgtctggtga aaaactaa 1338
<210> 7
<211> 445
<212> PRT
<213> Artificial Sequence
<220>
<223> SPEGT1-tr M10
<400> 7
Pro Ala Met Leu Gln Leu Pro Leu Gln Pro Cys Pro Ser Leu Ala Glu
1 5 10 15
Trp Asp Ala Leu Arg Lys Val Trp Leu Phe Ile Thr Asn Lys Leu Leu
20 25 30
Asn Lys Asp Asn Met Tyr Thr Ala Trp Ile Pro Leu Arg His Pro Pro
35 40 45
Ile Leu Phe Ile Gly His Val Pro Val Phe Asn Asp Ile Tyr Leu Thr
50 55 60
Lys Ile Val Lys Asn Lys Ala Thr Ala Asn Lys Lys His Phe Trp Glu
65 70 75 80
Trp Phe Gln Arg Gly Ile Asp Pro Asp Ile Glu Asp Pro Ser Lys Cys
85 90 95
Asn Trp Asn Ser Glu Val Pro Glu Ser Trp Pro Ser Pro Asp Gln Leu
100 105 110
Arg Glu Tyr Glu Lys Glu Ser Trp Glu Tyr His Ile Val Lys Leu Cys
115 120 125
Lys Ala Met Asp Glu Leu Ser Thr Ser Glu Lys Arg Ile Leu Trp Leu
130 135 140
Cys Tyr Glu His Val Ala Leu His Val Glu Thr Thr Leu Tyr Ile Tyr
145 150 155 160
Val Gln Ser Phe Gln Asn Ala Asn Gln Thr Val Ser Ile Cys Gly Ser
165 170 175
Leu Pro Glu Pro Ala Glu Lys Leu Thr Lys Ala Pro Leu Trp Val Asn
180 185 190
Val Pro Glu Thr Glu Ile Ala Val Gly Met Pro Leu Thr Thr Gln Tyr
195 200 205
Thr Ser Val Gly Ser Asn Leu Gln Ser Ser Asp Leu Ser Ala His Glu
210 215 220
Asn Thr Asp Glu Leu Phe Tyr Phe Ala Trp Asp Asn Glu Lys Pro Met
225 230 235 240
Arg Lys Lys Leu Val Ser Ser Phe Ser Ile Ala Asn Arg Pro Ile Ser
245 250 255
Asn Gly Glu Tyr Leu Asp Phe Ile Asn Lys Lys Ser Lys Thr Glu Arg
260 265 270
Val Tyr Pro Lys Gln Trp Ala Glu Ile Asp Gly Thr Leu Tyr Ile Arg
275 280 285
Thr Met Tyr Gly Leu Leu Pro Leu Asp Asp Tyr Leu Gly Trp Pro Val
290 295 300
Met Thr Ser Tyr Asp Asp Leu Asn Asn Tyr Ala Ser Ser Gln Gly Cys
305 310 315 320
Arg Leu Pro Thr Glu Asp Glu Leu Asn Cys Phe Tyr Asp Arg Val Leu
325 330 335
Glu Arg Thr Asp Glu Pro Tyr Val Ser Thr Glu Gly Lys Ala Thr Gly
340 345 350
Phe Gln Gln Leu His Pro Leu Ala Leu Ser Asp Asn Ser Ser Asn Gln
355 360 365
Ile Phe Thr Gly Ala Trp Glu Cys Thr Ser Thr Val Leu Glu Lys His
370 375 380
Glu Asp Phe Glu Pro Glu Glu Leu Tyr Pro Asp Tyr Thr Arg Asp Phe
385 390 395 400
Phe Asp Gly Lys Leu Asn Val Val Leu Gly Gly Ser Phe Ala Thr Ala
405 410 415
Thr Arg Ile Ser Asn Arg Arg Ser Leu Arg Asn Phe Tyr Gln Ala Gly
420 425 430
Tyr Lys Ser Ala Trp Ile Gly Ala Arg Leu Val Lys Asn
435 440 445
<210> 8
<211> 1338
<212> DNA
<213> Artificial Sequence
<220>
<223> SPEGT1-tr M10
<400> 8
ccagccatgc tgcagctgcc gctgcagcct tgtccgagcc tggcagaatg ggatgccctg 60
cgcaaagtgt ggctgttcat taccaacaaa ctgctgaata aggacaatat gtacaccgcc 120
tggattccgc tgcgtcatcc accgatcctc ttcattggcc atgtgccggt attcaacgat 180
