CN1290750A - 编码eno基因的新核苷酸序列 - Google Patents
编码eno基因的新核苷酸序列 Download PDFInfo
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- CN1290750A CN1290750A CN00129571A CN00129571A CN1290750A CN 1290750 A CN1290750 A CN 1290750A CN 00129571 A CN00129571 A CN 00129571A CN 00129571 A CN00129571 A CN 00129571A CN 1290750 A CN1290750 A CN 1290750A
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Abstract
本发明涉及分离的多核苷酸,其包括选自如下一组的多核苷酸序列:a)与编码包括SEQ ID NO:2的氨基酸序列的多肽的多核苷酸至少70%相同的多核苷酸,b)编码含括与SEQ ID NO:2的氨基酸序列至少70%相同的氨基酸序列的多肽的多核苷酸,c)与a)或b)的多核苷酸互补的多核苷酸,以及d)包括a),b)或c)的多核苷酸序列的至少15个连续碱基的多核苷酸。本发明还涉及用eno基因的扩增而发酵制备L－氨基酸的方法。
Description
本发明提供了编码eno基因的核苷酸序列，和用棒状细菌发酵生产氨基酸、尤其是L-赖氨酸的方法，其中棒状细菌中eno基因是扩增的。
氨基酸、尤其是L-赖氨酸用于人用药物及制药工业，但特别是用于动物营养。
已知氨基酸可通过棒状细菌菌株，尤其谷氨酸棒杆菌的发酵而生产。由于氨基酸的极其重要性，已持续进行改良生产方法的尝试。生产方法的改良可涉及发酵措施，如搅拌和供氧，或营养培养基的组分如发酵期间的糖浓度，或产物形式的加工方法，例如通过离子交换层析，或微生物本身的固有生产性质。
为改良这些微生物的生产性质，可使用诱变，选择及突变体选择等方法，以此方法可获得对抗代谢物如赖氨酸类似物S-(2-氨乙基)-半胱氨酸有抗性或重要的调节氨基酸营养缺陷的并产生L-赖氨酸的菌株。
一段时间以来，重组DNA技术的方法也用于棒杆菌的生产氨基酸的菌株的改良，其是通过扩增个体氨基酸生物合成基因，并研究对氨基酸生产的影响来改良生产氨基酸的棒杆菌菌株。相关参考文献有：Kinoshita(“谷氨酸细菌”，工业微生物的生物学，Demain和Solomon编辑，Benjamin Cummings，英国伦敦，1985，115-142)，Hilliger(BioTec 2，40-44(1991))，Eggeling(氨基酸，6：261-272(1994))，Jetten和Sinskey(生物技术关键综述15，73-103(1995))和Sahm等(纽约科学协会年报782，25-39(1996))。
本发明人目的在于为改良发酵制备氨基酸、特别是L-赖氨酸而提供新措施。
氨基酸、尤其是L-赖氨酸用于人用药物及制药工业，但特别是用于动物营养。因而感兴趣的是提供新的制备氨基酸，尤其L-赖氨酸的改良方法。
当在下文提及L-赖氨酸或赖氨酸时，不仅仅是碱，还可以是盐，如赖氨酸单盐酸盐或赖氨酸硫酸盐。
本发明提供了来自棒状细菌的分离的多核苷酸，其包括选自如下一组的多核苷酸序列：
a)与编码包括SEQ ID NO：2的氨基酸序列的多肽的多核苷酸至少70％相同的多核苷酸，
b)编码包括与SEQ ID NO：2的氨基酸序列至少70％相同的氨基酸序列的多肽的多核苷酸，
c)与a)或b)的多核苷酸互补的多核苷酸，以及
d)包括a)，b)或c)的多核苷酸序列的至少15个连续碱基的多核苷酸。
本发明还提供了根据权利要求1的多核苷酸，其优选是能复制的DNA，包括
(ⅰ)SEQ ID NO：1的核苷酸序列，或
(ⅱ)在遗传密码简并范围内相应于序列(ⅰ)的至少一个序列，或
(ⅲ)与互补于序列(ⅰ)或(ⅱ)的序列杂交的至少一个序列，和任选地，
(ⅳ)(ⅰ)中有功能的中义突变。
本发明还提供了
权利要求4的多核苷酸，包括SEQ ID NO：1所示的核苷酸序列，
权利要求6的多核苷酸，其编码包括SEQ ID NO：2所示的氨基酸序列的多肽，
含有权利要求1的多核苷酸的载体，特别是穿梭载体或质粒载体，以及含有所述载体的作为宿主细胞的棒状细菌。
本发明还提供了多核苷酸，其基本上包括一个多核苷酸序列，其可通过用含有SEQ ID NO：1所述多核苷酸的序列或其片段的探针杂交相应的基因文库，并分离所述的DNA序列来筛选获得，所述的文库含有具有相应于SEQ ID NO：1的多核苷酸序列的完整基因。本发明的多核苷酸序列适用作RNA、cDNA和DNA的杂交探针，以分离编码烯醇化酶的全长cDNA，以及分离与烯醇化酶基因具有高度序列相似性的cDNA或基因。
本发明的多核苷酸序列还适用作通过聚合酶链反应(PCR)制备编码烯醇化酶的DNA或基因的引物。
作为探针或引物的这种寡核苷酸含有至少30个、优选至少20个、特别优选至少15个连续碱基。具有至少40或50个碱基对的寡核苷酸也是合适的。
“分离的”是指从其天然环境中分离出来。
“多核苷酸”一般地指多聚核糖核苷酸和多聚脱氧核糖核苷酸，其可以是非修饰的RNA或DNA，或修饰的RNA或DNA。
“多肽”应理解为包括经肽键结合的两个或多个氨基酸的肽或蛋白质。
本发明的多肽包括SEQ ID NO：2的多肽，特别是具有烯醇化酶生物学活性的多肽，以及与SEQ ID NO：2的多肽至少70％、优选至少80％相同、特别是与SEQ ID NO：2的多肽至少90-95％相同并具有所述活性的多肽。
本发明还提供了用尤其已生产氨基酸的棒状细菌发酵生产氨基酸、尤其L-赖氨酸的方法，其中编码eno基因的核苷酸序列是扩增的，尤其是超量表达的。
文中术语“扩增”是指微生物中由相应DNA编码的一或多种酶的胞内活性的提高，例如通过提高基因的拷贝数，或用强启动子或编码高活性相应酶的基因，及如果需要组合使用这些方法。
本发明的微生物可从葡萄糖、蔗糖、乳糖、果糖、麦芽糖、糖蜜、淀粉、纤维素或从甘油和乙醇中生产L-氨基酸，此微生物可以是棒状细菌的代表菌，尤其是棒杆菌属。在棒杆菌属中尤其应提及的是谷氨酸棒杆菌，本领域技术人员已知其生产L-氨基酸的能力。
适当的棒杆菌菌属，尤其谷氨酸棒杆菌菌株，是例如已知的野生型菌株：
