CN1756835A - 用作选择标记的转位酶 - Google Patents
用作选择标记的转位酶 Download PDFInfo
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- CN1756835A CN1756835A CNA2004800057644A CN200480005764A CN1756835A CN 1756835 A CN1756835 A CN 1756835A CN A2004800057644 A CNA2004800057644 A CN A2004800057644A CN 200480005764 A CN200480005764 A CN 200480005764A CN 1756835 A CN1756835 A CN 1756835A
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Abstract
本发明涉及一种选择微生物的体系,其主要失活转位酶,并通过相同的因子恢复所述的失活,其中所述的因子通过载体可用于各个细胞。所述的发明体系特别适用于通过微生物菌株的细胞培养制备蛋白质的方法,其特征在于所述的选择体系、位于恢复载体上的各种转基因。所述的发明还涉及各种有机体以及转录酶基因和载体的用途,特别是革兰氏阳性或者革兰氏阴性细菌的<I<secA</I>基因,例如<i>地衣芽孢杆菌。
Description
本发明涉及微生物的选择体系,其基于关键转位酶的失活和通过相同作用的因子消除该失活,所述因子通过载体用于有关细胞。
需要大量的蛋白,这些蛋白当中,特别是用于工业应用领域的酶,如今通常通过微生物发酵获得。对天然产生所研究蛋白的微生物而言,遗传修饰生产菌株的重要性日益显著。现有技术早已经建立了这类用于蛋白质生产的遗传工程方法。其原理在于所研究蛋白的基因作为转基因结合到宿主细胞中,被这些细胞转录和翻译,并任选分泌穿过细胞膜进入细胞周质或周围介质中。然后它们可从有关细胞或培养上清液中获得。
在用于蛋白质生产的工业生产方法中,首先利用微生物用于合成蛋白和任选地用于分泌所述蛋白的天然能力。基本上,选择用于蛋白质生产的细菌体系是发酵中价格低廉的,其可以从一开始实现高的待生产的蛋白产品形成率和保证正确的折叠、修饰等等;后者由于与生物体原来生产所研究蛋白的关系增强从而是更为可能的。特别建立用于本目的的宿主细胞是革兰氏阴性细菌,例如大肠杆菌(Escherichia coli)或克雷伯氏杆菌属(Klebsiella)或***,例如葡萄球菌(Staphylococcus)或杆菌(Bacillus)属的种类。
生物技术方法的经济性主要依赖于可达到的蛋白产量。除了采用的表达体系外,产量取决于采用的方法,特别是依赖于发酵参数和基质。通过优化表达体系和发酵方法,可以明显增加生产生物体的潜力和可实现的产量。
此外,表达体系基本上被开发,并根据两个根本上不同的遗传结构进一步开发。另一方面,待生产蛋白的基因被整合到宿主生物体的染色体中。这类构建体在不加以选择(见下文)的条件下对附加的标记基因是非常稳定的。缺点是该基因只有一个拷贝存在于宿主中,通过基因剂量效果整合更多的拷贝以提高产品形成率是以非常复杂的方式***地布置。现有技术可以简要地解释如下。
欧洲专利EP 284 126 B1解决稳定的多重整合的问题,在于大量基因拷贝结合进细胞中,所述细胞在拷贝之间包含内源的和关键的染色体DNA片段。
另一个稳定的多重整合的解决方案在专利申请WO 99/41358 A1中公开。据其所述,所研究基因的两个拷贝以相反转录方向整合并通过非必需的DNA片段分开,这样以免两个拷贝同源重组。
从专利申请DD 277467 A1,生产细胞外酶的方法基于所述酶的基因编码稳定有利地多重整合到细菌染色体中。整合作用通过同源区域发生。为调控成功的整合作用,使用包含在质粒上的红霉素基因,其由成功的整合作用失活。
根据DE 4231764 A1的说明书,整合到染色体中可以通过胸苷酸合成酶基因的单交换或双交换而实现。后者允许调控该方法,因为对于单交换,胸苷酸合成酶活性得以保持,而双交换中该活性丧失,也就是说获得营养缺陷体。伴随单交换,在该特定体系中具有对抗生素三甲氧苄二氨嘧啶的抗性,而双交换则对应对抗生素敏感。
在申请WO 96/23073 A1中,公开了为整合多拷贝所研究基因到细菌染色体中的基于转座子的体系,其特征在于质粒的标记基因通过整合作用删除,从而包含的菌株不含抗性标记。此外,根据说明书,标记物只有在控制所需菌株的构建时是需要的。
此外在申请WO 01/90393 A1中也公开了提高某些转基因整合到细菌染色体中拷贝数的体系。
第二种构建生产菌株的方法在于对所研究基因传递自主复制元件,例如质粒,如此将其传递到宿主生物体。通常在这种情况下每个细胞的高质粒拷贝数通过基因剂量作用具有有益的效果。整个培养期施加选择压力以将质粒保留在细胞中是不利的。默认的是,施加选择压力通过添加抗生素到培养基中而进行,而给予有关物质抗性的基因被传递给质粒。从而只有具有足够数量的该质粒细胞能够生长。
抗生素抗性用作选择标记近来日益收到批评。一方面,应用抗生素实际上是昂贵的,特别是如果抗性基于酶降解抗生素,而且有关物质必需在整个培养期间增加。另一方面,其普遍的应用,特别是在其他的技术领域,导致抗性基因散布到其他菌株,甚至到病理菌株。由于多重抗性的人病源菌株的存在,这已经使得例如内科卫生学和特别地在传染性疾病处理中相当困难。
因此,在很大程度上为稳定地整合基因到生产细胞的染色体中,对上述体系进行复原,因为这些质粒在没有持久的选择压力下是稳定的。然而,如上所述的有关菌株只能通过昂贵的花费制备。在生物工程实践中,将例如具有选择标记的质粒上新发现的或修饰的基因结合到宿主细胞中并用这样的方式表达它是更快和更方便的。
在现有技术中,同时还开发了无抗生素的选择体系。例如,在出版物J.Bacteriol.,Volume 172,6557-6567页(1990)中Herrero等的“Transposon vectors containing non-antibiotic resistence selectionmarkers for cloning and stable chromosomal insertion of foreign genes ingram-negative bacteria”,描述了对除草剂和重金属的抗性作为选择标记。然而对这些化合物的应用有着和抗生素应用类似的顾虑。
通过营养缺陷体的选择,例如,通过使有关细胞取决于某些代谢产物的供应,作用原则上与对抗生素的选择相似。营养缺陷型的菌株然后接受,与消除该营养缺陷体的所研究的转基因结合。就损失来说,在合适的培养条件下它们将同时丧失成活力,从而对所需的营养缺陷体生产者进行选择。例如,在出版物Netherlands Milk and DairyJournal,Volume 40,(1986)141-154页中de Vos的“Gene cloning in lacticstreptococci”中,参考例如148页从乳链球菌代谢产生的不同选择标记;这些当中是来自乳链球菌的乳糖代谢、铜抗性和不同细菌素抗性基因的选择标记。专利EP 284126 B1,其考虑所研究基因稳定整合到细菌染色体的问题(参见上面),该专利文献在第7页以术语″生存选择″总结了可能用于选择的营养缺陷体、抗微生物剂抗性和对病毒感染抗性体系。这里提到的营养缺陷型选择标记的例子是新陈代谢基因leu、his、trp“或类似的”;显而易见是指来自氨基酸合成途径的基因。
但是在实践中,这类营养缺陷体的应用到目前为止是非常有问题的,因为特别是在工业发酵介质中,几乎所有的必需基质都是足量的,有关细胞可以通过从培养基吸收相同的化合物而补偿某特定化合物合成的不足。
例外迄今仅是必需的胸腺嘧啶脱氧核苷,其在工业发酵介质中只以痕量存在,因此必需通过胸苷酸合酶从增殖的并因而合成DNA的生物体形成。
因此EP 251579 A2的应用提供采用对核苷酸代谢必要的胸苷酸合酶基因缺陷的宿主菌株的解决方案。据文献所述通过载体有可能使该基因(来自Escherichia coli K12的thyA)精确地用于所述功能并消除基因缺陷。如果这些载体另外带有所研究蛋白的基因,可以产生对生产者细胞类似于抗生素的选择。
概括地说,应该理解在现有技术中尽管存在大量生物工程生产蛋白的经验,并且通过染色体整合和抗生素选择表达所研究基因是***性可调控的,对于这两个体系迄今没有同样好的实际应用的替换物存在,特别是不存在比染色体整合复杂性小且同时无需通过昂贵的或有生态问题的化合物进行选择。特别是,对于工业惯常的复合培养基,通过营养缺陷型标记选择的方法目前只得到非常不充分的结果。
因此本发明的目的是开发新的选择体系,其与通过抗生素的选择具有可比较的简便性,并且无需通过昂贵的和某些情况下环境有害的物质进行选择。它应该可在工业规模上利用。它不应该基于这样的必需基因,所述基因在工业介质中不存在时可通过污染物补偿。
根据本发明上述目的通过微生物的选择而实现,其特征在于
(a)编码必需转位活性的内源性存在的基因被失活,和
(b)根据(a)必需转位活性的失活通过载体得到消除。
令人惊讶的是,已经公认转位涉及的关键因子适合用于选择。对于选择,使用根据发明的基因,其衍生的蛋白包括在蛋白转位中作为有关细胞必需的因子。这表明缺乏该基因是致命的,因此微生物的抗生素样选择是可能的。
该选择体系运行无需添加剂(例如,现有技术已知的抗生素),且原则上作用时不受营养培养基组成的影响。为此,对所研究微生物进行分子生物学修饰是必需的,其按照转位的细节进行描述并且在本申请的实施例中阐述。
转位过程包括由细菌形成的蛋白分泌到周质中(就革兰氏阴性细菌而言)、或到周围介质中(就革兰氏阴性和***两者而言)。其描述于,例如A.J.Driessen(1994)的论文:“How proteinns crossthe bacterial cytoplasmic membrane”in J.Membr.Biol.,
142(2),pp.145-59。为此所必需的分泌装置由一系列不同的、主要是膜-相关的蛋白组成,其在本申请的图1中显示。这些包括,特别是,蛋白SecA、SecD、SecF(共同作为复合SecDF),E、G和Y较好地表征,例如枯草杆菌(Bacillus subtilis)(van Wely,K.H.,Swaving,J.,Freudl,R.,Driessen,A.J.(2001):“Translocation of proteins across the cell envelopof Gram-positive bacteria”,FEMS Microbiol Rev.2001,
25(4).,pp.437-54)。被认为是体系一部分的其它因子是YajC,其同样地与Sec复合物直接接触,且在图1中确认了因子Bdb(Dsb)、SPase(为″信号肽酶″)、PrsA和b-SRP(Ffh,Ffs/Scr、SRP-RNA)。