atctacctga ccaagattgt gaagaataag gcaaccgcca ataagaaaca tttctgggaa 240
tggtttcagc gtggtattga tccggatatt gaagatccga gcaaatgcaa ttggaacagt 300
gaagttccgg aaagttggcc gtctccggat cagctgcgtg aatatgagaa agaaagttgg 360
gaatatcata tcgtgaagct gtgtaaagca atggatgaac tgagtaccag tgagaaacgt 420
attctgtggc tgtgttatga acatgttgcc ctgcatgtgg aaaccaccct gtacatctat 480
gtgcagagct ttcagaatgc aaatcagacc gttagcattt gtggcagtct gccagaaccg 540
gcagagaaac tgaccaaagc acctctgtgg gtgaatgtgc cggaaaccga aattgcagtt 600
ggcatgccgc tgaccaccca gtataccagt gtgggtagca atctgcagag cagtgatctg 660
agcgcacatg agaataccga tgaactgttc tatttcgcat gggataatga gaaaccgatg 720
cgtaagaaac tggtgagcag ctttagtatt gccaatcgtc cgattagtaa tggtgaatat 780
ctggatttca tcaataagaa atccaagacc gaacgtgttt atccgaaaca gtgggcagaa 840
attgatggta ccctgtatat ccgtaccatg tatggcctgc tgccgctgga tgattatctg 900
ggctggccag ttatgaccag ttatgatgat ctgaacaatt acgcaagtag ccagggctgc 960
cgtctgccga ccgaagatga actgaattgt ttctatgatc gtgttctgga acgcaccgat 1020
gaaccgtatg tgagtaccga aggcaaagcc accggctttc agcagctgca tccgctggca 1080
ctgagcgata acagcagtaa tcagatcttt accggtgcct gggaatgtac cagtaccgtt 1140
ctggagaaac atgaagattt cgaaccggaa gaactgtacc cggattacac ccgtgatttc 1200
tttgatggca aacttaatgt ggtgctgggt ggtagctttg ccaccgcaac ccgtattagt 1260
aatcgtcgta gtctccgtaa cttctaccaa gccggttaca aatccgcctg gattggtgca 1320
cgtctggtga aaaactaa 1338
<210> 9
<211> 392
<212> PRT
<213> Artificial Sequence
<220>
<223> SPEGT2 M3
<400> 9
Met Ala Glu Asn Asn Val Tyr Gly His Glu Met Lys Lys His Phe Met
1 5 10 15
Leu Asp Pro Asp Tyr Val Asn Val Asn Asn Gly Pro Cys Gly Thr Glu
20 25 30
Ser Leu Ala Val Tyr Asn Lys His Val Gln Leu Leu Lys Glu Ala Gln
35 40 45
Ser Lys Pro Asp Phe Met Cys Asn Ala Tyr Met Pro Met Tyr Met Glu
50 55 60
Ala Thr Arg Asn Glu Val Ala Lys Leu Ile Gly Ala Asp Ser Ser Asn
65 70 75 80
Ile Val Phe Cys Asn Ser Ala Thr Asp Gly Ile Ser Thr Val Leu Leu
85 90 95
Thr Phe Pro Trp Glu Gln Asn Asp Glu Ile Leu Met Leu Asn Val Ala
100 105 110
Phe Pro Thr Cys Thr Tyr Ala Ala Asp Phe Ala Lys Asn Gln His Asn
115 120 125
Leu Arg Leu Asp Val Ile Asp Val Gly Val Glu Ile Asp Glu Asp Leu
130 135 140
Phe Leu Lys Glu Val Glu Gln Arg Phe Leu Gln Ser Lys Pro Arg Ala
145 150 155 160
Phe Ile Cys Asp Ile Leu Ala Ser Met Pro Val Ile Leu Phe Pro Trp
165 170 175
Glu Lys Val Val Lys Leu Cys Lys Lys Tyr Asn Ile Val Ser Ile Ile
180 185 190
Asp Gly Ala His Ala Ile Gly His Ile Pro Met Asn Leu Ala Asn Val
195 200 205
Asp Pro Asp Phe Leu Phe Thr Asn Ala His Lys Trp Leu Asn Ser Pro
