CN101240258A - 用于发酵制备尸胺的方法 - Google Patents
用于发酵制备尸胺的方法 Download PDFInfo
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- CN101240258A CN101240258A CNA2008100053323A CN200810005332A CN101240258A CN 101240258 A CN101240258 A CN 101240258A CN A2008100053323 A CNA2008100053323 A CN A2008100053323A CN 200810005332 A CN200810005332 A CN 200810005332A CN 101240258 A CN101240258 A CN 101240258A
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Abstract
本发明涉及重组微生物,在该重组微生物中增强编码赖氨酸脱羧酶的多核苷酸,且在使用该重组微生物的条件下发酵生产了尸胺(1,5-二氨基戊烷),其中所用碳源优选可再生的原材料如,例如,葡萄糖、蔗糖、糖蜜等等。
Description
技术领域
本发明的主题在于重组微生物,在该重组微生物中增强用于编码赖氨酸脱羧酶的多核苷酸,且在使用该重组微生物情况下发酵生产尸胺(1,5-二氨基戊烷),其中优选使用可再生的原材料如,例如葡萄糖、蔗糖、糖蜜等等用作碳源。
背景技术
聚酰胺(PA)是一类重要的聚合物,从它们可以制取一系列用于汽车、体育和生活工业的特种塑料。二胺是这些聚胺的重要单体单元。其与二羧酸一起缩合以生产各种聚合物,二胺和二羧酸的链长决定塑料的性质。
迄今为止,二胺是由石油基原材料(Albrecht,Klaus等人;Plastics;Winnacker-Kuechler:Chemische Technik(第5版)(2005),5 465-819)经二羧酸中间体或者通过氨基酸的化学的脱羧作用(Suyama,Kaneo.TheDecarboxylation of Amino Acids(4),Yakugaku Zasshi,(1965),Vol.85(6),513-533)进行化学生产。由于油价升高,迅速转变到由可再生的原材料通过生物工程学的方法(如,例如发酵)合成二胺是理想的。
在该类问题的背景下,已经发现,从生产赖氨酸的微生物开始,通过引入编码赖氨酸脱羧酶的任选地异源基因可以产生尸胺生产者。
能够生产尸胺的有机体在以下文献中得到描述(Tabor,Herbert;Hafner,Edmund W.;Tabor,Celia White.Construction of an Escherichiacoli strain unable to synthesize putrescine,spermidine,or cadaverine:characterization of two genes controlling lysine decarboxylase.Journal ofBacteriology(1980),144(3),952-6,Takatsuka Yumiko;Kamio YoshiyukiMolecular dissection of the Selenomonas ruminantium cell envelope andlysine decarboxylase involved in the biosynthesis of a polyamine covalentlylinked to the cell wall peptidoglycan layer.Bioscience,biotechnology,andbiochemistry(2004),68(1),1-19)。在增加尸胺的合成的尝试中,使用了具有用于过表达宿主同源的赖氨酸脱羧酶(cadA)的质粒的大肠杆菌菌株。这种大肠杆菌菌株过表达同源的cadA基因后,生产尸胺的量增加(JP2002-223770)。在更进一步发展中,和在大肠杆菌中培养和表达cadA之后,这些有机体被用来作为用于转化外部进料赖氨酸的全细胞催化剂(JP 2002-223771、JP 2004-000114、EP 1482055),其中所述脱羧酶也可以呈递于大肠杆菌细胞表面上(JP 2004-208646)。另外的方法是通过分离的cadA酶将赖氨酸-HCl转化为尸胺(JP 2005-060447)。
从上述的生物催化方法向发酵的方法的转变在生产过程的经济和生态方面是关键性的进步,在发酵方法中,产物是直接地获得的。
发明内容
发明人的目的是提供用于从可再生的原材料发酵生产尸胺的新方法。
本发明的主题在于具有高L-赖氨酸滴定度的产尸胺重组微生物,其中编码赖氨酸脱羧酶的多核苷酸以与作为亲株的、这种酶未被修饰的微生物相比较增强量存在。
限定词″具有高赖氨酸滴定度″表明该亲株优选为L-赖氨酸生产者,它在更大量地生产L-赖氨酸和在细胞或者在周围发酵培养基中积聚L-赖氨酸方面不同于初始菌株(如,例如,野生型菌株)。该滴定度是按质量/体积(g/l)测量的。
在野生型菌株中,严格的调节机制阻止代谢物(如L-氨基酸)的生产超过该自身需要的量,并阻止它们释放到培养基中。因此,该被厂家称为氨基酸生产者的菌株的构造要求克服这些代谢调节。
诱变方法,采用挑选和选择突变体以消除调节机制并改善这些微生物的性能。这样获得的菌株对代谢物(如,例如,对赖氨酸类似物S-(2-氨乙基)半胱氨酸或者缬氨酸类似物2-噻唑丙氨酸(2-Thiazoloalanin)有抗性并产生化合物(例如L-氨基酸如L-赖氨酸或者L-缬氨酸)。
很多年来,还使用了重组DNA技术的方法,通过增强或者减弱各氨基酸生物合成基因和研究对化合物生产的影响,使用产L-氨基酸的菌株(例如,谷氨酸棒状杆菌(Corynebacterium glutamicum)和大肠杆菌)以进行定向菌株改进。
关于谷氨酸棒状杆菌的生物学、遗传学和生物工程学的综述可以在以下文献中找到:在″Handbook of Corynebacterium glutamicum″(编者:L.Eggeling和M.Bott,CRC Press,Taylor & Francis,2005);在Journal ofBiotechnology(总编:A.Pühler)的专刊中,题目为″A New Era inCorynebacterium glutamicum Biotechnology″(Journal of Biotechnology104/1-3,(2003));和在T.Scheper(主编)的书中″Microbial Production ofL-Amino Acids″(Advances in Biochemical Engineering/Biotechnology 79,Springer Verlag,Berlin,德国,2003)。