前面提到的因子是细菌因子,其原则上起着与最初在真核生物中描述的SRP(信号识别粒子)相同的作用。其亚基是Ffh因子,特征来自枯草杆菌(B.Subtilis)和大肠杆菌(E.coli)。b-SRP相邻的亚基在枯草杆菌中被称为Scr,在E.coli中被称为Ffs。此外,RNA(SRP-RNA)是功能b-SRP复合物的一部分。功能上与此联合的其他因子在大肠杆菌中被称为Srb和在枯草杆菌中被称为FtsY。就其功能对应于真核的停靠蛋白。
在另外的背景中,例如还包括因子PrfB(肽链释放因子B;也叫RF2)。它已知为蛋白合成装置的一部分,即,既在***又在革兰氏阴性细菌中。与翻译相关,它功能特别地是脱离刚翻译的核糖体,即翻译的终止。由于prfB基因在许多细菌中与因子SecA的基因同时转录,因而只间接地提供与上述转位的关系。从而具有调控关系。
转位的前提是待释放的蛋白具有N-末端信号肽(Park,S.,Liu,G.,Topping,T.B.,Cover,W.H.,Randall,L.L.(1988):“Modulationof folding pathways of exported proteins by the leader sequence”,Science,
239,pp.1033-5)。这适用于细胞外的蛋白和膜蛋白。
当翻译在核糖体上进行后,得到的肽链通过具有伴护作用的胞浆蛋白保持解折叠的状态并运输到膜。肽的穿膜运输随着消耗ATP而被催化(Mitchell,C.,Oliver,D.(1993):“Two distinct ATP-bindingdomains are needed to promote protein export by Escherichia coli SecAATPase”,Mol.Microbiol.,
10(3),pp.483-97)。这里SecA作为多酶复合物转位酶的能量供给组分(ATPase)。在穿膜以后,信号肽通过信号肽酶的活性***,细胞外的蛋白以这样的方式与膜分离。就***而言,外蛋白(exoproteins)以这样方式释放直接进入周围介质。就革兰氏阴性细菌而言,随后通常在周质空间发现该蛋白,并需要另外的修饰以实现其释放到周围介质中。
B.v.d.Berg等近期的研究(2004;Nature,Volume 427,36到44页)描述了转位酶的x-射线结构,即在其他生物体中作为对应复合物模型的詹氏甲烷球菌(Methanococcus jannaschi)中的SecY复合物。
因此该方法的中央分子是转位酶蛋白前体,由SecA、SecY、SecE、SecD、SecF(SecDF)和SecG亚单位组成。因为ATPase控制该过程,因子SecA对转位具有决定性的作用。本发明的优选实施方案的特征是这些因子(见下文)。
在下面的表1中,目前已知包括在转位中的因子根据它们在两种模式生物体大肠杆菌(革兰氏阴性)和枯草杆菌(格兰氏阳性)之一中是否是必需的而进行分类。如果这些因子中的一个在各种情况下的有关生物体中是必需的,那么其适合于本发明的选择。基本上,由此可以假定对应的模式还存在于其他的生物体,特别是革兰氏阴性和***。
表1:目前已知包括在革兰氏阴性和***转位中的蛋
白因子,根据它们在这些生物体中是否是需的而进行分类。
大肠杆菌 | 枯草杆菌 | |
SecA | 必需的 | 必需的 |
SecY | 必需的 | 必需的 |
SecE | 必需的 | 必需的 |
SecG | 非必需的(冷敏感表型) | 非必需的(过量生产输出蛋白的冷敏感表型) |
SecD、SecF(SecDF) | 必需的 | 非必需的(冷敏感表型) |
信号肽酶 | 必需的 | 非必需的,以冗余形式存在 |
b-SRP(Ffh;Ffs/Scr;SRP-RNA) | 必需的 | 必需的 |
FtsY/Srb | 必需的 | 必需的 |
PrsA | 不存在 | 必需的 |
Bdb/Dsb | 非必需的 | 非必需的 |
YajC | 必需的 | 不知道是否是必需的,但以冗余形式存在 |
根据本发明在革兰氏阴性细菌,特别是在大肠菌类细菌中,更具体是在大肠杆菌中,可通过下列转位酶或它们的相关基因进行选择:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或FfS)、Srbor YajC。
根据本发明在***,特别是在杆菌中,更具体是在枯草杆菌中,可通过下列转位酶或它们的相关基因而选择:SecA、SecY、SecE、b-SRP(Ffh或Scr)、FtsY或PrsA。
这些列表中的限定或连接语不应理解为排他的。技术上而言,其应该还可能同时关闭一些相关的基因。然而根据本发明,只选择一个就足够。
在各种情况下,相关基因的单独序列可以从例如下列可访问的数据库获得:GenBank(National Center For Biotechnology InformationNCBI,National Institute of Health,Bethesda,MD,USA;http://www3.ncbi.nlm.nih.gov);EMBL European Bio-informatics Institute(EBI)in Cambridge,Great Britain(http://www.ebi.ac.uk);Swiss-Prot(Geneva Bio-informatics(GeneBio)S.A.,GeneVa,Switzerland;http://www.genebio.com/sprot.html);″Subtilist″or″Colibri″of the PasteurInstitute,25,28rue du Docteur Roux,75724Paris CEDEX 15,Francefor genes and factors from枯草杆菌or E.coli(http://genolist.pasteur.fr/SubtiList/or http://genolist.pasteur.fr/Colibri/)。此外,可以求助于通过在提及的数据库交叉引用而获得的数据库。根据本发明,在各种情况下只需要鉴定和恰当地使用设计用于培养的菌株中转位装置的单个必需基因。
本发明序列表中表明的不同微生物SecA因子的序列产生了另外的起点。这些能被直接使用(见下文:优选实施方案)或者用于鉴定基因库中事先已经设计用于所研究微生物的同源体。
这些转位酶或因子主要被理解为表示野生型分子。但是,如果有可能制备原理上在转位装置中具有与野生型酶相同作用的变体,则根据变体构建的选择体系另外地也包括在保护范围内。
为实现本发明,设计用于培养的菌株,如果它不属于本申请研究的种类中的一种,则必需首先确认是否至少一种因子对其是必需的。有可能以简单的方式实现,例如通过从菌株除去一种这些已知的基因,所述菌株是尽可能紧密相关的(例如相似的革兰氏阴性或***),或借助于通常可进入的数据库的条目而合成并将它整合到基因敲除的载体中。这类方法通常是所属技术领域的专业人员公知的。如果用所述载体转化和随后这些基因的同源重组物进入宿主细胞的基因组具有致死效应,优选与转化分开启动,则该基因被认为是必需的。根据本发明和特别地根据本申请实施例的模型,认为是必需的基因可以用作选择标记。
根据特征(a)进行必需的失活,例如通过对已经被引入到所研究微生物菌株细胞中的失活基因拷贝的同源重组,例如通过用合适的载体进行转化。该方法本质上是已知的。作为重组事件的结果,基因的染色体拷贝被完全或部分删除,从而不会起作用。这可以通过例如已经事先进行致死性检测的相同基因进行。然而优选,假定内源同源染色体是已知的或可以用合理的花费分离,那么其可用于达到高的重组成功率。失活是否成功对本发明的完成是决定性的。
这个概念可以通过,例如,具有温度敏感性的复制起点和待删除的基因同源DNA区域被另外***到其中的质粒载体(删除载体)来实现。可逆的失活,例如,将还可能通过可移动的遗传成分例如转座子的整合作用进入到靶基因中而实现。
在本文中,在各种情况下均应考虑特征(b),即,甚至在重组或失活事件前,或最迟同时,在有关细胞中制备用于本发明选择的基因完整的拷贝,因为,否则的话所述细胞将不能从失活作用中存活。根据本发明,产生的缺陷通过载体来弥补,即载体能消除失活。在这方面,如上所述,优选使用内源性存在于宿主细胞并根据(a)删除的基因。然而,还可以采用来自其他生物体的功能相同的基因,优选相关的菌株,只要它们能够消除所研究的缺陷。因此有可能,例如,通过提供来自肉葡萄球菌(Staphylococcus carnosus)的secA基因消除枯草杆菌SecA的缺陷。
还可能通过载体,消除第一个缺陷的另一种遗传成分被带进细胞,例如功能基本相同但经过突变修饰的因子的基因。
在该细胞中,存在通过单独的遗传因子补偿致死缺陷的情况是占优势的。所述单独的遗传因子的缺失将是致死的,所以这种细胞被迫在任何细胞***情况下将该元件传递给后代。
在优选实施方案中特征(c)利用这一点(见下文),据上所述补偿基因缺陷的载体携带所述转基因,所研究蛋白的基因将根据本发明的方法精确制备。
在某种程度上内源的选择压力占优势,无需添加外部必需的其他化合物例如重金属或抗生素,即通过培养基来避免丧失具有转基因的载体。另一方面,开始论述为整合转基因本身进入染色体DNA而进行复杂的修饰是不适用的。例如,已制备的微生物菌株使用类似构建的载体而用于新的转化,其每次能利用相同的作用消除基因缺陷,其中制备所述的微生物菌株用于转位装置确定的失活,但在各种情况下携带不同的转基因。因此可获得非常实用且可以多种方式使用的选择体系。
根据本发明选择方法的目的在于获得在细胞中经多个世代保持稳定的遗传元件。精确地讲该元件是载体,通过其来补偿必需转位活性的失活,即消除。
在优选的实施方案中,根据本发明的选择方法特征在于(c)根据(b)的载体携带转基因。
那么,这是选择体系技术上最重要的应用。经多个世代稳定的遗传因子是携带转基因的,特别地是其基因产物具有商业价值的转基因。优选的实施方案如下进行。
在优选的实施方案中,根据本发明的选择过程的特征在于必需的转位活性是以下因子中的一个:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或Ffs/Scr)、FtsY/Srb、PrsA或YajC。
如表1中所述,这些因子或相关的基因是从大肠杆菌或从枯草杆菌已知必需的那些基因。因此,特别是在这两种生物体中,而且在相关的乃至较少相关的种类中,根据本发明通过有关同源体建立选择体系是显而易见的。因为众所周知在各种情况下即使是这些基因的单个构件也可以代替另一个生物体中涉及的功能,就是说超过了革兰氏阴性/革兰氏阳性的限度,根据本发明至少甚至来自很远相关物种有关基因的单个构件应该可以使用。
优选,必需的转位活性是蛋白前体转位酶以下亚基中的一种:SecA、SecY、SecE、SecD或SecF,优选是SecA亚基。