谷氨酸棒杆菌ATCC 13032
醋谷棒杆菌ATCC 15806
嗜乙酰乙酸棒杆菌ATCC 13870
嗜热产氨棒杆菌FERM BP-1539
Corynebacterium melassecola ATCC17965
黄色短杆菌ATCC 14067
乳发酵短杆菌ATCC 13869和
扩展短杆菌ATCC 14020
和从中获得的生产生产L-赖氨酸的突变体或菌株如：
谷氨酸棒杆菌FERM-P 1709
黄色短杆菌FERM-P 1708
乳发酵短杆菌FERM-P 1712
谷氨酸棒杆菌FERM-P 6463
谷氨酸棒杆菌FERM-P 6464和
谷氨酸棒杆菌DSM5715
本发明人已成功地分离谷氨酸棒杆菌的编码烯醇化酶(EC4．2．1．11)的eno基因。
为了分离谷氨酸棒杆菌的eno基因或其他基因，首先在大肠杆菌中建立这一微生物的基因文库。可根据通常已知的教材和手册建立基因文库。例如由Winnacker所著教材：基因与克隆，基因工程入门(Verlag Chemie，Weinheim，德国，1990)，或由Sambrook等所著手册：分子克隆实验手册(Cold Spring Harbor Laboratory Press，1989)。一非常熟知的基因文库是已由Kohara等(细胞50，495-508(1987))在λ载体中建立的E．coli K-12菌株W3110的基因文库。Bathe等(分子及普通遗传学，252：255-265，1996)阐述了借助于粘粒载体SuperCos I(Wahl等，1987，Proceeding of the NationalAcademy of Sciences USA，84：2160-2164)，在E．coli K-12菌株NM554(Raleigh等，1988，核酸研究16：1563-1575)中建立的谷氨酸棒杆菌ATCC 13032的基因文库。Bormann等(分子微生物学6(3)，317-326)描述了用粘粒pHC79(Hohn和Collins，基因11，291-298(1980))制备谷氨酸棒杆菌ATCC13032的基因文库。为在大肠杆菌中制备谷氨酸棒杆菌的基因文库，也可使用质粒如pBR322(Bolivar，生命科学25，807-818(1979))或pUC9(Viera等，1982，基因19：259-268)。合适的宿主尤其是限制和重组缺陷的大肠杆菌菌株，一个例子是菌株DH5αmcr，如Grant等(美国科学院院报7(1990)4645-4649)所述。借助于粘粒克隆的长DNA片段随后可亚克隆并用适于测序的通用载体测序，如Sanger等(美国科学院院报74：5463-5467，1977)所述。
以此方式可获得编码eno基因的谷氨酸棒杆菌的新DNA序列，示作SEQ ID NO：1，用前述方法从此DNA序列中也已衍生出相应蛋白质的氨基酸序列。所得eno基因产物的氨基酸序列以SEQ IDNO：2表示。
通过遗传密码的简并性从SEQ ID NO：1产生的编码DNA序列也是本发明的一部分。同样，与SEQ ID NO：1或SEQ ID NO：1的部分杂交的DNA序列也是本发明的一部分。另外，蛋白质中的保守氨基酸置换，如丙氨酸和甘氨酸的置换，或谷氨酸和天冬氨酸的置换，本领域已知是“有义突变”，其不引起蛋白质活性的基本改置换，本领域已知是“有义突变”，其不引起蛋白质活性的基本改变，即是功能中性的。另外已知蛋白质N和／或C-末端的改变基本不影响其功能，或者甚至可以稳定其功能，本领域技术人员可在以下文献中发现对此的论述，参见Ben-Bassat等(细菌学杂志169：751-757(1987))O’Regan等(基因77：237-251．(1989))，Sahin-Toth等(蛋白质科学3：240-247(1994))，Hochuli等(生物／技术6：1321-1325(1988))，及已知关于遗传和分子生物学的教材。以相应方式产生自SEQ ID NO：2的氨基酸序列也是本发明的一部分。
同样，与SEQ ID NO：1或SEQ ID NO：1的部分杂交的DNA序列也是本发明的组成部分。最后，用产生自SEQ ID NO：1的引物经聚合酶链反应(PCR)制备的DNA序列也是本发明的组成部分。这种寡核苷酸典型地具有至少15bp的长度。
通过杂交鉴别DNA序列的指导可参见宝灵格曼海姆有限公司的手册“用于滤膜杂交的DIG系统用户指南”(曼海姆，德国，1993)以及Liebl等(系统细菌学国际杂志(1991)41：255-260)。用聚合酶链反应(PCR)扩增DNA序列的指导参见Gait的手册：寡核苷酸合成实用方法(IRL出版社，英国牛津，1984)及Newton和Graham：PCR(Spektrum Akademischer Verlag，Heidelberg，德国，1994)。
本发明人发现，eno基因超量表达后，棒状细菌以改进的方式生产氨基酸特别是L-赖氨酸。
为获得超量表达，可提高相应基因的拷贝数，或可使位于结构基因上游的启动子和调节区或核糖体结合位点突变。掺入结构基因上游的表达盒以同样方式工作。通过可诱导启动子，在L-赖氨酸发酵生产期间增强表达也是可能的。通过目的在于延长mRNA寿命的措施，也可改良表达。通过防止酶蛋白的分解也可提高酶活性。基因或基因构建体可以不同拷贝数存在于质粒中，或可在染色体中整合与扩增。或者，通过改变培养基的组分和培养条件，也可获得相关基因的超量表达。
本领域熟练技术人员从以下文献中可发现对此的详述，参见Martin等(生物／技术5，137-146(1987))，Guerrero等(基因138，35-41(1994))，Tsuchiya和Morinaga(生物／技术6，428-430(1988))，Eikmanns等(基因102，93-98(1991))，欧洲专利说明书EPS0472869，美国专利4，601，893，Schwarzer和Puhler(生物／技术9，84-87(1991))，Reinscheid等(应用及环境微生物学60，126-132(1994))，LaBarre等(细菌学杂志175，1001-1007(1993))，专利申请WO 96／15246，Malumbres等(基因134，15-24(1993))，日本特许公开JP-A-10-229891，Jensen和Hammer(生物技术及生物工程58，191-195(1998))，Makrides(微生物学综述60：512-538(1996))及已知关于遗传及分子生物学的教材。