谷氨酸棒状杆菌的基因组的核苷酸序列在Ikeda和Nakagawa(Applied Microbiology and Biotechnology 62,99-109(2003))中,在EP1108790和在Kalinowski等人的(Journal of Biotechnology 104/1-3,(2003))中得到描述。
编码赖氨酸脱羧酶的适当的多核苷酸可以从以下微生物的菌株获得,例如,大肠杆菌(Escherichia coli)、耐碱芽孢杆菌(Bacillushalodurans)、蜡样芽孢杆菌(Bacillus cereus)、枯草芽孢杆菌(Bacillussubtilis)、苏云金芽孢杆菌(Bacillus thuringensis)、伯克霍尔德氏菌(Burkholderia ambifaria)、越南伯克霍尔德氏菌(Burkholderiavietnamensia)、石竹伯克霍尔德氏菌(Burkholderia cenocepatia)、青紫色素杆菌(Chromobacterium violaceum)、反刍月形单胞菌(Selenomonasruminantium)、霍乱弧菌(Vibrio cholerae)、副溶血弧菌(Vibrioparahaemolyticus)、天蓝色链霉菌(Streptomyces coelicolor)、毛链霉菌(Streptomyces polosus)、啮蚀艾肯氏菌(Eikenalla corrodens)、嗜氨基酸真杆菌(Eubacterium acidaminophilum)、土拉热弗朗西丝氏菌(Francisellatulariensis)、Geobacillus kaustophilus、伤寒沙门氏菌(Salmonella typhi)、鼠伤寒沙门氏菌(Salmonella typhimurium)、蜂房哈夫尼亚菌(Hafniaalvei)、脑膜炎奈瑟氏球菌(Neisseria meningitides)、嗜酸热原体(Thermoplasma acidophilum)、恶性疟原虫(Plasmodium falciparum)、耐辐射动球菌(Kineococcus radiotolerans)、Oceanobacillus iheyensis、火球菌(Pyrococcus abyssi)、Porochlorococcus marinus、普通变形杆菌(Proteusvulgaris)、红育菌(Rhodoferax ferrireducens)、Saccharophagusdegradans、肺炎链球菌(Streptococcus pneumoniae)、聚球蓝细菌属的物种(Synechococcus sp.)。
可用在本发明的方法的适当的赖氨酸脱羧酶被理解为能够脱羧赖氨酸的酶和它们的等位基因或突变体。
根据本发明使用的用于编码赖氨酸脱羧酶的多核苷酸优选地源于大肠杆菌SEQ ID NO:1。后者在国际可用的数据库中(如,例如,美国国家医学图书馆和国家卫生研究院(NIH)的数据库)以登录号NC 007946是可免费获得的。相同的序列也可在巴斯德研究所(法国)在colibri网络服务器以编号b4131或者基因名cadA免费获得。该相同序列也可通过网络服务器ExPasy以编号P0A9H4或者基因名cadA免费获得,该网络服务器由瑞士生物信息学研究所维护。
使用产生提高量L-赖氨酸的本发明的微生物的措施不能从现有技术中推导出来。
相反地,US 5,827,698描述了降低赖氨酸脱羧酶的活性提高了大肠杆菌中L-赖氨酸的产量。
在该产尸胺的重组细胞中另外的过表达编码被称为尸胺/赖氨酸反向转运蛋白的蛋白质的多核苷酸有助于尸胺的生产,优选地,该多核苷酸从大肠杆菌(SEQ ID NO:3;TC 2.A.3.2.2)中获得,该多核苷酸促进上述的化合物从细胞向培养基中转运。其他合适的尸胺/赖氨酸反向转运蛋白源自于例如大肠杆菌、嗜酸热原体或者霍乱弧菌的菌株。
使用能自然地输出尸胺或者相关二胺,或者由于突变获得能输出尸胺或者相关二胺的这种能力的转运蛋白也是可行的。
本发明还包括谷氨酸棒状杆菌的内源性转运蛋白基因的过表达,所述基因编码催化尸胺的输出的蛋白质。同样地,本发明优选地包括在产尸胺的菌株中进行无竞争性赖氨酸或者精氨酸的输出,即,相应的输出基因或者输出功能以降低水平存在或者是被关闭的。
本发明的主题在于重组微生物,特别涉及棒状杆菌,其包含增强量的编码上述的蛋白质的多核苷酸。优选地增强、特别是过表达该编码赖氨酸脱羧酶和/或赖氨酸/尸胺反向转运蛋白的核苷酸序列。
优选的微生物来自肠杆菌科,特别地为埃希氏杆菌属、芽孢杆菌属和特别地为大肠杆菌属物种和枯草芽孢杆菌属物种,提高尸胺产量的赖氨酸脱羧酶可以为内源性的或者外源性的。
在根据本发明的重组微生物中,所述编码赖氨酸脱羧酶和/或赖氨酸/尸胺反向转运蛋白的被过表达多核苷酸可以来自于不同的科或属的微生物。
由于上述基因的过表达,分别地或者共同地,同上述基因没被过表达的微生物相比,这些微生物在增加程度上生产尸胺。
根据本发明的重组微生物通过本领域技术人员已知的重组基因工程方法形成。
通常,具有上述基因的载体通过传统的转化或者转染技术被引入到细胞中。适当的方法可以在Sambrook等人(Molecular Cloning:ALaboratory Manual,第二版,Cold Spring Harbor Laboratory,1989)中找到。
本发明的主题还在于载体,特别涉及到质粒,其包含根据本发明使用的多核苷酸和视需要在细菌中进行复制。同样地,本发明的主题在于重组微生物,其已经用上述的载体进行转化。
在本文中,该两种多核苷酸可以是在单一启动子控制下,或者两种启动子控制下。
在本上下文中,术语″增强″描述在微生物中一种或多种酶或者蛋白质在胞内的活性或者浓度的增加,该酶或者蛋白质由相应的DNA进行编码,其中例如通过使一种或多种基因的、一种或多种ORF的拷贝数增加至少一个(1)拷备,通过功能连接强启动子与基因,或者通过使用编码相应的具有高活性的酶或蛋白质的基因或等位基因或ORF,和,视需要通过结合这些措施。在大肠杆菌中lac、tac和trp被称为强启动子。
开放阅读框(ORF)指的是编码或能编码蛋白质或多肽或核糖核酸的核苷酸序列片段,根据现有技术,没有功能归于这些核苷酸序列片段。在功能已经分配给核苷酸序列的相关片段之后,通常叫做基因。等位基因通常被理解是指所给基因的替换形式。这些形式的区别在于在核苷酸序列中的差异。
基因产物泛指由核苷酸序列(即ORF、基因或者等位基因)编码的蛋白质、或者被编码的核糖核酸。