如图1所示,在某种程度上这些因子代表转位装置的功能核心。对于SecA,正如已经在上述中另外说明的,该因子占据ATP酶活性的关键位置。因此,在本申请的实施例中,本发明还可以借助secA基因进行变换。
优选,本发明选择过程的特征在于根据(b)发生通过与失活的内源性存在的必需转位活性相同的活性而消除,优选通过遗传相关的活性,特别地优选通过同一活性。
据反映由于通常有关因子在物种之间具有高同源值,来自较少密切相关物种的有关基因也具有应用前景。然而,当然来自更紧密相关的物种的基因和很特别地来自相同生物体的基因是更优选的,因为就失活所必需的交换而言这些基因是最有前景的。可以再次指出只有单个基因适于失活对根据本发明实现选择是足够的。
如上所述,有关DNA和氨基酸序列可从通常可进入的数据库获得。例如,来自来自Pasteur Institute的″Subtilist″数据库(参见上面)在SEQ ID NO.1和2序列列表中表示的枯草杆菌SecA蛋白序列已经除去(日期:2003年2月3日);上述序列与Swiss-Prot(参见上面)登记号码为P28366的序列完全一致。
序列表明SEQ ID NO.3和4代表的来自大肠杆菌SecA蛋白的序列方案来源于Pasteur Institute的″Colibri″数据库(参见上面;日期:2003年2月3日);这与Swiss-Prot(参见上面)登记号码为P10408的序列完全一致。
地衣芽孢杆菌(B.licheniformis)的SEQ ID NO.5和6如本申请实施例1的描述从商业可购买的菌株地衣芽孢杆(DSM13)中获得(Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,Mascheroder Weg 1b,38124 Brunswick;
http://www.dsmz.de)。
因为物种枯草杆菌、大肠杆菌和地衣芽孢杆菌是技术上最经常采用的微生物,这些细菌对于实现本发明的方法特别重要。使用本申请的序列表,能够利用来自这三个最重要生物体的同源secA基因,而不必将它们分离用于复制。通过这些基因,有可能例如鉴定其他微生物中的有关同源染色体,例如通过制备基因库和使用这些基因中的一种作为探针进行筛选。但特别是在有关的物种中,还有可能采用这些基因本身用于本发明的失活。
因此优选实施方案的特征在于根据(b)的消除通过来自枯草杆菌、大肠杆菌和地衣芽孢杆菌的secA基因的区域恢复转位活性而实现,其分别见于SEQ ID NO.1,SEQ ID NO.3和SEQ ID NO.5的序列表。
优选的方法特征还在于发生根据(a)的失活,以使在根据(a)失活的基因区域和载体上根据(b)的同源区域的重组被阻止,优选完全失去包含在有关染色体基因中的基因区域。
如果载体被整合进宿主细胞的染色体,致死突变将被永久消除,而无需同时存在有关载体上的选择压力。通过这种方法,所真正关注的转基因可能通过后续的细胞分离而丧失。在失活步骤(a)中的广泛删除可以防止这一点。
在现有技术中,特别是出版物J.Biotechnol.,Volume
19,221-240页(1991)中J.Vehmaanper_ et al.的“Genetic manipulation of Bacillusamyloliquefaciens”,描述了通过删除载体进行基因失活的方法。借助上述的描述,有可能在实施例3中从地衣芽孢杆菌成功地删除secA基因。该删除载体的复制起点的特点在于其是温度依赖性的。
因此,在相对低的温度下首先选择成功的转化,然后通过提高温度对成功的整合施加选择压力(即失活内源基因)是非常简单的。类似的,例如通过添加低分子量化合物构建体用作对照也是可能的。
因此根据本发明优选的方法特征在于根据(a)的失活通过删除载体而进行,优选通过具有外源可调控复制起点的删除载体,特别优选通过具有温度依赖性的复制起点的删除载体。
如上所述,原理上有可能(b)包含转基因的消除载体被整合到细菌染色体中。然而,这种情况下存在转基因永久丧失的危险,优选的方法特征在于根据(b)的载体是在微生物中自主复制的质粒。其可以在衍生的细胞系中复制其自身。
如果该质粒是多拷贝数(例如每细胞2到100)自我复制的质粒则是非常有利的,优选多拷贝数(每细胞大于100质粒)。存在的拷贝数越多,消除越可能成功。此外,当载体携带有编码所研究蛋白的转基因时,其可以通过基因剂量效应增加该产品的产量。
由于革兰氏阴性细菌的重要性,特别是在基因或基因产物的克隆和定性时,优选的选择方法特征在于微生物是革兰氏阴性的细菌菌株。
其中,特别地,应当理解方法的特征在于涉及的是革兰氏阴性大肠杆菌属或克雷伯杆菌属(Klebsiella planticola)的细菌,特别地是大肠杆菌K12,大肠杆菌B的衍生物或植生克雷伯杆菌的衍生物,以及非常特别地是E.coli BL21(DE3)、E.coli RV308,E.coli DH5α,E.coliJM109,E.coli XL-1或植生克雷伯杆菌(Klebsiella planticola)(Rf)的衍生物。这些是分子生物学中最常用的生物体。
特别对发酵生产蛋白而言,***是特别重要的。一定程度上这适用于分泌的蛋白。因此根据本发明优选的方法特征在于微生物是革兰氏阳性的细菌菌株。
这些当中,特别是在工业上,金黄色葡萄球菌(Staphylococcus)属、棒状杆菌(Corynebacteria)属或芽孢杆菌(Bacillus)是已经建立的,特别是肉葡萄球菌(Staphylococcus carnosus),谷氨酸棒杆菌(Corynebacterium glutamicum),枯草杆菌(Bacillus subtilis),地衣芽胞杆菌(B.licheniformis),解淀粉芽孢杆菌(B.amyloliquefaciens),克鲁伯氏芽孢杆菌(B.globigii)或缓慢芽孢杆菌(B.lentus),及非常特别地,地衣芽胞杆菌或解淀粉芽孢杆菌的衍生物,这些决定了对应优选选择方法的特征。
特别感兴趣的是涉及通过培养微生物而产生特定产物的本发明的方法。因此对应地优选的选择方法是特征为根据(c)的转基因是编码非酶蛋白的那些方法,特别是药物相关蛋白,非常特别的是胰岛素或降钙素。
然而,酶也是在工业上是非常重要的。因此,根据本发明这些方法还要求保护特征在于根据(c)的转基因是编码酶的转基因,优选编码水解酶或氧化还原酶,特别优选蛋白酶、淀粉酶、半纤维素酶、纤维素酶、脂肪酶、角质素分解酶(cutinase)、氧化酶、过氧化物酶或漆酶。其中,优选生产用于去污剂和清洁剂的代表性的酶阐述如下。
一般来说,这类组合物可以用于提高现有技术中所有酶的去污或清洁效力。在这些蛋白酶中,枯草杆菌类的酶是优选的,例如缓慢芽孢杆菌的碱性蛋白酶。来自缓慢芽孢杆菌DSM 5483(WO 91/02792 A1)的蛋白酶派生出使用BLAP_作为名称的变体,其详细在WO 92/21760A1,WO 95/23221 A1,WO 02/088340 A2和WO 03/038082 A2中描述。来自不同的芽孢杆菌属sp.和克鲁伯氏芽孢杆菌的另外的可根据本发明制备的蛋白酶从以下专利申请显而易见地得到:WO 03/054185A1,WO 03/056017 A2,WO 03/055974 A2和WO 03/054184 A1。
可以根据本发明制备的淀粉酶的例子是来自地衣芽孢杆菌、解淀粉芽孢杆菌或嗜热脂肪杆菌芽孢(B.stearothermophilus)的α-淀粉酶,和它们改进的进一步发展,特别用于去污剂和清洁剂的应用。此外在专利申请WO 02/10356 A2公开了来自芽孢杆菌sp.A 7-7(DSM 12368)的α-淀粉酶和在申请WO 02/44350 A2中描述的来自B.agaradherens(DSM 9948)大环糊精葡聚糖转移酶(CGTase)重点用于此目的。此外,属于α-淀粉酶序列部分的分解淀粉酶是本申请的重点,其在申请WO03/002711 A2中定义,且在WO 03/054177 A2中有描述。同样地,提及到分子的融合产物指例如来自申请DE 10138753 A1的产物。
根据本发明,还可以生产脂肪酶或角质素分解酶,例如那些原先可从Humicola lanuginosa(Thermomyces lanuginosus)获得的酶,或进一步发展的脂肪酶,特别是那些具有氨基酸交换D96L的酶或其起始酶分离自门多萨假单胞菌(Pseudomonas mendocina)和茄病镰孢(Fusarium solanii)的脂肪酶或角质素分解酶。
此外,其特别地设计用于纺织品的工业处理和用于依赖纤维素酶例如葡聚糖内切酶和/或纤维二糖水解酶的清洁剂。例如,也通过来自天然生产者生产的纤维素酶是来自芽孢杆菌sp.CBS 670.93和CBS669.93的那些,如WO 96/34092 A2的公开。此外,也可根据本发明生产以术语半纤维素酶概括的另外的酶。这些包括,例如,甘露聚糖酶、黄原胶裂解酶、果胶裂解酶(=果胶胸)、果胶酯酶、果胶酸盐裂解酶(=木聚糖酶)、支链淀粉酶和β-葡聚糖酶。
去污剂和清洁剂酶同样地包括氧化还原酶,例如氧化酶、氧酶、过氧化氢酶、过氧化物酶,例如盐、氯、溴、木质素、葡萄糖或锰过氧化物酶、二氧酶或漆酶(酚类氧化酶、多酚氧化酶)或所有在现有技术描述用于这些应用领域的其他酶。
如同引言中解释的,构成本发明基础的发明目的特别明显地依赖于大规模发酵的背景。因为准确地讲,其缺点表现为一方面,通过抗生素选择是昂贵的和从环境观点来看是有问题的,另一方面根据代谢缺陷症的营养缺陷型可以由于工业培养基的复杂性而得到补偿。
因此根据本发明的选择方法转化为大规模的方法是特别重要的,例如用于低分子量化合物例如抗生素或维生素的生产或很特别地用于蛋白质生产过程。
通过培养微生物菌株细胞生产蛋白的方法是现有技术公知的。它们基于的事实是:以适合的方式培养细胞,其天然地或用有关基因转化后生产所研究的蛋白,优选被刺激以形成所研究的蛋白。
因此通过培养微生物菌株细胞生产蛋白的方法形成本发明的另一个主题,特征为采用前述的选择方法。这一点上,尤其是上述的实施方案强调消除载体本身包含转基因,该转基因优选编码非酶蛋白或酶。其中,特别有必要了解商业上重要的蛋白。因此,转基因生产胰岛素被用于治疗糖尿病,使用许多酶,蛋白酶、脂肪酶和淀粉酶以至氧化酶来生产去污剂和清洁剂。
由于简单的工业操作性能,如果在载体上能获得所研究的转基因和消除基因,那些根据本发明的蛋白质生产方法是优选的,其特征在于根据(c)的转基因编码通过该方法生产的蛋白。
原则上,细菌能被用在固体表面上。这对检测它们的代谢性质或在实验室规模持续培养是特别重要的。为生产蛋白,另一方面,特征为微生物培养发生在液体培养基中优选在发酵罐中的方法是优选的。这类技术在现有技术中是普遍的,并且准确地通过本发明中由必需的转位因子通过转化来选择得到进一步发展。
特别重要的是特征为所研究的蛋白分泌到周围介质中的蛋白质生产方法。用这种方法获得的产品的发展被显著地促进。然而本发明可能的替换方法也在于裂解所研究的细胞,其制备遵循实际生产的蛋白,从而获得该产物。