例如，本发明的eno基因可用质粒超量表达。适当的质粒是那些在棒状细菌中复制的质粒。一些已知质粒载体如pZ1(Menkel等，应用及环境微生物学(1989)64：549-554)，pEKEx1(Eikmanns等，基因102：93-98(1991))，或pHS2-1(Sonnen等，基因107：69-74(1991))，是基于隐蔽性质粒pHM1519，pBL1或pGA1。其它质粒载体，如那些基于pCG4(US-A4，489，160)，或pNG2(Serwold-Davis等，FEMS微生物学通信66，119-124(1990))，或pAG1(US-A5，158，891)的载体可以相同方式使用。
另外，除eno基因之外，超量表达特定生物合成途径，糖酵解，回补反应，柠檬酸循环或氨基酸输出的一或多种酶，对氨基酸尤其是L-赖氨酸的生产是有益的。
因此，例如，当生产L-赖氨酸时，
·编码二氢-2，6-吡啶二羧酸合酶的dapA基因(EP-B0197335)可以同时超量表达，或
·编码甘油醛-3-磷酸脱氢酶的gap基因(Eikmanns等，细菌学杂志174：6076-6086(1992))可以同时超量表达，或
·编码丙糖磷酸异构酶的tpi基因(Eikmanns等，细菌学杂志174：6076-6086(1992))可以同时超量表达，或
·编码3-磷酸甘油酸激酶的pgk基因(Eikmanns等，细菌学杂志174：6076-6086(1992))可以同时超量表达，或
·编码丙酮酸羧化酶的pyc基因(Eikmanns等，细菌学杂志174：6076-6086(1992))可以同时超量表达，或
·编码赖氨酸输出的lysE基因(DE-A-19548222)可以同时超量表达。
除了超量表达eno基因之外，消除非所需的副反应对氨基酸特别是L-赖氨酸的生产也是有益的(Nakayama：“生产氨基酸的微生物的育种”，微生物产物的过量产生，Krumphanzl，Sikyta，Vanek(编辑)，学术出版社，伦敦，英国，1982)。
为生产氨基酸，特别是L-赖氨酸，根据本发明产生的微生物可连续培养或用分批方法(分批培养)，或补料分批(补料法)或重复补料分批方法(重复补料法)分批培养。已知的培养法由Chmiel(Bioprozesstechnik 1．Einfuhrung in die Bioverfahrenstechnik(GustavFischer Verlag，Stuttgart，1991)所著教材，或由Storhas(Bioreaktorenund periphere Einrichtungen(Vieweg Verlag，Brunswick／Wiesbaden，1994))所著教材中提供。
所用培养基必须以适当方式符合特定菌株的需求，关于各种微生物培养基的阐述见于，美国细菌学会的“细菌学通用方法手册”(华盛顿D．C．，USA，1981)。可使用的碳源包括糖及碳水化合物，例如葡萄糖，蔗糖，乳糖，果糖，麦芽糖，糖蜜，淀粉和纤维素，油和脂肪如豆油，葵花油，落花生油和椰子油，脂肪酸如棕榈酸，硬脂酸和亚油酸，醇如甘油和乙醇，及有机酸如乙酸，这些物质可单独或混合使用。可使用的氮源包括含氮有机化合物如胨，酵母提取物，肉膏，麦芽提取物，玉米浸液、大豆粉和尿素，或无机化合物如硫酸铵，氯化铵，磷酸铵，碳酸铵和硝酸铵。氮源可单独或混合使用。可使用的磷源包括磷酸，磷酸二氢钾或磷酸氢二钾，或相应钠盐。培养基另外还必须含有为生长所需的金属盐如硫酸镁或硫酸铁。最后，除了上述物质之外，也可使用促进生长必需物质如氨基酸和维生素。此外，可将适当前体加入培养基中。上述物质可以单批形式或在培养期间以适当方式加入培养物中。
可以适当方式加入碱性化合物如NaOH，KOH，氨或氨水，或酸性化合物如磷酸或硫酸，以调节培养物的pH值，抗泡沫剂例如脂肪酸聚乙二醇酯可用于控制泡沫产生。适当的选择性作用物质例如抗生素，可加入培养基中以保持质粒的稳定性。氧气或含氧混合气，例如空气，可充入培养物中以保持有氧条件。培养温度通常在20℃～45℃，优选25℃～40℃，持续培养直至赖氨酸形成最大量。此目的通常在10～160小时范围达到。
L-赖氨酸的分析可通过阴离子交换层析，随后经茚三酮衍生化作用进行，如Speckman等(分析化学，30，(1958)，1190)所述。
本发明方法用于发酵制备氨基酸，尤其是L-赖氨酸。
本发明借助于以下提供的实施例得以更详述阐述。
实施例1制备谷氨酸棒杆菌ATCC 13032的基因组粘粒基因文库
如Tauch等(1995，质粒33：168-179)所述分离谷氨酸棒杆菌ATCC13032的染色体DNA并用限制性内切酶Sau3AI(AmershamPharmacia，Freiburg，德国，产品描述Sau3AI，编码27-0913-02)部分酶切。用虾碱性磷酸酶(Roche Molecular Biochemicals，德国曼海姆，产品描述SAP，编码1758250)将DNA片段去磷酸化。购自Stratagene公司(La Jolla，USA，产品描述SuperCosl粘粒载体试剂盒，编码251301)的粘粒载体SuperCosl(Wahl等(1987)美国科学院院报84：2160-2164)的DNA用限制性内切酶XbaI(AmershamPharmacia，Freiburg，德国，产品描述XbaI，编码27-0948-02)酶切并类似地用虾碱性磷酸酶去磷酸化。粘粒DNA然后用限制性内切酶BamHI(Amersham Pharmacia，Freiburg，德国，产品描述BamHI，编码27-0868-04)酶切。以此方式处理的粘粒DNA与处理的ATCC13032 DNA片段混合并用T4 DNA连接酶(AmershamPharmacia，Freiburg，德国，产品描述T4-DNA-连接酶，编码27-0870-04)处理。连接混合物然后用GigapackⅡXL包装提取物(Stratagene，La Jolla，USA，产品描述GigapackⅡXL包装提取物，编码200217)包装进噬菌体中。为感染大肠杆菌菌株NM554(Raleigh等，1988，核酸研究16：1563-1575)，将细胞悬浮于10mM MgSO4并与噬菌体悬液混合。如Sambrook等(1989，分子克隆实验手册，冷泉港)所述进行粘粒文库的感染和滴定，细胞在含100微克／毫升氨苄青霉素的LB琼脂(Lennox，1955，病毒学，1：190)上铺板。在37℃保温过夜后，选择重组克隆。