通过增强、特别是过表达的方法,通常提高所述蛋白质的活性或者浓度至少10%、25%、50%、75%、100%、150%、200%、300%、400%、或者500%,最大直至1000%或者2000%(以野生型蛋白质的活性或者浓度,或者相应酶或蛋白质未重组的微生物或者亲株中的蛋白质的活性或者浓度为基准)。未重组微生物或亲株理解为是指在其上进行根据本发明的增强或过表达的微生物。
所述基因或者基因构建体可以或者存在于具有不同拷贝数的质粒中,或者在该染色体中被整合和扩增。或者,所述基因的过表达还可以通过改变培养基组成和过程控制(Kulturfü hrung)来实现。
为了提高cadA等位基因的拷贝数,合适的是在棒状细菌中进行复制的质粒。大量已知的质粒载体如,例如,pZ1(Menkel等人,Applied andEnvironmental Microbiology(1989)64:549-554),pEKEx1(Eikmanns等人,Gene 102:93-98(1991))或pHS2-1(Sonnen等人,Gene 107:69-74(1991))是基于隐蔽性质粒pHM1519、pBL1或pGA1。其他的质粒载体如,例如那些基于pCG4(US-A 4,489,160)或pNG2(Serwold-Davis等人,FEMSMicrobiology Letters 66,119-124(1990))或pAG1(US-A 5,158,891)的质粒载体,可以相同方式进行使用。在Tauch等人(Journal of Biotechnology104(1-3),27-40(2003)中综述了谷氨酸棒状杆菌的质粒载体。
用于复制或者扩增该hom-thrB操纵子的染色体基因扩增方法(例如由Reinscheid等人(Applied and Environmental Microbiology 60,126-132(1994))所描述)也可以用于提高拷贝数。在该方法中,完整的基因或者等位基因被克隆到能够在宿主(一般地为大肠杆菌)中、但不能在谷氨酸棒状杆菌中复制的质粒载体中。合适的载体是,例如,pSUP301(Simon等人,Bio/Technology 1,784-791(1983)),pK18mob或pK19mob(Schfer等人,Gene 145,69-73(1994)),pGEM-T(Promega Corporation,Madison,WI,USA),pCR2.1-TOPO(Shuman,Journal of Biological Chemistry 269:32678-84(1994);US-A 5,487,993),pCRBlunt(Invitrogen公司,Groningen,Netherlande;Bernard等人,Journal of Molecular Biology,234:534-541(1993)),pEM1(Schrumpf等人,Journal of Bacteriology 173:4510-4516(1991))或pBGS8(Spratt等人,Gene 41:337-342(1986))。包含待扩增的基因或者等位基因的质粒载体随后通过接合或者转化被转移到所希望的谷氨酸棒状杆菌菌株。该接合方法例如在Schfer等人(Applied and Environmental Microbiology 60,756-759(1994))中得到描述。转化方法在例如Thierbach等人(Applied Microbiology andBiotechnology 29,356-362(1988)),Dunican和Shivnan(Bio/Technology 7,1067-1070(1989))以及Tauch等人(FEMS Microbiological Letters 123,343-347(1994))中得到描述。通过“交换”事件进行同源重组后,所得菌株包含至少两个拷贝的所述基因或等位基因。特别地,还可以使用如在WO 03/014330中描述的串联扩增方法或者如在WO 03/040373中描述的在期望的位点上通过整合进行扩增的方法以使拷贝数提高至少1、2或者3。
术语″减少″或者″以减少″描述了在微生物中一种或多种由相应DNA编码的酶或者蛋白质的胞内活性的减少或关闭,其中例如使用弱的启动子,或者使用编码相应的低活性酶的基因或者等位基因,或者通过对相关基因或者酶或者蛋白质灭活,和视需要结合这些方法。
通过该减少措施,相应的蛋白质的活性或者浓度通常被减少到野生类型蛋白质的活性或者浓度、或者起始微生物中该蛋白质的活性或者浓度的0-75%、0-50%、0-25%、0-10%、或者0-5%。″起始微生物″理解为是指在其中进行相应基因减少的微生物。
要求保护的特别地为棒状杆菌,在其中存在增强的,优选过表达的编码赖氨酸脱羧酶的上述多核苷酸。
因为棒状杆菌不天然地包含任何编码这种酶的多核苷酸,所以已经存在编码赖氨酸脱羧酶的来自于异源有机体的基因之一的拷贝被称为过表达。
本发明的主题还在于生产尸胺的方法,其中微生物、特别地为棒状杆菌,用上述的多核苷酸之一进行转化,获得的重组细菌在合适的培养基中和在适于表达由这种多核苷酸编码的赖氨酸脱羧酶条件下被发酵,累积并分离形成的尸胺,视需要还与来自发酵液的其它溶解组分和/或该生物量(≥0至100%)一起被分离。
特别地,本发明的主题在于生产尸胺的方法,其中通常进行以下步骤:
a)在适于形成酶和尸胺的条件下进行重组微生物、特别是棒状杆菌的发酵,其中编码赖氨酸脱羧酶的核苷酸序列,且优选编码被称为赖氨酸/尸胺反向转运蛋白的蛋白质的多核苷酸,以增强的量、特别地以过表达的量存在,和
b)尸胺在发酵液和/或在上述的细菌的细胞中的累积。
随后可以对尸胺从该发酵液和/或在上述的细菌的细胞中进行分离,视需要,来自发酵液的组分和/或该生物量也部分地或者完全地被去除,或者完全地保留在产物中。
来自大肠杆菌的cadA基因的核苷酸序列示于SEQ ID NO:1中。
在棒状杆菌属中,特别地提及在本专业领域内已知的谷氨酸棒状杆菌物种。用于本发明的微生物的起始物料例如为已知的谷氨酸棒状杆菌的野生型菌株,如,例如
谷氨酸棒状杆菌(Corynebacterium glutamicum)ATCC13032醋谷棒状杆菌(Corynebacterium acetoglutamicum)ATCC15806嗜乙酰乙酸棒状杆菌(Corynebacterium acetoacidophilum)ATCC13870
栖糖蜜棒状杆菌(Corynebacterium melassecola)ATCC17965热产氨棒状杆菌(Corynebacterium thermoaminogenes)FERMBP-1539
黄色短杆菌(Brevibacterium flavum)ATCC14067乳酸发酵短杆菌(Brevibacterium lactofermentum)ATCC13869和谷氨酸棒状杆菌(Brevibacterium divaricatum)ATCC14020。