原则上,通过对微生物的各自分子生物学转化产生新的菌株。因此,新的微生物菌株还通过本发明的转化产生,确切地说是通过特定的必需转位活性的失活和通过供给相同作用的转位因子消除而不同于起始菌株的那些菌株(更确切地说:不同于起始细胞)。因此使用本发明的选择方法产生新的微生物。
因此已经通过前述的选择方法获得的微生物属于本申请保护的范围。
特别有益的方面在于通过总是进行相同类型的失活和在消除载体上的消除来制备种群相关的微生物,但每次制备另一种转基因。该方法一旦使用成功可用该方式转移无数其他的选择问题。
为实现尤其是上述解释的蛋白质生产方法,必要的是表达转基因。通过这种方法,表征根据本发明优选的微生物。
这些特征当中,根据上述关于蛋白质生产的所述内容,特征在于转基因是分泌的微生物是优选的。
据上所述,只可能发现本发明的选择体系,其中编码转位活性的必需基因被认为是这样的,通过该基因可以进行选择。这些类型基因的使用迄今仍然未被考虑,尽管许多这类基因已知来自于大量微生物。准确地讲这些知识对根据本发明的选择体系是有利的,因为实际上所有微生物基因能通过可实现的合适选择方式来定义。为实现上述目的,它们只需如上所述失活,并被功能同源体在有关细胞中代替。
因此本发明的一个主题是编码微生物选择的必需转位活性的基因的应用,其特征在于
(a)内源性存在于微生物中的该必需转位活性被失活,和
(b)根据(a)的必需转位活性失活通过载体消除。
对应于上述的介绍,以下解释的本发明该主题的实施方案因此是优选的。
(c)如果这些应用的特征在于根据(b)的载体携带转基因,
那么其为特别的分子基因在技术上有意义。
本发明的要点包括任何合适的应用,其特征在于必需的转位活性是以下因子之一:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或Ffs/Scr)、FtsY/Srb、PrsA或YajC。
这些当中,基于具有以下蛋白转位酶亚基之一的必需转位活性的任何应用是优选的:SecA、SecY、SecE、SecD或SecF,优选SecA亚基。
有利的应用在于进行根据(b)的消除,其通过与失活的内源性存在的必需转位活性相同的活性进行消除,优选通过遗传相关的活性,特别优选通过同一活性。
为此,本申请能够获得一些合适的优选起点,即,提及的应用是可能的,其特征特别在于根据(b)的消除通过来自枯草杆菌、大肠杆菌或地衣芽孢杆菌的基因secA的修复转位活性的区域进行,其分别显示在SEQ ID NO1,SEQ ID NO.3和SEQ ID NO.5的序列表中。
特别有利的应用特征在于根据(b)的载体是在微生物中自主复制的质粒。
另外优选的应用特征在于质粒是多于一个的拷贝数、优选多重拷贝数的质粒。
最后本发明还通过提供有合适的载体而实现。因此携带必需转位活性基因和能够表达转基因的载体是想要的,但是,如果其作为单个的转基因出现,则不编码抗生素抗性。
在抗生素抗性的基因是除了根据本发明消除必需转位活性失活的基因之外仅有的转基因的情况下,排除该抗性基因目的是为了不在技术上对本申请加以限制。只有在现有技术中,准确地讲这些是已经描述与根据本发明能被使用的转位蛋白的特征有关,才予以考虑。当然这还包括现有技术中通过最普遍的克隆载体已经测序和克隆的基因,准确地讲是那些包含抗生素抗性基因作为标记的载体。因此,只包含必需转位酶和抗生素标记的载体是现有技术已知的。
对应于上文所述,根据本发明的载体优选特征在于其上包含的转基因,优选设计用于蛋白质生产,编码药理学相关的非酶蛋白或水解酶或氧化还原酶。这些特征在于待表达的基因具备起作用的启动子。当然,本发明中所有这类构造体被包括在保护范围内,其也可编码药理学有利的因子,假定这些载体的存在不通过该性质选择,而是通过必需转位活性选择时,其可以介导抗生素抗性。
根据选择体系的细节,某些载体还代表本发明的优选实施方案。
这些包括特性在于其编码的转位活性能够消除内源性存在于微生物菌株中失活的必需转位活性的适当载体,优选通过遗传相关活性,特别优选通过同一活性。
进一步优选,这些包括其特性在于必需的转位活性是以下因子之一的适当载体:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或Ffs/Scr)、FtsY/Srb、PrsA或YajC。
其中,特性在于必需的转位活性是蛋白前体转位酶的以下亚基之一的载体是优选的:SecA、SecY、SecE、secD或SecF,优选SecA亚基。
根据本申请的教导,进一步优选的载体特性在于必需的转位活性是来自枯草杆菌、大肠杆菌或地衣芽孢杆菌secA基因之一,分别显示在SEQ ID NO.1,SEQ ID NO.3和SEQ ID NO.5的序列表中。
此外,若质粒是在使用的微生物中自主复制的质粒,这是根据本发明载体的有利性质。
就此而论,尤其是由于基因剂量效应,如果质粒特征在于它们是多于一个、优选多重拷贝数质粒的情况是特别有利的。
实施例
所有的分子生物学操作遵循标准方法,例如在如Fritsch,Sambrook和Maniatis的″Molecular cloning:a laboratory manual″,ColdSpring Harbor Laboratory Press,New York,1989,和可比较的相关论文中表明的方法。根据各个生产商详述使用酶和试剂盒。
实施例1
来自地衣芽孢杆菌(B.licheniformis)的secA基因的分离
地衣芽孢杆菌(B.licheniformis)中secA位点的鉴定
为鉴定地衣芽孢杆菌的secA/prfB位点,借助于枯草杆菌prfB-secA基因位点的已知序列通过PCR得到基因探针(Databank″Subtilist″ofthe Pasteur Institute,25,28rue du Docteur Roux,75724Paris CEDEX15,France;http://genolist.pasteur.fr/SubtiList/;日期:2002年8月16日)。该基因位点还显示于图2。获得的探针长3113bp,并另外包括prfB基因氨基末端区域的开始451bp。随后,制备地衣芽孢杆菌的染色体DNA,其可从例如Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH,Mascheroder Weg 1b,38124 Brunswick(http://www.dsmz.de)序号13获得,并作为对照,枯草杆菌的染色体DNA使用不同的限制性内切酶消化,并使用提及的探针进行Southern杂交。在用限制性内切酶MunI处理的地衣芽孢杆菌染色体DNA上,鉴定出大小约5.5kB的单个片段,而使用MunI消化地衣芽孢杆菌的染色体DNA产生地衣芽孢杆菌的期望的片段。
来自地衣芽孢杆菌(B.licheniformis)DSM 13的鉴定区域的克隆
分离相同株系地衣芽孢杆菌的染色体DNA,预先使用MunI消化,并通过琼脂糖凝胶电泳分离大约5.5kB的DNA片段,使用商业上可获得的试剂盒从中提取核酸。MunI切割获得的DNA片段的混合物被连接在与MunI匹配的低拷贝数载体pHSG575的EcoRI切割位置(在Gene(1987),Volume
61,pages(63-74)中S.Takeshita;M.Sato;M.Toba;W.Masahashi;T.Hashimoto-Gotoh的″High-copy-number and low-copy-number vectors for lacz alpha-complementation andchloramphenicol-or kanamycin-resistance selection″)并转化成大肠杆菌JM109(从Promega,Mannheim,Germany得到)。
进行载体编码的抗性选择。另外,蓝/白筛选方法(含80μg/ml X-Gal的选择板)被用于鉴定包含具有***物载体的克隆。在该方法中获得200个克隆,其中有可能通过集落杂交鉴定5个携带地衣芽孢杆菌secA基因的克隆。通过新鲜的Southern印迹分析使用如上所述的探针进行核对,来源于包含携带地衣芽孢杆菌secA基因的MunI片段的pHSG575并包括5.5kB的载体的名称为pHMH1。
限制性分析
克隆的5.5kB区域首先通过限制性作图来确定其特征。为此,使用不同的酶进行pHMH1的单独消化和双消化,并通过Southern印迹分析鉴定那些携带secA/prfB操纵子部分的片段。由此限制性作图的结果补充在5.5kB片段的完整序列之后(见下文),并可以见于图3。
序列分析
图3显示的5.5kB大小的片段根据标准方法测序到子序列。子序列显示与以下来自枯草芽孢杆菌的基因具有强的同源性:fliT(编码鞭毛蛋白)、orf189/yvyD(功能未知)、secA(转位酶结合亚基;ATP酶)和prfB(肽链释放因子2),与枯草芽孢杆菌具有完全相同的基因序列。这些同样显示于图3。
根据这些值,还可以假定来自地衣芽孢杆菌的SecA与来自枯草芽孢杆菌的SecA发挥相同的生化活性,并且从而承担相同的生理功能。因此它被认为是转位所必需的酶。
根据该实施例确定从此派生的DNA序列和氨基酸序列在SEQ IDNO.5或6中给出。因此,翻译在154位开始,并且在2677到2679位为终止密码子。从60到65位或从77到82位的子序列推测上被认为是启动子区域,138到144位推测为核糖体结合位。
实施例2
含secA基因和枯草杆菌蛋白酶基因的质粒的制备
根据实施例1获得的secA基因使用其自己的启动子通过PCR从地衣芽孢杆菌的染色体DNA开始扩增。为此,如图4所示,借助于地衣芽孢杆菌基因的DNA序列选择引物,其在各自的5’端具有BamHI限制酶切位点。通过这种方法,使用这些引物扩增多片段被克隆到质粒pCB56C的酶切位置处。这在专利申请WO 91/02792 A1中描述,并且包含来自缓慢芽孢杆菌(BLAP)的碱性蛋白酶基因。
该克隆策略还显示于图4,产生大小为8319bp的pCB56CsecA载体,除了secA和BLAP基因外,还包含一个编码四环素抗性的基因。
载体pCB56CsecA和用于对照的起始载体pCB56C被转化进地衣芽孢杆菌,主要是pCB56C转化进能形成Sec A的野生型地衣芽孢杆菌(secA)株系中。就pCB56CsecA而言,进行转化以同时失活内源的secA。该方法描述于实施例3。
在该方式中,获得两个菌株地衣芽孢杆菌(ΔSecA)pCB56CsecA和地衣芽孢杆菌(secA)pCB56C,两种都能表达质粒编码的碱性蛋白酶基因。它们在实施例4中进一步研究。
实施例3
地衣芽孢杆菌(ΔsecA)pCB56CsecA菌株的制备
通过删除载体完成secA基因的关闭。该方法遵循J.Vehmaanper_等(1991)在J.Biotechnol.,Volume
19,221-240页的描述。