实施例2 eno基因的分离和测序
用Qiaprep Spin微量制备试剂盒(产品号27106，Qiagen，Hilden，德国)根据厂商指导分离各个菌落的粘粒DNA，并用限制性内切酶Sau3AI(Amersham Pharmacia，Freiburg，德国，产品描述Sau3AI，编码27-0913-02)部分酶切。用虾碱性磷酸酶(Roche MolecularBiochemicals，德国曼海姆，产品描述SAP，编码1758250)将DNA片段去磷酸化。凝胶电泳分离后，用QiaExⅡ凝胶提取试剂盒(产品号20021，Qiagen，Hilden，德国)分离大小范围为1500-2000bp的粘粒片段。得自Invitrogen公司(Groningen，荷兰，产品描述Zero背景克隆试剂盒，产品号K2500-01)的测序载体pZero-1的DNA用限制性内切酶BamHI(Amersham Pharmacia，Freiburg，德国，产品描述BamHI，产品号27-0868-04)酶切。如Sambrook等(1989，分子克隆实验手册，冷泉港)所述进行粘粒片段在测序载体pZero-1中的连接，其中DNA混合物与T4连接酶(Pharmacia Biotech，Freiburg，德国)保温过夜。然后将连接混合物电穿孔(Tauch等，1994，FEMS微生物学通信，123：343-7)进大肠杆菌菌株DH5αMCR(Grant，1990，美国科学院院报87：4645-4649)并在含有50微克／毫升zeocin的LB琼脂(Lennox，1955，病毒学，1：190)上铺板。重组克隆的质粒制备用Biorobot 9600(产品号900200，Qiagen，Hilden，德国)进行。测序用Zimmermann等(1990，核酸研究18：1067)改良的Sanger等(1977，美国科学院院报74：5463-5467)的双脱氧链终止法进行。使用得自PE应用生物系统公司(产品号403044，Weiterstadt，德国)的“RR罗丹明终止循环测序试剂盒”。用购自PE应用生物系统公司(Weiterstadt，德国)的“ABI Prism 377”测序仪在“RotiphoresisNF 丙烯酰胺／双丙烯酰胺”凝胶(29：1)(产品号A124．1，Roth，Karlsruhe，德国)中进行凝胶电泳分离和序列分析。
得到的原始序列数据然后用Staden软件包(1986，核酸研究，14：217-231)版本97-0处理。pZero-1衍生物的各个序列组装成连续重叠群。用XNIP软件(Staden，1986，核酸研究，14：217-231)进行计算机辅助编码区分析。进一步的分析用“BLAST搜索程序”(Altschul等，1997，核酸研究，25：3389-3402)对“国家生物技术信息中心”(NCBI，Bethesda，MD，USA)的非冗余NCBI数据库进行。
获得的核苷酸序列如SEQ ID NO：1所示。对该核苷酸序列的分析显示一1275碱基对的开放读框，其被称为eno基因。eno基因编码425个氨基酸的多肽。
序列表<110>，德古萨-于尔斯股份公司<120> 编码eno基因的新核苷酸序列<130> 990152 BT<140><141><160> 2<170> Patent In Ver．2．1<210> 1<211> 1578<212> DNA<213> 谷氨酸棒杆菌<220><221> CDS<222> (151)．．(1425)<400> 1ggctggggat atgggtagtt ttcgccacta atttcaactg attgcctcat cgaaacaaga 60ttcgtgcaac aattgggtgt agacgtgatt gaagacattt gatcacgtga ataattctag 120ttagctccca agttggcata ggaggccaca gtg gct gaa atc atg cac gta ttc 174Val Ala Glu Ile Met His Val Phe1 5gct cgc gaa att ctc gac tcc cgc ggt aac cca acc gtc gag gca gag 222Ala Arg Glu Ile Leu Asp Ser Arg Gly Asn Pro Thr Val Glu Ala Glu10 15 20gtt ttc ctg gat gac ggt tcc cac ggt gtc gca ggt gtt cca tcc ggc 270Val Phe Leu Asp Asp Gly Ser His Gly Val Ala Gly Val Pro Ser Gly25 30 35 40gca tcc acc ggc gtc cac gag gct cat gag ctg cgt gac ggt ggc gat 318Ala Ser Thr Gly Val His Glu Ala His Glu Leu Arg Asp Gly Gly Asp45 50 555 cgc tac ctg ggc aag ggc gtt ttg aag gca gtt gaa aac gtc aac gaa 366Arg Tyr Leu Gly Lys Gly Val Leu Lys Ala Val Glu Asn Val Asn Glu60 65 70gaa atc ggc gac gag ctc gct ggc cta gag gct gac gat cag cgc ctc 414Glu Ile Gly Asp Glu Leu Ala Gly Leu Glu Ala Asp Asp Gln Arg Leu75 80 85atc gac gaa gca atg atc aag ctt gat ggc acc gcc aac aag tcc cgc 462Ile Asp Glu Ala Met Ile Lys Leu Asp Gly Thr Ala Asn Lys Ser Arg90 95 100ctg ggt gca aac gca atc ctt ggt gtt tcc atg gct gtt gca aag gct 510Leu Gly Ala Asn Ala Ile Leu