根据本发明使用的菌株合适的前体为已知的棒状杆菌的菌株,该菌株具有产L-赖氨酸的能力,如,例如以下菌株:
在EP 0358940中描述的谷氨酸棒状杆菌DM58-1/pDM6(=DSM4697),
在EP 0435l32中描述的谷氨酸棒状杆菌MH20(=DSM5714),
在EP 1108790中描述的谷氨酸棒状杆菌AHP-3(=FermBP-7382),
在US 5250423中描述的热产氨棒状杆菌AJ12521(=FERMBP-3304),
谷氨酸棒状杆菌DM1800(Georgi T,Rittmann D,Wendisch VF(2005)Metabolic Engineering 7:291-301)
名为″ATCC″的菌株可以从American Type Culture Collection(Manassas,VA,USA)获得。名为″DSM″的菌株可以从DeutscheSammlung von Mikroorganismen und Zellkulturen(DSMZ,Braunschweig,德国)获得。名为″FERM″的菌株可以从the National Institute of AdvancedIndustrial Science and Technology(AIST Tsukuba Central 6,1-1-1 Higashi,Tsukuba Ibaraki,Japan)获得。
关于上组细菌的菌株的分类学分类的信息,尤其,在Kmpfer和Kroppenstedt(Canadian Journal of Microbiology 42,989-1005(1996))和在US-A-5,250,434找到。多年来,(Liebl等人,International Journal ofSystematic Bacteriology 41(2),255-260(1991)),种名为“黄色短杆菌”“乳酸发酵短杆菌”和“谷氨酸棒状杆菌(Brevibacterium divaricatum)”的棒状杆菌被指定到谷氨酸棒状杆菌属物种。种名为″栖糖蜜棒状杆菌″的棒状杆菌也属于谷氨酸棒状杆菌属物种。
适于本发明措施的微生物优选具有产L-赖氨酸的能力,在细胞中积聚L-赖氨酸能力或者将L-赖氨酸分泌到周围营养培养基并在那里积聚L-赖氨酸的能力。特别地,所使用的菌株在它们被赖氨酸脱羧酶基因转化之前具有在≤(最大值)120小时、≤96小时、≤48小时、≤36小时、≤24小时或≤12小时的时间里产>(至少)1g/l、≥15g/l、≥20g/l或≥30g/l的L-赖氨酸的能力。它们可以是已经通过诱变和筛选、通过重组DNA技术、或者通过这两种方法的结合产生的菌株。
传统的体内诱变方法可以用来进行所述诱变,其中使用诱变剂如,例如N-甲基-N′-硝基-N-亚硝基胍,或者紫外线。
此外,对于该诱变,使用体外方法如,例如用羟胺处理(Miller,J.H.:A Short Course in Bacterial Genetics.A Laboratory Manual and Handbookfor Escherichia coli and Related Bacteria,Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,1992)或者用诱变寡核苷酸处理(T.A.Brown:Gentechnologie für Einsteiger,Spektrum Akademischer Verlag,Heidelberg,1993)或者用如在Handbuch von Newton und Graham(PCR,Spektrum Akademischer Verlag,Heidelberg,1994)中所描述的聚合酶连锁反应(PCR)也是可行的。
对于突变的产生的进一步的指导可以在现有技术和已知的遗传学和分子生物学的教科书如,例如Knippers的教科书(″Molekulare Genetik″,第6版,Georg Thieme Verlag,Stuttgart,德国,1995),Winnacker的教科书(″Gene und Klone″,VCH Verlagsgesellschaft,Weinheim,德国,1990)或者Hagemann的教科书(″Allgemeine Genetik″,Gustav Fischer Verlag,Stuttgart,1986)可以找到。
当使用体外方法时,在现有技术中描述的cadA基因从野生型菌株的分离的总DNA借助于聚合酶链式反应进行扩增,视需要被克隆到合适的质粒载体中,然后DNA经受所述诱变方法。关于DNA序列借助于聚合酶链式反应(PCR)的扩增的指导尤其可以由本领域技术人员在Handbuchvon Gait:Oligonucleotide Synthesis:A Practical Approach(IRL Press,Oxford,UK,1984)和在Newton和Graham:PCR(Spektrum AkademischerVerlag,Heidelberg,德国,1994)中找到。同样地,使用体外诱变方法也是可行的,该方法如,例如在已知的Sambrook等人的手册(MolecularCloning,A Laboratory Manual,第二版,Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,New York,USA,1989)中得到描述。相应方法也可以在市场上以所谓“试剂盒”的形式得到,如,例如,来自Stratagene公司(La Jolla,USA)的″QuikChange Site-Directed Mutagenesis Kit″,其由Papworth等人(Strategies 9(3),3-4(1996))进行了描述。随后使用上述方法对合适的cadA等位基因进行选择和研究。
本发明的主题在于用于发酵产生尸胺的菌株,优选棒状杆菌,特别是谷氨酸棒状杆菌,其具有至少一种异源表达的编码赖氨酸脱羧酶的基因,优选来自大肠杆菌的cadA。
合适的还有埃希氏杆菌属的相应的菌株。
该优选使用的赖氨酸脱羧酶等位基因或者基因可以通过基因置换方法被转移到合适的菌株之中,该基因置换方法由Schwarzer和Pühler(Bio/Technology 9,84-87(1991))或Peters-Wendisch等人(Microbiology144,915-927(1998))进行了描述。这里,所述的赖氨酸脱羧酶等位基因被克隆到不在谷氨酸棒状杆菌中进行复制的载体,如,例如pK18mobsacB或者pK19mobsacB(Jger等人,Journal of Bacteriology 174:5462-65(1992))或pCRBlunt(Invitrogen公司,Groningen,Netherlande;Bernard等人,Journal of Molecular Biology,234:534-541(1993)),且这种载体随后通过转化或者接合被转移到希望的谷氨酸棒状杆菌宿主中。在通过第一次“交换”事件和合适的第二次“交换”事件进行的同源重组之后,该突变成功地被引入,其中该第一次“交换”事件引起整合,该第二次“交换”事件引起在靶基因或者靶序列中的切除。最后,可以使用在WO 03/014330和WO 03/040373中描述的扩增方法。