选择用于secA删除的载体是在相同出版物中描述的pE194质粒。该删除载体的优点在于它具有温度依赖性的复制起点。在33℃时,pE194可以在细胞中复制,从而在该温度首先选择成功的转化。随后,包含该载体的细胞在42℃温育。在这个温度下,删除载体不再复制,且通过两个同源区域(secA的上游和下游区域)中的一个对质粒整合到染色体中的整合作用施加选择压力。通过另一个(第二)同源区域的另外同源重组导致secA的删除。第一个同源区域的重复重组也是可能的。就此而论,载体再次与染色体重组,因此保持染色体的secA。因此secA删除必需在使用酶限制性消化染色体DNA或借助于PCR技术通过扩增区域的尺寸以后在Southern印迹中检测。
为构建删除载体,通过PCR扩增位于secA上游和下游的区域。扩增用的引物和随后克隆用的限制性酶切位点(XbaI和EcoRV)与这些借助于根据实施例1确定的地衣芽孢杆菌secA/prfB位点的DNA序列的选择有关。就SecA删除而言,应该考虑到位于secA下游的prfB与secA处于同一操纵子,也就是说没有其自己的启动子(比较图2)。prfB编码RF2蛋白,其与蛋白生物合成保证蛋白从核糖体的脱离有关。为保证prfB的转录,其对蛋白生物合成是重要的,甚至在SecA删除以后,orf189与其位于secA和下游的secA启动子之前的自己的终止子被扩增,因此prfB可以在secA删除以后直接从secA启动子转录(图5)。
在对照步骤中,扩增的区域(orf189′和prfB′)被克隆到大肠杆菌载体pBBRMCS2中。随后orf189′prfB′构建体的测序表明扩增片段的克隆是正确的。
在下一步orf189′prfB′构建体被重克隆到选择用于删除的枯草芽孢杆菌DB104的pE194载体中(图6)。关于这点,使用根据Chang &Cohen,1979的原生质体转化方法,获得携带删除载体pEorfprfB的转化体。所有的操作在33℃下进行以保证载体的复制。
在下一步,实施例2描述的pCB56CsecA载体被同样地通过原生质体转化方法转化进携带pEorfprfB质粒的地衣芽孢杆菌宿主菌株中。如此获得和使用常规方法鉴定为阳性的转化体随后在42℃时在选择压力(对pCB56CsecA的四环素和对pEorfprfB的红霉素)下选择两个质粒的存在。在该温度下,删除载体不再复制,只有其中载体整合到染色体上的细胞存活,该整合作用在同源或相同区域以最高概率发生。通过在33℃时无红霉素选择压力下培养,随后可诱导删除载体的切除,染色体编码的secA基因完全从染色体除去。
pCB56CsecA质粒保留在细胞中,其介导枯草杆菌蛋白酶合成的能力以及使必需的转位因子secA可以利用。用这样的方式获得的菌株命名为地衣芽孢杆菌(ΔsecA)pCB56CsecA。
实施例4
质粒稳定性的研究
为鉴定携带secA枯草杆菌蛋白酶质粒pCB56CsecA的遗传稳定性,根据实施例2和3获得的两个菌株地衣芽孢杆菌(secA)pCB56C和地衣芽孢杆菌(ΔsecA)pCB56CsecA在不添加抗生素的条件下在摇瓶实验中的液体培养基中的研究。为此,各自从一个单独的克隆开始,在所有情况下过夜培养并使用该14ml LB培养基(根据标准配方)在600nm(OD600)光密度为0.05接种。在100ml Erlenmeyer摇瓶中进行培养。在各种情况下8-16小时后,培养物被接种到14ml新鲜的培养基中,并在其中依次设定OD600为0.05。培养进行8昼夜,在该方法中培养物被接种共计16次。每天,稀释液系列被平板涂布,随机选择获得的克隆转入到蛋白酶检测平板中。结果显示于表2和图7。
表2:转化子地衣芽孢杆菌(secA)pCB56C(对照)和地衣芽孢杆菌(ΔsecA)pCB56CsecA的质粒稳定性,借助于具有蛋白酶活性克隆的各自比例进行检测
地农芽孢杆菌(secA)pCB56C | 地衣芽孢杆菌(ΔsecA)pCB56CsecA | |||||
时间[天数] | 检验克隆的数目 | 具有蛋白酶活性的克隆的比例[%] | 检验克隆的数目 | 具有蛋白酶活性的克隆的比例[%] | ||
总数 | 无蛋白酶活性 | 总数 | 无蛋白酶活性 | |||
1 | 72 | 0 | 100 | 72 | 0 | 100 |
2 | 72 | 0 | 100 | 70 | 0 | 100 |
3 | 72 | 1 | 98.6 | 49 | 0 | 100 |
4 | 52 | 0 | 100 | 52 | 0 | 100 |
5 | 78 | 0 | 100 | 78 | 0 | 100 |
6 | 78 | 1 | 98.7 | 78 | 0 | 100 |
7 | 78 | 1 | 98.7 | 77 | 0 | 100 |
8 | 104 | 6 | 94.2 | 104 | 0 | 100 |
对各培养时间而言,全部地衣芽孢杆菌(ΔsecA)pCB56CsecA菌株的克隆显示蛋白酶活性,而地衣芽孢杆菌(secA)pCB56C单独的克隆不再具有任何蛋白酶活性。这被解释为pCB56C质粒的丢失,该丢失另外通过质粒微制备来核对。
通过这些数据,因此可明确在没有添加抗生素,尤其是没有四环素的LB培养基上,该质粒给予对所述抗生素的抗性,携带secA枯草杆菌蛋白酶的pCB56CsecA质粒在ΔsecA菌株中是稳定的,而枯草杆菌蛋白酶pCB56C质粒在没有染色体secA删除的菌株中在培养过程中丢失。来自地衣芽孢杆菌的secA基因可以因此消除染色体secA在转入到表达载体中的不足,且用这样的方式可以选择表达另外蛋白基因的细菌培养,在这种情况下为碱性蛋白酶。
序列表
<110>汉高两合股份公司
<120>用作选择标记的转位酶
<130>SCT053012-46
<140>
<141>
<150>DE10309557.8
<151>2003-03-04
<160>6
<170>PatentIn Ver.2.1
<210>1
<211>4148
<212>DNA
<213>Bacillus subtilis
<220>
<221>CDS
<222>(544)..(3069)
<400>1
gtccgaggtg cataacgagg atatgtacaa cgcaattgat ctcgcaacaa acaaactgga 60
acgtcaaatc cgtaagcata aaacgaaagt aaaccgtaaa ttccgtgagc agggctctcc 120
aaaatattta ttggcaaacg gtcttggctc tgatacagat attgcggttc aggatgacat 180
agaagaggag gagagcttgg acatcgtccg tcagaaacgc tttaatttaa agccgatgga 240
tagtgaagaa gcgatcttgc aaatgaatat gctcggccat aatttctttg ttttcacaaa 300
tgcggaaaca aaccttacaa atgtcgtgta ccgcagaaat gacgggaaat atggcttaat 360
tgaaccgact gaataatgaa gagaagcctt ccgtgatgtc cgcggaaggt ttttgttttt 420
cttatttgca aattctttgg aaataacaaa aggtatgata tgataatgag aggtatacat 480
ggactagtaa attatttata catgcctcta aaataggcgt gtgatgatag aggagcgtta 540
taa atg ctt gga att tta aat aaa atg ttt gat cca aca aaa cgt acg 588
Met Leu Gly Ile Leu Asn Lys Met Phe Asp Pro Thr Lys Arg Thr
1 5 10 15
ctg aat aga tac gaa aaa att gct aac gat att gat gcg att cgc gga 636
Leu Asn Arg Tyr Glu Lys Ile Ala Asn Asp Ile Asp Ala Ile Arg Gly
20 25 30
gac tat gaa aat ctc tct gac gac gca ttg aaa cat aaa aca att gaa 684
Asp Tyr Glu Asn Leu Ser Asp Asp Ala Leu Lys His Lys Thr Ile Glu
35 40 45
ttt aaa gag cgt ctt gaa aaa ggg gcg aca acg gat gat ctt ctt gtt 732
Phe Lys Glu Arg Leu Glu Lys Gly Ala Thr Thr Asp Asp Leu Leu Val
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gaa gct ttc gct gtt gtt cga gaa gct tca cgc cgc gta aca ggc atg 780
Glu Ala Phe Ala Val Val Arg Glu Ala Ser Arg Arg Val Thr Gly Met
65 70 75
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Phe Pro Phe Lys Val Gln Leu Met Gly Gly Val Ala Leu His Asp Gly
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Asn Ile Ala Glu Met Lys Thr Gly Glu Gly Lys Thr Leu Thr Ser Thr
100 105 110
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Leu Pro Val Tyr Leu Asn Ala Leu Thr Gly Lys Gly Val His Val Val
115 120 125
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Thr Val Asn Glu Tyr Leu Ala Ser Arg Asp Ala Glu Gln Met Gly Lys
130 135 140
att ttc gag ttt ctc ggt ttg act gtc ggt ttg aat tta aac tca atg 1020
Ile Phe Glu Phe Leu Gly Leu Thr Val Gly Leu Asn Leu Asn Ser Met
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tca aaa gac gaa aaa cgg gaa gct tat gcc gct gat att act tac tcc 1068