Gly Val Ser Met Ala Val Ala Lys Ala105 110 115 120gct gct gat tcc gca ggc ctc cca ctg ttc cgc tac atc ggt gga cca 558Ala Ala Asp Ser Ala Gly Leu Pro Leu Phe Arg Tyr Ile Gly Gly Pro125 130 135aac gca cac gtt ctt cca gtt cca atg atg aac atc atc aac ggt ggc 606Asn Ala His Val Leu Pro Val Pro Met Met Asn Ile Ile Asn Gly Gly140 145 150gct cac gct gac tcc ggt gtt gac gtt cag gaa ttc atg atc gct cca 654Ala His Ala Asp Ser Gly Val Asp Val Gln Glu Phe Met Ile Ala Pro155 160 165atc ggt gca gag acc ttc tct gag gct ctc cgc aac ggc gcg gag gtc 702Ile Gly Ala Glu Thr Phe Ser Glu Ala Leu Arg Asn Gly Ala Glu Val170 175 180tac cac gca ctg aag tcc gtc atc aag gaa aag ggc ctg tcc acc gga 750Tyr His Ala Leu Lys Ser Val Ile Lys Glu Lys Gly Leu Ser Thr Gly185 190 195 200ctt ggc gat gag ggc ggc ttc gct cct tcc gtc ggc tcc acc cgt gag 798Leu Gly Asp Glu Gly Gly Phe Ala Pro Ser Val Gly Ser Thr Arg Glu205 210 215gct ctt gac ctt atc gtt gag gca atc gag aag gct ggc ttc acc cca 846Ala Leu Asp Leu Ile Val Glu Ala Ile Glu Lys Ala Gly Phe Thr Pro220 225 230ggc aag gac atc gct ctt gct ctg gac gtt gct tcc tct gag ttc ttc 894Gly Lys Asp Ile Ala Leu Ala Leu Asp Val Ala Ser Ser Glu Phe Phe235 240 245aag gac ggc acc tac cac ttc gaa ggt ggc cag cac tcc gca gct gag 942Lys Asp Gly Thr Tyr His Phe Glu Gly Gly Gln His Ser Ala Ala Glu250 255 260atg gca aac gtt tac gct gag ctc gtt gac gcg tac cca atc gtc tcc 990Met Ala Asn Val Tyr Ala Glu Leu Val Asp Ala Tyr Pro Ile Val Ser265 270 275 280atc gag gac cca ctg cag gaa gat gac tgg gag ggt tac acc aac ctc 1038Ile Glu Asp Pro Leu Gln Glu Asp Asp Trp Glu Gly Tyr Thr Asn Leu285 290 295acc gca acc atc ggc gac aag gtt cag atc gtt ggc gac gac ttc ttc 1086Thr Ala Thr Ile Gly Asp Lys Val Gln Ile Val Gly Asp Asp Phe Phe300 305 310gtc acc aac cct gag cgc ctg aag gag ggc atc gct aag aag gct gcc 1134Val Thr Asn Pro Glu Arg Leu Lys Glu Gly Ile Ala Lys Lys Ala Ala315 320 325aac tcc atc ctg gtt aag gtg aac cag atc ggt acc ctc acc gag acc 1182Asn Ser Ile Leu Val Lys Val Asn Gln Ile Gly Thr Leu Thr Glu Thr330 335 340ttc gac gct gtc gac atg gct cac cgc gca ggc tac acc tcc atg atg 1230Phe Asp Ala Val Asp Met Ala His Arg Ala Gly Tyr Thr Ser Met Met345 350 355 360tcc cac cgt tcc ggt gag acc gag gac acc acc att gct gac ctc gca 1278Ser His Arg Ser Gly Glu Thr Glu Asp Thr Thr Ile Ala Asp Leu Ala365 370 375gtt gca ctc aac tgt ggc cag atc aag act ggt gct cca gca cgt tcc 1326Val Ala Leu Asn Cys Gly Gln Ile Lys Thr Gly Ala Pro Ala Arg Ser380 385 390gac cgt gtc gca aag tac aac cag ctt ctc cgc atc gag cag ctg ctt 1374Asp Arg Val Ala Lys Tyr Asn Gln Leu Leu Arg Ile Glu Gln Leu Leu395 400 405ggc gac gcc ggc gtc tac gca ggt cgc agc gca ttc cca cgc ttt cag 1422Gly Asp Ala Gly Val Tyr Ala GIy Arg Ser