另外,除表达根据本发明使用的赖氨酸脱羧酶基因或者等位基因之外,同时地增强特别是过表达一种或多种赖氨酸生物合成酶对于尸胺的生产可以是有利的。通常优选使用内源性基因。
″内源性基因″或者″内源性核苷酸序列″理解为是指存在于种群中的基因或者核苷酸序列和等位基因。
在本文中,术语″增强″描述了在微生物中一种或多种由相应的DNA编码的酶或者蛋白质的胞内活性或者浓度的增加,例如增加该一种或多种基因的拷贝数,使用强的启动子,或者使用编码具有高活性的相应酶或蛋白质的基因或者等位基因,和视需要结合这些措施。
另外,为了提高赖氨酸在要求保护的有机体中的产量,在用上述方法生产的棒状杆菌中,过表达各自生物合成途径的、糖酵解的、糖回补的、戊糖磷酸循环的、氨基酸输出的一种或多种酶,和视需要调节蛋白质对于提高尸胺的产量可以是有利的。通常在上述措施中,使用内源性基因是优选的。
因此,过表达一种或多种选自以下的基因对于提高棒状杆菌微生物中L-赖氨酸的产量是有利的:
编码二氢吡啶二羧酸合成酶的dapA基因如,例如在EP 0197335中描述的野生型谷氨酸棒状杆菌的dapA基因。
编码葡萄糖-6-磷酸脱氢酶的zwf基因如,例如野生型谷氨酸棒状杆菌的zwf基因,该基因在JP-A-09224661和EP-A-1108790中得到描述。
在US-2003-0175911-A1中描述的编码蛋白质的谷氨酸棒状杆菌的zwf等位基因,在所述蛋白质中,例如在氨基酸序列的243位的L-丙氨酸被L-苏氨酸取代,或者在其中245位的L-天冬氨酸被L-丝氨酸取代。
在WO 2005/058945中描述的编码蛋白质的谷氨酸棒状杆菌的zwf等位基因,在所述蛋白质中,例如在氨基酸序列8位的L-丝氨酸被L-苏氨酸取代,或者在其中在321位的L-甘氨酸被L-丝氨酸取代。
编码丙酮酸羧化酶的pyc基因如,例如野生型谷氨酸棒状杆菌的pyc基因,该基因在DE-A-198 31 609和EP 1108790得到描述。
在EP 1108790中描述的编码蛋白质的谷氨酸棒状杆菌的pyc等位基因,在所述蛋白质中,在氨基酸序列的458位的L-脯氨酸被L-丝氨酸取代。
在WO 02/31158和特别地在EP1325135B1中描述的编码蛋白质的谷氨酸棒状杆菌的pyc等位基因,其中所述蛋白质包含一个或多个选自以下的氨基酸取代:在1位的L-缬氨酸被L-甲硫氨酸取代,在153位的L-谷氨酸被L-天冬氨酸取代,在182位的L-丙氨酸被L-丝氨酸取代,在206位的L-丙氨酸被L-丝氨酸取代,在227位的L-组氨酸被L-精氨酸取代,在455位的L-丙氨酸被甘氨酸取代,和在1120位的L-天冬氨酸被L-谷氨酸取代。
编码天冬氨酸激酶的lysC基因如,例如,野生型谷氨酸棒状杆菌的lysC基因,该基因在EP-A-1108790中被描述为SEQ ID NO:281(参看登录号AX120085和120365),和该基因在WO 01/00843描述为SEQ ID NO:25(参看登录号AX063743)。
编码抗反馈的天冬氨酸激酶变体的lysCFBR等位基因。
抗“反馈”的天冬氨酸激酶被理解是指与野生型相比显示出对抑制作用敏感性降低的天冬氨酸激酶,该抑制作用由赖氨酸和苏氨酸的混合物或者AEC(氨乙基半胱氨酸)和苏氨酸的混合物或者单独赖氨酸或者单独的AEC引起。编码这些脱敏天冬氨酸激酶的基因或者等位基因也被称为lysCFBR等位基因。现有技术描述大量的编码天冬氨酸激酶变体的lysCFBR等位基因,同野生型蛋白质相比,该变体具有氨基酸取代。谷氨酸棒状杆菌的野生型lysC基因的编码区相应于NCBI数据库的登录号AX756575。
下列lysCFBR等位基因是优选的:lysC A279T(在被编码的天冬氨酸激酶蛋白的279位,苏氨酸取代丙氨酸)、lysC A279V(在被编码的天冬氨酸激酶蛋白的279位,缬氨酸取代丙氨酸)、lysC S301F(在被编码的天冬氨酸激酶蛋白的301位,苯丙氨酸取代丝氨酸)、lysC T308I(在被编码的天冬氨酸激酶蛋白的308位,异亮氨酸取代苏氨酸)、lysC S301Y(在被编码的天冬氨酸激酶蛋白的308位,酪氨酸取代丝氨酸)、lysCG345D(在被编码的天冬氨酸激酶蛋白的345位,天冬氨酸取代甘氨酸)、lysC R320G(在天冬氨酸激酶蛋白的320位,甘氨酸取代精氨酸)、lysCT311I(在被编码的天冬氨酸激酶蛋白的311位,异亮氨酸取代苏氨酸)、lysC S381F(在被编码的天冬氨酸激酶蛋白的381位,苯丙氨酸取代丝氨酸)、1ysC S317A(在被编码的天冬氨酸激酶蛋白的317位,丙氨酸取代丝氨酸)和lysC T380I(在被编码的天冬氨酸激酶蛋白的380位,异亮氨酸取代苏氨酸)。
尤其优选的是lysCFBR等位基因lysC T311I(在被编码的天冬氨酸激酶蛋白的311位,异亮氨酸取代苏氨酸)和包含至少一种选自以下取代的lysCFBR等位基因:A279T(在被编码的天冬氨酸激酶蛋白的279位,苏氨酸取代丙氨酸)和S317A(在被编码的天冬氨酸激酶蛋白的317位,丙氨酸取代丝氨酸)。
不同的是,编码赖氨酸输出蛋白的lysE基因(如,例如,在DE-A-19548222中描述的野生型谷氨酸棒状杆菌的lysE基因)被减少或被关闭。
编码二氨基庚二酸脱氢酶的ddh基因如,例如在EP 1108790中描述的野生型谷氨酸棒状杆菌的ddh基因。
编码Zwa1蛋白的野生型谷氨酸棒状杆菌的zwa1基因(US6,632,644)。
同样地,还要求保护埃希氏杆菌属的产尸胺微生物,其中选自下列的一种或多种来自大肠杆菌的基因同时被增强或者过表达:
a)根据US 5,827,698的编码抗反馈天冬氨酸激酶的基因或者等位基因,
b)编码二氢吡啶二羧酸合成酶的基因,
c)编码二氢吡啶二羧酸还原酶的基因,
d)编码琥珀酰二氨基庚二酸转氨酶的基因,
e)编码琥珀酰二氨基庚二酸脱酰基酶的基因
根据本发明的微生物可以连续地或者通过分批处理法或者分批进料处理法或者重复分批进料处理法分批地进行培养以生产尸胺。已知的培养方法的综述在Chmiel的教科书(Bioprozesstechnik 1.Einführung indie Bioverfahrenstechnik(Gustav Fischer Verlag,Stuttgart,1991))中得到描述,或者在Storhas的教科书(Bioreaktoren und periphere Einrichtungen(Vieweg Verlag,Braunschweig/Wiesbaden,1994))中得到描述。