Ser Lys Asp Glu Lys Arg Glu Ala Tyr Ala Ala Asp Ile Thr Tyr Ser
160 165 170 175
aca aac aac gag ctt ggc ttc gac tat ttg cgt gac aat atg gtt ctt 1116
Thr Asn Asn Glu Leu Gly Phe Asp Tyr Leu Arg Asp Asn Met Val Leu
180 185 190
tat aaa gag cag atg gtt cag cgc ccg ctt cat ttt gcg gta ata gat 1164
Tyr Lys Glu Gln Met Val Gln Arg Pro Leu His Phe Ala Val Ile Asp
195 200 205
gaa gtt gac tct att tta att gat gaa gca aga aca ccg ctt atc att 1212
Glu Val Asp Ser Ile Leu Ile Asp Glu Ala Arg Thr Pro Leu Ile Ile
210 215 220
tct gga caa gct gca aaa tcc act aag ctg tac gta cag gca aat gct 1260
Ser Gly Gln Ala Ala Lys Ser Thr Lys Leu Tyr Val Gln Ala Asn Ala
225 230 235
ttt gtc cgc acg tta aaa gcg gag aag gat tac acg tac gat atc aaa 1308
Phe Val Arg Thr Leu Lys Ala Glu Lys Asp Tyr Thr Tyr Asp Ile Lys
240 245 250 255
aca aaa gct gta cag ctt act gaa gaa gga atg acg aag gcg gaa aaa 1356
Thr Lys Ala Val Gln Leu Thr Glu Glu Gly Met Thr Lys Ala Glu Lys
260 265 270
gca ttc ggc atc gat aac ctc ttt gat gtg aag cat gtc gcg ctc aac 1404
Ala Phe Gly Ile Asp Asn Leu Phe Asp Val Lys His Val Ala Leu Asn
275 280 285
cac cat atc aac cag gcc tta aaa gct cac gtt gcg atg caa aag gac 1452
His His Ile Asn Gln Ala Leu Lys Ala His Val Ala Met Gln Lys Asp
290 295 300
gtt gac tat gta gtg gaa gac gga cag gtt gtt att gtt gat tcc ttc 1500
Val Asp Tyr Val Val Glu Asp Gly Gln Val Val Ile Val Asp Ser Phe
305 310 315
acg gga cgt ctg atg aaa ggc cgc cgc tac agt gag ggg ctt cac caa 1548
Thr Gly Arg Leu Met Lys Gly Arg Arg Tyr Ser Glu Gly Leu His Gln
320 325 330 335
gcg att gaa gca aag gaa ggg ctt gag att caa aac gaa agc atg acc 1596
Ala Ile Glu Ala Lys Glu Gly Leu Glu Ile Gln Asn Glu Ser Met Thr
340 345 350
ttg gcg acg att acg ttc caa aac tac ttc cga atg tac gaa aaa ctt 1644
Leu Ala Thr Ile Thr Phe Gln Asn Tyr Phe Arg Met Tyr Glu Lys Leu
355 360 365
gcc ggt atg acg ggt aca gct aag aca gag gaa gaa gaa ttc cgc aac 1692
Ala Gly Met Thr Gly Thr Ala Lys Thr Glu Glu Glu Glu Phe Arg Asn
370 375 380
atc tac aac atg cag gtt gtc acg atc cct acc aac agg cct gtt gtc 1740
Ile Tyr Asn Met Gln Val Val Thr Ile Pro Thr Asn Arg Pro Val Val
385 390 395
cgt gat gac cgc ccg gat tta att tac cgc acg atg gaa gga aag ttt 1788
Arg Asp Asp Arg Pro Asp Leu Ile Tyr Arg Thr Met Glu Gly Lys Phe
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aag gca gtt gcg gag gat gtc gca cag cgt tac atg acg gga cag cct 1836
Lys Ala Val Ala Glu Asp Val Ala Gln Arg Tyr Met Thr Gly Gln Pro
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gtt cta gtc ggt acg gtt gcc gtt gaa aca tct gaa ttg att tct aag 1884
Val Leu Val Gly Thr Val Ala Val Glu Thr Ser Glu Leu Ile Ser Lys
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Leu Leu Lys Asn Lys Gly Ile Pro His Gln Val Leu Asn Ala Lys Asn
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cat gaa cgt gaa gcg cag atc att gaa gag gcc ggc caa aaa ggc gca 1980
His Glu Arg Glu Ala Gln Ile Ile Glu Glu Ala Gly Gln Lys Gly Ala
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Val Thr Ile Ala Thr Asn Met Ala Gly Arg Gly Thr Asp Ile Lys Leu
480 485 490 495
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Gly Glu Gly Val Lys Glu Leu Gly Gly Leu Ala Val Val Gly Thr Glu
500 505 510
cga cat gaa tca cgc cgg att gac aat cag ctt cga ggt cgt tcc gga 2124
Arg His Glu Ser Arg Arg Ile Asp Asn Gln Leu Arg Gly Arg Ser Gly
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Arg Gln Gly Asp Pro Gly Ile Thr Gln Phe Tyr Leu Ser Met Glu Asp
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Glu Leu Met Arg Arg Phe Gly Ala Glu Arg Thr Met Ala Met Leu Asp
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Arg Phe Gly Met Asp Asp Ser Thr Pro Ile Gln Ser Lys Met Val Ser
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Arg Ala Val Glu Ser Ser Gln Lys Arg Val Glu Gly Asn Asn Phe Asp
580 585 590
tcg cgt aaa cag ctt ctg caa tat gat gat gtt ctc cgc cag cag cgt 2364
Ser Arg Lys Gln Leu Leu Gln Tyr Asp Asp Val Leu Arg Gln Gln Arg
595 600 605
gag gtc att tat aag cag cgc ttt gaa gtc att gac tct gaa aac ctg 2412
Glu Val Ile Tyr Lys Gln Arg Phe Glu Val Ile Asp Ser Glu Asn Leu
610 615 620
cgt gaa atc gtt gaa aat atg atc aag tct tct ctc gaa cgc gca att 2460
Arg Glu Ile Val Glu Asn Met Ile Lys Ser Ser Leu Glu Arg Ala Ile
625 630 635
gca gcc tat acg cca aga gaa gag ctt cct gag gag tgg aag ctt gac 2508
Ala Ala Tyr Thr Pro Arg Glu Glu Leu Pro Glu Glu Trp Lys Leu Asp
640 645 650 655
ggt cta gtt gat ctt atc aac aca act tat ctt gat gaa ggt gca ctt 2556
Gly Leu Val Asp Leu Ile Asn Thr Thr Tyr Leu Asp Glu Gly Ala Leu
660 665 670
gag aag agc gat atc ttc ggc aaa gaa ccg gat gaa atg ctt gag ctc 2604
Glu Lys Ser Asp Ile Phe Gly Lys Glu Pro Asp Glu Met Leu Glu Leu
675 680 685