Ala Phe Pro Arg Phe Gln410 415 420ggc taaataaaag cgcttttcga cgcccggtaa cctcaaggtt gccgggcgtc 1475Gly425gttgccttac tactgttact ggtgtgacta tgatcgagga ttatggcaaa gcagaagaaa 1535actcataaag gccttgttcc tgtctcaagc agggaacgtg ctt 1578<210> 2<211> 425<212> PRT<213> 谷氨酸棒杆菌<400> 2Val Ala Glu Ile Met His Val Phe Ala Arg Glu Ile Leu Asp Ser Arg1 5 10 15Gly Asn Pro Thr Val Glu Ala Glu Val Phe Leu Asp Asp Gly Ser His20 25 30Gly Val Ala Gly Val Pro Ser Gly Ala Ser Thr Gly Val His Glu Ala35 40 45His Glu Leu Arg Asp Gly Gly Asp Arg Tyr Leu Gly Lys Gly Val Leu50 55 60Lys Ala Val Glu Asn Val Asn Glu Glu Ile Gly Asp Glu Leu Ala Gly65 70 75 80Leu Glu Ala Asp Asp Gln Arg Leu Ile Asp Glu Ala Met Ile Lys Leu85 90 95Asp Gly Thr Ala Asn Lys Ser Arg Leu Gly Ala Asn Ala Ile Leu Gly100 105 110Val Ser Met Ala Val Ala Lys Ala Ala Ala Asp Ser Ala Gly Leu Pro115 120 125Leu Phe Arg Tyr Ile Gly Gly Pro Asn Ala His Val Leu Pro Val Pro130 135 140Met Met Asn Ile Ile Asn Gly Gly Ala His Ala Asp Ser Gly Val Asp145 150 155 160Val Gln Glu Phe Met Ile Ala Pro Ile Gly Ala Glu Thr Phe Ser Glu165 170 175Ala Leu Arg Asn Gly Ala Glu Val Tyr His Ala Leu Lys Ser Val Ile180 185 190Lys Glu Lys Gly Leu Ser Thr Gly Leu Gly Asp Glu Gly Gly Phe Ala195 200 205Pro Ser Val Gly Ser Thr Arg Glu Ala Leu Asp Leu Ile Val Glu Ala210 215 220Ile Glu Lys Ala Gly Phe Thr Pro Gly Lys Asp Ile Ala Leu Ala Leu225 230 235 240Asp Val Ala Ser Ser Glu Phe Phe Lys Asp Gly Thr Tyr His Phe Glu245 250 255Gly Gly Gln His Ser Ala Ala Glu Met Ala Asn Val Tyr Ala Glu Leu260 265 270Val Asp Ala Tyr Pro Ile Val Ser Ile Glu Asp Pro Leu Gln Glu Asp275 280 285Asp Trp Glu Gly Tyr Thr Asn Leu Thr Ala Thr Ile Gly Asp Lys Val290 295 300Gln Ile Val Gly Asp Asp Phe Phe Val Thr Asn Pro Glu Arg Leu Lys305 310 315 320Glu Gly Ile Ala Lys Lys Ala Ala Asn Ser Ile Leu Val Lys Val Asn325 330 335Gln Ile Gly Thr Leu Thr Glu Thr Phe Asp Ala Val Asp Met Ala His340 345 350Arg Ala Gly Tyr Thr Ser Met Met Ser His Arg Ser Gly Glu Thr Glu355 360 365Asp Thr Thr Ile Ala Asp Leu Ala Val Ala Leu Asn Cys Gly Gln Ile370 375 380Lys Thr Gly Ala Pro Ala Arg Ser Asp Arg Val Ala Lys Tyr Asn Gln385 390 395 400Leu Leu Arg Ile Glu Gln Leu Leu Gly Asp Ala Gly Val Tyr Ala Gly405 410 415Arg Ser Ala Phe Pro Arg Phe Gln Gly420 425
Claims (17)
1、来自棒状细菌的分离的多核苷酸，其包括选自如下一组的多核苷酸序列：
a)与编码包括SEQ ID NO：2的氨基酸序列的多肽的多核苷酸至少70％相同的多核苷酸，
b)编码包括与SEQ ID NO：2的氨基酸序列至少70％相同的氨基酸序列的多肽的多核苷酸，
c)与a)或b)的多核苷酸互补的多核苷酸，以及
d)包括a)，b)或c)的多核苷酸序列的至少15个连续碱基的多核苷酸。
2、权利要求1的多核苷酸，其中该多核苷酸是能在棒状细菌中复制的优选地为重组的DNA。
3、权利要求1的多核苷酸，其中该多核苷酸是RNA。
4、权利要求2的多核苷酸，包括如SEQ ID NO：1所示的核酸序列。
5、权利要求2的能复制的DNA，包括
(ⅰ)如SEQ ID NO：1所示的核苷酸序列，或
(ⅱ)在遗传密码简并范围内相应于的序列(ⅰ)的至少一个序列，或
(ⅲ)与互补于序列(ⅰ)或(ⅱ)的序列杂交的至少一个序列，和任选地
(ⅳ) (ⅰ)中有功能的中义突变。
6、权利要求2的多核苷酸序列，其编码含包括SEQ ID NO：2的氨基酸序列的多肽。