将被使用的培养基必须合适地满足各菌株的要求。用于各种微生物的培养基的描述可以在American Society for Bacteriology(WashingtonD.C.,USA,1981)的手册″Manual of Methods for General Bacteriology″中找到。
可以使用的碳源是糖和碳水化合物如,例如,葡萄糖、蔗糖、乳糖、果糖、麦芽糖、糖蜜、淀粉、和纤维素,油类和脂肪类如,例如,豆油、向日葵油、花生油和椰子脂,脂肪酸如,例如,棕榈酸、硬脂酸、和亚油酸,醇类如,例如,甘油和乙醇,和有机酸如,例如,乙酸。这些物质可以单独地或者以混合物进行使用。
可以使用的氮源为包含有机氮的化合物如,蛋白胨、酵母提取物、肉类提取物、麦芽提取物、玉米浆、大豆粉和尿素,或者无机化合物如,硫酸铵、氯化铵、磷酸铵、碳酸铵、和硝酸铵。该氮源可以单独地或者以混合物进行使用。
可以使用的磷源为磷酸、磷酸二氢钾或者磷酸氢二钾、或者相应的包含钠的盐。而且,该培养基还必须包含对于生长必需的金属盐如,例如,硫酸镁或者硫酸铁。最后,除上述的物质外,可使用必需生长因子如,氨基酸和维生素。而且,可以将合适的前体添加到该培养基中。上述物质可以以单批批料形式被加到该培养物中,或者可以在培养期间以合适的方式被加入。
用于以合适的方式调节培养物pH的物质为碱性化合物如氢氧化钠、氢氧化钾、氨或氨水、或者酸性化合物如磷酸或者硫酸。为了控制泡沫产生,可以使用消泡剂如,例如,脂肪酸聚乙二醇酯。为了维持质粒的稳定性,可以向该培养基添加合适的选择性作用物质,如,例如,抗生素。为了维持有氧条件,氧或者含氧气体混合物如,例如,空气被引入到该培养物中。培养温度一般为20℃-45℃,且优选地在25℃-40℃。继续该培养直到生产出最大量的尸胺为止,或者直到产量或者产率达到期望的最优值。该目标一般在10小时-160小时内达到。
以这种方式生产的尸胺随后被收集,然后优选地进行分离和视需要进行纯化。
用于尸胺和L-氨基酸例如L-赖氨酸的测定的方法是现有技术中已知的。该分析可以以例如Spackman等人(Analytical Chemistry,30,(1958),1190)描述的通过阴离子交换色谱法后接茚三酮衍生作用而进行,或者该分析可以通过Lindroth等人(Analytical Chemistry(1979)51:1167-1174)所描述的反相HPLC实现。
根据本发明的方法通过使用具有高的赖氨酸滴定度的微生物用于改善的尸胺的发酵生产,其中赖氨酸脱羧酶基因和/或被称为赖氨酸/尸胺反向转运蛋白的蛋白质被过表达。
具体实施方式
实施例
一般技术
通过使用标准技术进行DNA操作,该标准技术如,例如在Sambrook,J.等人(1989),Molecular Cloning:a laboratory manual,第二版,ColdSpring Harbor Laboratory Press,Cold Spring Harbor,New York所描述。通过使用SAWADY Pwo-DNA聚合酶(Peqlab Biotechnologie,Erlangen,德国)或者Platinum Pfx-DNA聚合酶(Invitrogen,Karlsruhe,德国)进行DNA扩增。除非另作说明,该聚合酶按厂商的说明进行使用。用于PCR扩增和引入限制切割位点的寡核苷酸从MWG-Biotech(Ebersberg,德国)获得。通过使用READYMIX Taq聚合酶(Sigma,Taufkirchen,德国)和质粒制备由菌落PCR(Kolonie-PCR)进行构建的菌株的检测。通过使用MinElute凝胶回收试剂盒(Quiagen,Hilden,德国)根据厂商指导纯化和获得DNA片段。通过Qiaprep spin Miniprep Kit(Quiagen,Hilden,德国)分离质粒DNA。所有的被构建的质粒通过限制性分析(Restriktionsanalyse)后接测序进行验证。
实施例1:pEKEx2cadA的构建
pEKEx2cadA通过使用载体pEKEx2(Kleinertz等人,1991 Gene 102:93)进行构建,该载体使得被克隆的基因在异丙基-β-D-硫代半乳糖吡喃糖苷(IPTG)可诱导的tac启动子和lac阻抑蛋白体系(lacIq)的调控下进行转录。编码cadA基因的2.2kb尺寸DNA片段通过以下寡核苷酸和来自大肠杆菌的DH5的DNA作为模板进行扩增:
SEQ ID NO 5:
pcadAFr 5′-
ttgtcgacaaggagatatagatATGAACGTTATTGCAATATTGAATC-3′(SalI)
SEQ ID NO 6:
pcadARe 5′-aaggatccTTATTTTTTGCTTTCTTCTTTCAATACC-3′(BamHI)
(与该基因组序列互补的序列以黑体大写进行打印。该扩增物(Amplificate)中还被引入针对SalI和BamHI的限制切割位点,和起始密码子上游8个核苷酸的核糖体结合位点(aaggag)。
该PCR扩增物用多核苷酸激酶进行磷酸化(Roche,Basle,Switzerland),并被平端克隆到载体pUC18的SmaI切割位点(Yanisch-Perron等人,1985,Gene 33:103-19)。该插入的同一性和正确性通过测序进行证实。其后,2.2kb片段从pUC18衍生物中被分离为SalI-BamHI片段并与SalI-BamHI-切割载体pEKEx2进行连接。所希望的质粒根据限制消化进行选择,且该质粒的一种被命名为pEKEx2cadA。
实施例2:pEKEx2cadBA的构建
pEKEx2cadBA通过使用载体pEKEx2进行构建(Kleinertz等人,1991Gene 102:93),该载体使得被克隆的基因在异丙基-β-D-硫代半乳糖吡喃糖苷(IPTG)可诱导的tac启动子和乳糖阻抑蛋白体系(lacIq)的调控下进行转录。编码cadB和cadA基因的3.6kb尺寸DNA片段通过以下寡核苷酸和来自大肠杆菌DH5的DNA作为模板进行扩增:
SEQ ID NO 7:
pcadBAFr 5′-ttggatccaaggagatatagatATGAGTTCTGCCAAGAAGATCG-3′(Bam HI)
SEQ ID NO 8:
pcadBARe 5′-aaggatccTTATTTTTTGCTTTCTTCTTTCAATACC-3′(BamHI)
(与该基因组序列互补的序列以黑体大写进行打印。向该扩增物中引入另外的针对BamHI的限制切割位点,和起始密码子上游的8个核苷酸的核糖体结合位点(aaggag))。