att atg gat cgc atc atc aca aaa tat aat gag aag gaa gag caa ttc 2652
Ile Met Asp Arg Ile Ile Thr Lys Tyr Asn Glu Lys Glu Glu Gln Phe
690 695 700
ggc aaa gag caa atg cgc gaa ttc gaa aaa gtt atc gtt ctt cgt gcc 2700
Gly Lys Glu Gln Met Arg Glu Phe Glu Lys Val Ile Val Leu Arg Ala
705 710 715
gtt gat tct aaa tgg atg gat cat att gat gcg atg gat cag ctc cgc 2748
Val Asp Ser Lys Trp Met Asp His Ile Asp Ala Met Asp Gln Leu Arg
720 725 730 735
caa ggg att cac ctt cgt gct tac gcg cag acg aac ccg ctt cgt gag 2796
Gln Gly Ile His Leu Arg Ala Tyr Ala Gln Thr Asn Pro Leu Arg Glu
740 745 750
tat caa atg gaa ggt ttt gcg atg ttt gag cat atg att gaa tca att 2844
Tyr Gln Met Glu Gly Phe Ala Met Phe Glu His Met Ile Glu Ser Ile
755 760 765
gag gac gaa gtc gca aaa ttt gtg atg aaa gct gag att gaa aac aat 2892
Glu Asp Glu Val Ala Lys Phe Val Met Lys Ala Glu Ile Glu Asn Asn
770 775 780
ctg gag cgt gaa gag gtt gta caa ggt caa aca aca gct cat cag ccg 2940
Leu Glu Arg Glu Glu Val Val Gln Gly Gln Thr Thr Ala His Gln Pro
785 790 795
caa gaa ggc gac gat aac aaa aaa gca aag aaa gca ccg gtt cgc aaa 2988
Gln Glu Gly Asp Asp Asn Lys Lys Ala Lys Lys Ala Pro Val Arg Lys
800 805 810 815
gtg gtt gat atc gga cga aat gcc cca tgc cac tgc gga agc ggg aaa 3036
Val Val Asp Ile Gly Arg Asn Ala Pro cys His cys Gly Ser Gly Lys
820 825 830
aaa tat aaa aat tgc tgc ggc cgt act gaa tag ttcgccccgg caagtttact 3089
Lys Tyr Lys Asn cys cys Gly Arg Thr Glu
835 840
gaacgcggcg cctgcaggct gcgatctttt aatgaggtga atgaaatgaa ttatcagaaa 3149
ttagagcaga gctcgaaaat atggcttctc gtttagcgga ctttaggggg tctctttgac 3209
ctcgaatcaa aggaggcccg cattgctgag ctagatgaac aaatggctga tccggaattc 3269
tggaatgatc agcaaaaagc tcaaacggtt ataaatgaag caaacggttt aaaggattat 3329
gtcaattcgt ataaaaaatt gaatgaatcc cacgaagaat tacaaatgac tcatgatctt 3389
ttgaaagaag agccggacac tgatctccag cttgagcttg aaaaagaact aaagtcatta 3449
acaaaagagt tcaatgagtt tgagcttcag cttcttctca gcgagccgta tgataaaaat 3509
aacgcgattt tagaactgca ccctggtgct ggcggtacag agtcacagga ctggggctct 3569
atgcttctta gaatgtatac aagatgggga gagcgccgcg gctttaaagt agagactctc 3629
gattaccttc caggtgacga ggcgggaatc aagtcagtga cattgctcat caaaggacac 3689
aacgcttacg ggtatctcaa agcagaaaaa ggtgttcatc gtcttgtgcg gatctcacca 3749
tttgattcat caggccgccg ccacacatct ttcgtttcat gtgaagtcat gcctgaattt 3809
aacgatgaaa ttgatattga tattcgtacg gaggatatta aagttgacac gtaccgtgca 3869
agcggcgcgg gcggacagca cgtcaatacg acggattcag ccgttcggat tactcacttg 3929
ccgacgaacg tagttgtgac atgccaaacg gagcgctcac aaattaaaaa ccgtgaaaga 3989
gccatgaaaa tgctgaaggc caagctgtat cagcgcagaa ttgaagagca gcaggcagag 4049
ctggatgaaa ttcgcggtga acaaaaagaa atcggctggg gcagccaaat ccgttcttat 4109
gtattccatc cgtattccat ggtaaaagac catcgggac 4148
<210>2
<211>841
<212>PRT
<213>Bacillus subtilis
<400>2
Met Leu Gly Ile Leu Asn Lys Met Phe Asp Pro Thr Lys Arg Thr Leu
1 5 10 15
Asn Arg Tyr Glu Lys Ile Ala Asn Asp Ile Asp Ala Ile Arg Gly Asp
20 25 30
Tyr Glu Asn Leu Ser Asp Asp Ala Leu Lys His Lys Thr Ile Glu Phe
35 40 45
Lys Glu Arg Leu Glu Lys Gly Ala Thr Thr Asp Asp Leu Leu Val Glu
50 55 60
Ala Phe Ala Val Val Arg Glu Ala Ser Arg Arg Val Thr Gly Met Phe
65 70 75 80
Pro Phe Lys Val Gln Leu Met Gly Gly Val Ala Leu His Asp Gly Asn
85 90 95
Ile Ala Glu Met Lys Thr Gly Glu Gly Lys Thr Leu Thr Ser Thr Leu
100 105 110
Pro Val Tyr Leu Asn Ala Leu Thr Gly Lys Gly Val His Val Val Thr
115 120 125
Val Asn Glu Tyr Leu Ala Ser Arg Asp Ala Glu Gln Met Gly Lys Ile
130 135 140
Phe Glu Phe Leu Gly Leu Thr Val Gly Leu Asn Leu Asn Ser Met Ser
145 150 155 160
Lys Asp Glu Lys Arg Glu Ala Tyr Ala Ala Asp Ile Thr Tyr Ser Thr
165 170 175
Asn Asn Glu Leu Gly Phe Asp Tyr Leu Arg Asp Asn Met Val Leu Tyr
180 185 190
Lys Glu Gln Met Val Gln Arg Pro Leu His Phe Ala Val Ile Asp Glu
195 200 205
Val Asp Ser Ile Leu Ile Asp Glu Ala Arg Thr Pro Leu Ile Ile Ser
210 215 220
Gly Gln Ala Ala Lys Ser Thr Lys Leu Tyr Val Gln Ala Asn Ala Phe
225 230 235 240
Val Arg Thr Leu Lys Ala Glu Lys Asp Tyr Thr Tyr Asp Ile Lys Thr
245 250 255
Lys Ala Val Gln Leu Thr Glu Glu Gly Met Thr Lys Ala Glu Lys Ala
260 265 270
Phe Gly Ile Asp Asn Leu Phe Asp Val Lys His Val Ala Leu Asn His
275 280 285
His Ile Asn Gln Ala Leu Lys Ala His Val Ala Met Gln Lys Asp Val
290 295 300
Asp Tyr Val Val Glu Asp Gly Gln Val Val Ile Val Asp Ser Phe Thr
305 310 315 320
Gly Arg Leu Met Lys Gly Arg Arg Tyr Ser Glu Gly Leu His Gln Ala
325 330 335
Ile Glu Ala Lys Glu Gly Leu Glu Ile Gln Asn Glu Ser Met Thr Leu
340 345 350
Ala Thr Ile Thr Phe Gln Asn Tyr Phe Arg Met Tyr Glu Lys Leu Ala
355 360 365
Gly Met Thr Gly Thr Ala Lys Thr Glu Glu Glu Glu Phe Arg Asn Ile
370 375 380
Tyr Asn Met Gln Val Val Thr Ile Pro Thr Asn Arg Pro Val Val Arg
385 390 395 400
Asp Asp Arg Pro Asp Leu Ile Tyr Arg Thr Met Glu Gly Ly5 Phe Lys