210 215 220
Ala Ala Cys Thr Val Leu Tyr Val Ser Ala Lys Asn His Asn Leu Ile
225 230 235 240
Glu Ala Leu Pro Leu Ser Tyr Gly Tyr Gly Leu Arg Glu Lys Glu Ser
245 250 255
Ile Ala Val Asp Thr Leu Thr Asn Arg Phe Val Asn Ser Phe Lys Gln
260 265 270
Asp Leu Pro Lys Phe Ile Ala Val Gly Glu Ala Ile Lys Phe Arg Lys
275 280 285
Ser Ile Gly Gly Glu Glu Lys Ile Gln Gln Tyr Cys His Glu Ile Ala
290 295 300
Leu Lys Gly Ala Glu Ile Ile Ser Lys Glu Leu Gly Thr Ser Phe Ile
305 310 315 320
Lys Pro Pro Tyr Pro Val Ala Met Val Asn Val Glu Val Pro Leu Arg
325 330 335
Asn Ile Pro Ser Ile Glu Thr Gln Lys Val Phe Trp Pro Lys Tyr Asn
340 345 350
Thr Phe Leu Arg Phe Met Glu Phe Lys Gly Lys Phe Tyr Thr Arg Leu
355 360 365
Ser Gly Ala Val Tyr Leu Glu Glu Ser Asp Phe Tyr Tyr Ile Ala Lys
370 375 380
Val Ile Lys Asp Phe Cys Ser Leu
385 390
<210> 10
<211> 1179
<212> DNA
<213> Artificial Sequence
<220>
<223> SPEGT2 M3
<400> 10
atggctgaga acaacgtgta cggccacgaa atgaaaaaac atttcatgct ggatcctgac 60
tatgtaaacg tgaacaacgg tccctgcggt accgaatccc tggctgttta caacaaacac 120
gttcagctgc tgaaagaagc tcagtccaaa ccggacttca tgtgtaacgc ttacatgccg 180
atgtacatgg aagcgacccg taatgaagtc gccaaactga tcggtgcgga ctcttccaac 240
atcgtgttct gcaacagcgc aacggacggc atttctactg tcctgctgac cttcccgtgg 300
gagcagaacg atgaaatcct gatgctgaac gttgcgtttc cgacctgtac ctacgctgcg 360
gactttgcga aaaaccagca taacctgcgc ctggacgtta tcgatgttgg tgttgaaatc 420
gatgaagatc tgtttctgaa agaagttgaa cagcgcttcc tgcagtccaa accgcgtgcg 480
ttcatctgcg acatcctggc ctctatgccg gtcattctgt ttccgtggga gaaagtggtg 540
aagctgtgca aaaaatacaa tattgtgtcc atcatcgacg gtgcgcacgc gattggccac 600
atcccgatga atctggctaa cgtggatccg gattttctgt tcaccaacgc gcacaaatgg 660
ctgaactctc cggcagcgtg caccgtgctg tacgtttctg caaagaacca caacctgatc 720
gaagcactgc cactgagcta cggctacggc ctgcgtgaaa aagaatctat tgcagttgac 780
accctgacca accgcttcgt taacagcttc aaacaagatc tgccgaaatt catcgcagtc 840
ggcgaagcta tcaaattccg taagagcatc ggtggcgaag aaaaaatcca gcagtactgt 900
cacgaaatcg cgctgaaagg tgcggagatt atctctaaag agctgggcac ctccttcatc 960
aaaccgccgt atccagttgc catggttaac gttgaggttc cgctgcgtaa cattccaagc 1020
atcgaaaccc agaaagtttt ctggccgaaa tataatacct tcctgcgttt catggaattc 1080
aaaggcaaat tctacacccg tctgtctggc gccgtgtatc tggaagaatc tgacttctac 1140
tatatcgcca aagtaatcaa ggacttctgt tccctgtaa 1179
<210> 11
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr F1
<400> 11
ggacaatatg tacaccgcct ggattc 26
<210> 12
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr R1
<400> 12
caccagtttc ttacgcatcg gtttctc 27
<210> 13