该PCR扩增物用多核苷酸激酶进行磷酸化(Roche,Basel,Switzerland),并被平端克隆到载体pUC18的SmaI切割位点(Yanisch-Perron等人,1985,Gene 33:103-19)。该插入的同一性和正确性通过测序进行证实。其后,3.6kb片段从pUC18衍生物中被分离为BamHI片段并与BamHI切割载体pEKEx2进行连接。所希望的质粒根据限制消化进行选择,和该质粒的一种被命名为pEKEx2cadBA。
实施例3:获得重组细胞
谷氨酸棒状杆菌DM1800的感受态细胞(Georgi等人,Metab Eng.7(2005)291-301)如由Tauch等人(Curr Microbiol.(2002)45:362-367)所描述地进行制备。pEKEx2、pEKEx2cadA和pEKEx2cadBA的DNA通过电穿孔法被引入,在添加了50mg/l卡那霉素的来自Merck公司(达姆施塔特,德国)的脑-心琼脂上选择转化体(FEMS Microbiol Lett.,1989,53:299-303)。质粒DNA从转化体分离出来且通过限制消化进行表征。这样获得谷氨酸棒状杆菌pEKEx2、谷氨酸棒状杆菌pEKEx2cadA和谷氨酸棒状杆菌pEKEx2cadBA。
谷氨酸棒状杆菌DM1800菌株通过的特征在于如下性质(同野生型谷氨酸棒状杆菌ATCC13032相比较):在等位基因pyc P458S(丙酮酸脱羧酶)和lysC T311I(天冬氨酸激酶)中的突变,该突变引起赖氨酸产量的提高(Georgi T,Rittmann D,Wendisch VF Metab Eng.2005;7(4):291-301,Lysine and glutamate production by Corynebacterium glutamicum onglucose,fructose and sucrose:roles of malic enzyme andfructose-1,6-bisphosphatase.Metab Eng.2005.七月;7(4):291-301)。.
实施例4:使用细菌生产尸胺
该重组谷氨酸棒状杆菌DM1800菌株在30℃时在包含25mg/l卡那霉素的复合培养基CGIII上(Eggeling和Bott,Eds,Handbook ofCorynebacterium glutamicum.,CRC Press,Taylor Francis Group)被培养过夜。接着,细胞通过在每次以6000转每分离心5分钟进行收集、重悬浮,吸收到0.9%NaCl中、再次离心和最后吸收到0.9%NaCl中。该细胞悬液被用来接种基本培养基CGXII 4%葡萄糖、25mg/l卡那霉素(Eggeling和Bott,Eds,Handbook of Corynebacterium glutamicum.,CRC Press,TaylorFrancis Group)。然后,该细胞在30℃进行温育。在每种情况下进行至少两次独立的发酵。在47小时之后,取出样品以测定尸胺和氨基酸。该测定通过高压液相色谱分析进行(J Chromat(1983)266:471-482)。发酵作用的结果示于表格1中。由此,使用被构建和被描述的菌株提供了可以由糖微生物生产尸胺的方法。
表格1:尸胺在谷氨酸棒状杆菌DM1800的重组菌株的培养物上清液中的累积
谷氨酸棒状杆菌DM1800 | L-赖氨酸(mM) | 尸胺(mM) |
pEKEx2 | 27.9 | 0.0 |
pEKEx2cadA | 0.1 | 33.3 |
序列表
<110>Degussa GmbH
<120>用于发酵生产尸胺的方法
<130>2006E00257
<160>8
<170>PatentIn version 3.4
<210>1
<211>2148
<212>DNA
<213>大肠杆菌
<400>1
atgaacgtta ttgcaatatt gaatcacatg ggggtttatt ttaaagaaga acccatccgt 60
gaacttcatc gcgcgcttga acgtctgaac ttccagattg tttacccgaa cgaccgtgac 120
gacttattaa aactgatcga aaacaatgcg cgtctgtgcg gcgttatttt tgactgggat 180
aaatataatc tcgagctgtg cgaagaaatt agcaaaatga acgagaacct gccgttgtac 240
gcgttcgcta atacgtattc cactctcgat gtaagcctga atgacctgcg tttacagatt 300
agcttctttg aatatgcgct gggtgctgct gaagatattg ctaataagat caagcagacc 360
actgacgaat atatcaacac tattctgcct ccgctgacta aagcactgtt taaatatgtt 420
cgtgaaggta aatatacttt ctgtactcct ggtcacatgg gcggtactgc attccagaaa 480
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aaaggtgacg taaacgaaga aacctttaac gaagcctaca tgatgcacac caccacttct 1200
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gaaatcggcg ctcactatcc gggctttgaa accgatattc acggtgcata ccgtcaggct 2100
gatggccgct ataccgttaa ggtattgaaa gaagaaagca aaaaataa 2148
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aaggatcctt attttttgct ttcttctttc aatacc 36
Claims (17)
1.一种具有高赖氨酸滴定度的产尸胺的重组微生物,其中编码赖氨酸脱羧酶的多核苷酸以相对于对于这种酶没有修饰的微生物增强的量存在。
2.根据权利要求1的微生物,其中编码被称为赖氨酸/尸胺反向转运蛋白的蛋白质的多核苷酸以相对于对于这种蛋白质没有修饰的微生物增强的量存在。