7、发酵制备L-氨基酸尤其是L-赖氨酸的方法，其中进行以下步骤：
(a)发酵生产L-赖氨酸的棒状细菌，该细菌中至少eno基因或编码该基因的核苷酸序列是扩增的，尤其是超量表达的，
(b)富集培养基或细菌细胞中的L-氨基酸，及
(c)分离L-氨基酸。
8、权利要求7的方法，其中所用细菌中所需的L-氨基酸生物合成途径的其它基因被额外扩增。
9、权利要求7的方法，其中所用细菌中，降低L-赖氨酸生成的代谢途径至少被部分消除。
10、权利要求7的方法，其中使用经质粒载体转化的菌株，且此质粒载体携带编码eno基因的核苷酸序列。
11、权利要求7-10任一项的方法，其中使用产生L-赖氨酸的棒状细菌。
12、权利要求8的方法，其中编码二氢-2，6-吡啶二羧酸合酶的dapA基因同时超量表达。
13、权利要求8的方法，其中赋予S-(2-氨基乙基)-半胱氨酸抗性的DNA片段同时扩增。
14、权利要求8的方法，其中编码甘油醛-3-磷酸的gap基因同时超量表达。
15、权利要求8的方法，其中编码丙糖磷酸异构酶的tpi基因同时超量表达。
16、权利要求8的方法，其中编码3-磷酸甘油酸激酶的pgk基因同时超量表达。
17、权利要求8的方法，其中编码丙酮酸羧化酶的pyc基因同时超量表达。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| DE19947791A DE19947791A1 (de) | 1999-10-05 | 1999-10-05 | Neue für das eno-Gen codierende Nukleotidsequenzen |
| DE19947791.4 | 1999-10-05 |
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| CN1290750A true CN1290750A (zh) | 2001-04-11 |
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| CN00129571A Pending CN1290750A (zh) | 1999-10-05 | 2000-09-27 | 编码eno基因的新核苷酸序列 |
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| EP (1) | EP1090998A1 (zh) |
| JP (1) | JP2001161380A (zh) |
| KR (1) | KR20010050840A (zh) |
| CN (1) | CN1290750A (zh) |
| AU (1) | AU6135900A (zh) |
| BR (1) | BR0004643A (zh) |
| CA (1) | CA2319716A1 (zh) |
| DE (1) | DE19947791A1 (zh) |
| HU (1) | HUP0003893A2 (zh) |
| ID (1) | ID27338A (zh) |
| MX (1) | MXPA00009077A (zh) |
| PL (1) | PL342986A1 (zh) |
| RU (1) | RU2000125061A (zh) |
| SK (1) | SK14582000A3 (zh) |
| ZA (1) | ZA200005409B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111019877A (zh) * | 2019-12-31 | 2020-04-17 | 浙江工业大学 | 一种高产l-半胱氨酸的基因工程菌、构建方法及应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6797509B1 (en) | 1999-07-09 | 2004-09-28 | Degussa-Huls Ag | Nucleotide sequences which code for the tal gene |
| AU2001285878A1 (en) * | 2000-09-12 | 2002-03-26 | Degussa A.G. | Nucleotide sequences which code for the roda gene |
| AU2001287682A1 (en) * | 2000-09-12 | 2002-03-26 | Degussa A.G. | Nucleotide sequences coding for the ftsx gene |
| DE10046625A1 (de) * | 2000-09-20 | 2002-04-11 | Degussa | Neue für das ndkA-Gen kodierende Nukleotidsequenzen |
| DE10145043A1 (de) * | 2001-09-13 | 2003-04-03 | Degussa | Verfahren und Herstellung von Feinchemikalien |
| DE10210527A1 (de) | 2002-03-09 | 2003-09-18 | Degussa | Allele des aceA-Gens aus coryneformen Bakterien |
| KR100768748B1 (ko) * | 2004-12-30 | 2007-10-19 | 씨제이 주식회사 | 외래의 ｎａｄｐ 의존적 글리세르알데히드-3-포스페이트디히드로게나제 유전자를 포함하는 에세리키아 종 또는코리네박리움 종 미생물 및 그를 이용하여 ｌ-라이신을생산하는 방법 |
| US20070092951A1 (en) | 2005-03-24 | 2007-04-26 | Degussa Ag | Alleles of the zwf gene from coryneform bacteria |
| CN103725702A (zh) * | 2013-01-31 | 2014-04-16 | 北京师范大学 | Eno2基因在植物生长发育调控中的应用 |