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr F2
<400> 13
cgatgcgtaa gaaactgg 18
<210> 14
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr R2
<400> 14
aggcggtgta catattgtc 19
<210> 15
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr F3
<400> 15
agccaccggc tttcagcag 19
<210> 16
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr R3
<400> 16
caccagacgt gcaccaatcc ag 22
<210> 17
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr F4
<400> 17
ggattggtgc acgtctgg 18
<210> 18
<211> 17
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt1-tr R4
<400> 18
gctgctgaaa gccggtg 17
<210> 19
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 F1
<400> 19
agatatacca tgggcagcag c 21
<210> 20
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 R1
<400> 20
acagatcttc atcgatttca acacc 25
<210> 21
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 F2
<400> 21
tgaaatcgat gaagatctgt ttctg 25
<210> 22
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 R2
<400> 22
ctgctgccca tggtatatc 19
<210> 23
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 F3
<400> 23
ggtgttgaaa tcgatgaaga tctgtttc 28
<210> 24
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 R3
<400> 24
ctgctggatt ttttcttcgc cac 23
<210> 25
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 F4
<400> 25
gcgaagaaaa aatccagcag 20
<210> 26
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> Spegt2 R4
<400> 26
tcttcatcga tttcaacacc aac 23
Claims (10)
1.一种裂殖酵母麦角硫因合成酶SPEGT1-tr M10,其特征在于,所述合成酶的氨基酸序列如SEQ ID NO:7所示。
2.一种裂殖酵母麦角硫因合成酶SPEGT2 M3,其特征在于,所述合成酶的氨基酸序列如SEQ ID NO:9所示。
3.一种裂殖酵母麦角硫因合成酶SPEGT1-tr,其特征在于,所述的合成酶的氨基酸序列如SEQ ID NO:5所示。
4.一种麦角硫因合成酶表达载体,其特征在于,所述的表达载体用于表达如权利要求1-3任一所述的裂殖酵母麦角硫因合成酶。
5.一种表达盒,其特征在于,所述的表达盒用于表达如权利要求1-3任一所述的裂殖酵母麦角硫因合成酶。
6.一种重组菌株,其特征在于,所述的重组菌株含有如权利要求4中所述的表达载体,或其基因组中整合有编码如权利要求1-3中任一所述的合成酶的多核苷酸序列。
7.一种用于麦角硫因合成的化学-酶偶联系统,其特征在于,所述的化学催化系统包括:钯碳催化L-组氨酸的甲醛还原胺化双甲基化以及碘甲烷亲核取代合成三甲基取代的季铵盐组氨酸甜菜碱;
所述的催化酶系统包括:如权利要求2所述的合成酶SPEGT2 M3,和选自下组的合成酶:如权利要求1所述的合成酶SPEGT1-tr M10,或如权利要求3所述的合成酶SPEGT1-tr。
8.一种麦角硫因合成方法,其特征在于,包括以下步骤:
(3)在如权利要求2所述的合成酶SPEGT2 M3,和选自下组的合成酶:如权利要求1所述的合成酶SPEGT1-tr M10,或如权利要求3所述的合成酶SPEGT1-tr,或者如权利要求6所述的重组菌株存在下,用组氨酸甜菜碱和半胱氨酸反应,得到麦角硫因。
9.如权利要求8所述的方法,其特征在于,所述的化学合成步骤:
(1)用钯碳催化L-组氨酸进行甲醛还原胺化,得到二甲基组氨酸;
(2)用二甲基组氨酸与碘甲烷进行亲核取代,合成三甲基取代的季铵盐组氨酸甜菜碱。
10.如权利要求8所述的方法,其特征在于,所述的酶催化步骤在Fe2+、磷酸吡哆醛和beta巯基乙醇存在下进行。
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CN202380010573.XA CN117083377B (zh) | 2022-05-03 | 2023-05-04 | 一种用于合成麦角硫因的化学-酶偶联方法 |
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