3.根据权利要求1和2的微生物,其中编码赖氨酸脱羧酶的多核苷酸源自于选自以下的微生物:大肠杆菌(Escherichia coli)、耐碱芽孢杆菌(Bacillus halodurans)、蜡样芽孢杆菌(Bacillus cereus)、枯草芽孢杆菌(Bacillus subtilis)、苏云金芽孢杆菌(Bacillus thuringensis)、伯克霍尔德氏菌(Burkholderia ambifaria)、越南伯克霍尔德氏菌(Burkholderia vietnamensia)、石竹伯克霍尔德氏菌(Burkholderiacenocepatia)、青紫色素杆菌(Chromobacterium violaceum)、反刍月形单胞菌(Selenomonas ruminantium)、霍乱弧菌(Vibrio cholerae)、副溶血弧菌(Vibrio parahaemolyticus)、天蓝色链霉菌(Streptomycescoelicolor)、毛链霉菌(Streptomyces polosus)、啮蚀艾肯氏菌(Eikenalla corrodens)、嗜氨基酸真杆菌(Eubacteriumacidaminophilum)、土拉热弗朗西丝氏菌(Francisella tulariensis)、Geobacillus kaustophilus、伤寒沙门氏菌(Salmonella typhi)、鼠伤寒沙门氏菌(Salmonella typhimurium)、蜂房哈夫尼亚菌(Hafnia alvei)、脑膜炎奈瑟氏球菌(Neisseria meningitides)、嗜酸热原体(Thermoplasma acidophilum)、恶性疟原虫(Plasmodium falciparum)、耐辐射动球菌(Kineococcus radiotolerans)、Oceanobacillusiheyensis、火球菌(Pyrococcus abyssi)、Porochlorococcus marinus、普通变形杆菌(Proteus vulgaris)、红育菌(Rhodoferaxferrireducens)、Saccharophagus degradans、肺炎链球菌(Streptococcus pneumoniae)、聚球蓝细菌属的物种(Synechococcussp.)。
4.根据权利要求1-3的微生物,其中编码被称为赖氨酸/尸胺反向转运蛋白的蛋白质的多核苷酸源自于选自大肠杆菌、嗜酸热原体、或者霍乱弧菌的微生物。
5.根据权利要求1-4的微生物,其为埃希氏杆菌属或者芽孢杆菌属或者棒状杆菌属的重组菌株、特别是棒状杆菌属的重组菌株。
6.根据权利要求1-5的微生物,其中编码赖氨酸脱羧酶和被称为赖氨酸/尸胺反向转运蛋白的蛋白质的多核苷酸源自于大肠杆菌属物种的微生物。
7.根据权利要求1-6的微生物,其中通过同未转化微生物相比较使上述多核苷酸的拷贝数增加至少一个或者通过上述的多核苷酸与同初始菌株相比更强的启动子的结合而进行过表达。
8.根据权利要求1-7的微生物,其为棒状杆菌微生物且其中一种或多种选自下列的来自棒状杆菌的基因同时地被增强或者过表达:
a)编码二氢吡啶二羧酸合成酶的dapA基因,
b)编码甘油醛-3-磷酸脱氢酶的gap基因,
c)编码葡萄糖-6-磷酸脱氢酶的zwf基因和它们的等位基因,
d)编码丙酮酸羧化酶的pyc基因和它们的等位基因,
e)编码苹果酸-醌氧化还原酶的mqo基因,
f)编码抗反馈天冬氨酸激酶的lysC基因和它们的等位基因,
g)编码Zwa1蛋白的zwa1基因。
9.根据权利要求1-8的微生物,其中编码L-赖氨酸输出蛋白质的lysE基因被减少或关闭。
10.根据权利要求1-7的微生物,其为埃希氏杆菌属的微生物,其中一种或多种选自下列的来自大肠杆菌的基因同时地被增强或者过表达:
a)编码抗反馈天冬氨酸激酶的基因或者等位基因,
b)编码二氢吡啶二羧酸合成酶的基因,
c)编码二氢吡啶二羧酸还原酶的基因,
d)编码琥珀酰二氨基庚二酸转氨酶的基因,
e)编码琥珀酰二氨基庚二酸脱酰基酶的基因。
11.根据权利要求1-10的微生物,该微生物在被赖氨酸脱羧酶基因转化之前能够产L-赖氨酸。
12.包含编码赖氨酸脱羧酶多核苷酸和/或编码被称为赖氨酸/尸胺反向转运蛋白的蛋白质的多核苷酸的载体或者质粒。
13.根据权利要求12的载体或者质粒,其中所述多核苷酸源自于大肠杆菌。
14.一种生产尸胺的方法,其中:
a)根据权利要求1-11的微生物在形成尸胺的条件下在培养基中进行发酵,
b)尸胺在所述微生物的细胞中或者在发酵培养基中累积。
15.根据权利要求11的方法,其中
a)尸胺被分离,其中,视需要
b)发酵液的其它溶解组分和/或全部或量为≥0-100%的生物量保留在被分离的产物中。
16.根据权利要求14或15的方法,其中使用棒状杆菌。
17.根据权利要求14或15的方法,其中使用埃希氏杆菌属的微生物。
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DE102007005072A DE102007005072A1 (de) | 2007-02-01 | 2007-02-01 | Verfahren zur fermentativen Herstellung von Cadaverin |
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EP (1) | EP2121899A1 (zh) |
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CN102424811A (zh) * | 2011-12-13 | 2012-04-25 | 天津科技大学 | 一种产尸胺工程菌 |
WO2012114256A1 (en) * | 2011-02-22 | 2012-08-30 | Basf Se | Processes and recombinant microorganisms for the production of cadaverine |
CN102753682A (zh) * | 2009-12-17 | 2012-10-24 | 巴斯夫欧洲公司 | 用于生产尸胺的方法和重组微生物 |
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Also Published As
Publication number | Publication date |
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MX2009005666A (es) | 2009-06-15 |
DE102007005072A1 (de) | 2008-08-07 |
WO2008092720A1 (de) | 2008-08-07 |
CA2670074A1 (en) | 2008-08-07 |
EP2121899A1 (de) | 2009-11-25 |
JP2010517519A (ja) | 2010-05-27 |
US20110039313A1 (en) | 2011-02-17 |
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