| US11208649B2 (en) | 2015-12-07 | 2021-12-28 | Zymergen Inc. | HTP genomic engineering platform |
| BR112018011503A2 (pt) | 2015-12-07 | 2018-12-04 | Zymergen Inc | promotores da corynebacterium glutamicum |
| US9988624B2 (en) | 2015-12-07 | 2018-06-05 | Zymergen Inc. | Microbial strain improvement by a HTP genomic engineering platform |
| WO2018005655A2 (en) | 2016-06-30 | 2018-01-04 | Zymergen Inc. | Methods for generating a bacterial hemoglobin library and uses thereof |
| JP2019519241A (ja) | 2016-06-30 | 2019-07-11 | ザイマージェン インコーポレイテッド | グルコース透過酵素ライブラリーを生成するための方法およびその使用 |
| JP2020524492A (ja) | 2017-06-07 | 2020-08-20 | ザイマージェン インコーポレイテッド | Ｃｏｒｙｎｅｂａｃｔｅｒｉｕｍ ｇｌｕｔａｍｉｃｕｍ由来のプロモーターおよび補助遺伝子発現の制御におけるその使用 |
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| JPH0655149B2 (ja) * | 1985-03-12 | 1994-07-27 | 協和醗酵工業株式会社 | Ｌ―リジンの製造法 |
| MXPA01012842A (es) * | 1999-06-25 | 2002-07-09 | Basf Ag | Genes de corynebacterium glutamicum que codifican proteinas involucradas en el metabolismo del carbono y la produccion de energia. |
| JP2003180355A (ja) * | 1999-07-02 | 2003-07-02 | Ajinomoto Co Inc | Ｌ−アミノ酸の製造法 |
| US6797509B1 (en) * | 1999-07-09 | 2004-09-28 | Degussa-Huls Ag | Nucleotide sequences which code for the tal gene |
| CN100352926C (zh) * | 1999-07-09 | 2007-12-05 | 德古萨股份公司 | 编码opcA基因的核苷酸序列 |
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1999
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- 2000-09-25 ID IDP20000822D patent/ID27338A/id unknown
- 2000-09-27 CN CN00129571A patent/CN1290750A/zh active Pending
- 2000-09-28 AU AU61359/00A patent/AU6135900A/en not_active Abandoned
- 2000-09-29 SK SK1458-2000A patent/SK14582000A3/sk unknown
- 2000-09-29 EP EP00121158A patent/EP1090998A1/de not_active Withdrawn
- 2000-10-04 JP JP2000305110A patent/JP2001161380A/ja active Pending
- 2000-10-04 KR KR1020000058213A patent/KR20010050840A/ko not_active Application Discontinuation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111019877A (zh) * | 2019-12-31 | 2020-04-17 | 浙江工业大学 | 一种高产l-半胱氨酸的基因工程菌、构建方法及应用 |
| CN111019877B (zh) * | 2019-12-31 | 2022-04-19 | 浙江工业大学 | 一种产l-半胱氨酸的基因工程菌、构建方法及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| BR0004643A (pt) | 2001-06-12 |
| JP2001161380A (ja) | 2001-06-19 |
| ID27338A (id) | 2001-04-05 |
| HU0003893D0 (en) | 2000-12-28 |
| AU6135900A (en) | 2001-04-12 |
| PL342986A1 (en) | 2001-04-09 |
| RU2000125061A (ru) | 2003-04-10 |
| SK14582000A3 (sk) | 2001-07-10 |
| DE19947791A1 (de) | 2001-04-12 |
| CA2319716A1 (en) | 2001-04-05 |
| HUP0003893A2 (en) | 2002-09-28 |
| ZA200005409B (en) | 2001-04-23 |
| MXPA00009077A (es) | 2002-08-20 |
| EP1090998A1 (de) | 2001-04-11 |
| KR20010050840A (ko) | 2001-06-25 |
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