405 410 415
Ala Val Ala Glu Asp Val Ala Gln Arg Tyr Met Thr Gly Gln Pro Val
420 425 430
Leu Val Gly Thr Val Ala Val Glu Thr Ser Glu Leu Ile Ser Lys Leu
435 440 445
Leu Lys Asn Lys Gly Ile Pro His Gln Val Leu Asn Ala Lys Asn His
450 455 460
Glu Arg Glu Ala Gln Ile rle Glu Glu Ala Gly Gln Lys Gly Ala Val
465 470 475 480
Thr Ile Ala Thr Asn Met Ala Gly Arg Gly Thr Asp Ile Lys Leu Gly
485 490 495
Glu Gly Val Lys Glu Leu Gly Gly Leu Ala Val Val Gly Thr Glu Arg
500 505 510
His Glu Ser Arg Arg Ile Asp Asn Gln Leu Arg Gly Arg Ser Gly Arg
515 520 525
Gln Gly Asp Pro Gly Ile Thr Gln Phe Tyr Leu Ser Met Glu Asp Glu
530 535 540
Leu Met Arg Arg Phe Gly Ala Glu Arg Thr Met Ala Met Leu Asp Arg
545 550 555 560
Phe Gly Met Asp Asp Ser Thr Pro Ile Gln Ser Lys Met Val Ser Arg
565 570 575
Ala Val Glu Ser Ser Gln Lys Arg Val Glu Gly Asn Asn Phe Asp Ser
580 585 590
Arg Lys Gln Leu Leu Gln Tyr Asp Asp Val Leu Arg Gln Gln Arg Glu
595 600 605
Val Ile Tyr Lys Gln Arg Phe Glu Val Ile Asp Ser Glu Asn Leu Arg
610 615 620
Glu Ile Val Glu Asn Met Ile Lys Ser Ser Leu Glu Arg Ala Ile Ala
625 630 635 640
Ala Tyr Thr Pro Arg Glu Glu Leu Pro Glu Glu Trp Lys Leu Asp Gly
645 650 655
Leu Val Asp Leu Ile Asn Thr Thr Tyr Leu Asp Glu Gly Ala Leu Glu
660 665 670
Lys Ser Asp Ile Phe Gly Lys Glu Pro Asp Glu Met Leu Glu Leu Ile
675 680 685
Met Asp Arg Ile Ile Thr Lys Tyr Asn Glu Lys Glu Glu Gln Phe Gly
690 695 700
Lys Glu Gln Met Arg Glu Phe Glu Lys Val Ile Val Leu Arg Ala Val
705 710 715 720
Asp Ser Lys Trp Met Asp His Ile Asp Ala Met Asp Gln Leu Arg Gln
725 730 735
Gly Ile His Leu Arg Ala Tyr Ala Gln Thr Asn Pro Leu Arg Glu Tyr
740 745 750
Gln Met Glu Gly Phe Ala Met Phe Glu His Met Ile Glu Ser Ile Glu
755 760 765
Asp Glu Val Ala Lys Phe Val Met Lys Ala Glu Ile Glu Asn Asn Leu
770 775 780
Glu Arg Glu Glu Val Val Gln Gly Gln Thr Thr Ala His Gln Pro Gln
785 790 795 800
Glu Gly Asp Asp Asn Lys Lys Ala Lys Lys Ala Pro Val Arg Lys Val
805 810 815
Val Asp Ile Gly Arg Asn Ala Pro Cys His Cys Gly Ser Gly Lys Lys
820 825 830
Tyr Lys Asn Cys Cys Gly Arg Thr Glu
835 840
<210>3
<211>2706
<212>DNA
<213>Escherichia coli
<220>
<221>CDS
<222>(1)..(2706)
<400>3
atg cta atc aaa tta tta act aaa gtt ttc ggt agt cgt aac gat cgc 48
Met Leu Ile Lys Leu Leu Thr Lys Val Phe Gly Ser Arg Asn Asp Arg
1 5 10 15
acc ctg cgc cgg atg cgc aaa gtg gtc aac atc atc aat gcc atg gaa 96
Thr Leu Arg Arg Met Arg Lys Val Val Asn Ile Ile Asn Ala Met Glu
20 25 30
ccg gag atg gaa aaa ctc tcc gac gaa gaa ctg aaa ggg aaa acc gca 144
Pro Glu Met Glu Lys Leu Ser Asp Glu Glu Leu Lys Gly Lys Thr Ala
35 40 45
gag ttt cgt gcg cgt ctg gaa aaa ggc gaa gtg ctg gaa aat ctg atc 192
Glu Phe Arg Ala Arg Leu Glu Lys Gly Glu Val Leu Glu Asn Leu Ile
50 55 60
ccg gaa gct ttc gcc gtg gtg cgt gag gca agt aag cgc gtc ttt ggt 240
Pro Glu Ala Phe Ala Val Val Arg Glu Ala Ser Lys Arg Val Phe Gly
65 70 75 80
atg cgt cac ttc gac gtt cag tta ctc ggc ggt atg gtt ctt aac gaa 288
Met Arg His Phe Asp Val Gln Leu Leu Gly Gly Met Val Leu Asn Glu
85 90 95
cgc tgc atc gcc gaa atg cgt acc ggt gaa ggt aaa acc ctg acc gca 336
Arg Cys Ile Ala Glu Met Arg Thr Gly Glu Gly Lys Thr Leu Thr Ala
100 105 110
acg ctg cct gct tac ctg aac gca cta acc ggt aaa ggc gta cac gta 384
Thr Leu Pro Ala Tyr Leu Asn Ala Leu Thr Gly Lys Gly Val His Val
115 120 125
gtt acc gtc aac gac tac ctg gcg caa cgt gac gcc gaa aac aac cgt 432
Val Thr Val Asn Asp Tyr Leu Ala Gln Arg Asp Ala Glu Asn Asn Arg
130 135 140
ccg ctg ttt gaa ttc ctt ggc ctg act gtc ggt atc aac ctg ccg ggc 480
Pro Leu Phe Glu Phe Leu Gly Leu Thr Val Gly Ile Asn Leu Pro Gly
145 150 155 160
atg cca gca ccg gca aag cgt gaa gcc tac gct gct gac atc act tac 528
Met Pro Ala Pro Ala Lys Arg Glu Ala Tyr Ala Ala Asp Ile Thr Tyr
165 170 175
ggt acg aac aac gaa tac ggc ttt gac tac ctg cgc gac aac atg gca 576
Gly Thr Asn Asn Glu Tyr Gly Phe Asp Tyr Leu Arg Asp Asn Met Ala
180 185 190
ttc agc cct gaa gaa cgt gta caa cgt aaa ctg cac tat gcg ctg gtg 624
Phe Ser Pro Glu Glu Arg Val Gln Arg Lys Leu His Tyr Ala Leu Val
195 200 205
gac gaa gtg gac tcc atc ctc atc gat gaa gcg cgt aca ccg ctg atc 672
Asp Glu Val Asp Ser Ile Leu Ile Asp Glu Ala Arg Thr Pro Leu Ile
210 215 220
att tcc ggc cca gca gaa gac agc tcg gaa atg tat aaa cgc gtg aat 720
Ile Ser Gly Pro Ala Glu Asp Ser Ser Glu Met Tyr Lys Arg Val Asn
225 230 235 240
aaa att att ccg cac ctg atc cgt cag gaa aaa gaa gac tcc gaa acc 768
Lys Ile Ile Pro His Leu Ile Arg Gln Glu Lys Glu Asp Ser Glu Thr
245 250 255
ttc cag ggc gaa ggc cac ttc tcg gtg gat gaa aaa tct cgc cag gtg 816
Phe Gln Gly Glu Gly His Phe Ser Val Asp Glu Lys Ser Arg Gln Val
260 265 270
aac ctg acc gaa cgt ggt ctg gtt ctg att gaa gaa ctg ctg gtt aaa 864
Asn Leu Thr Glu Arg Gly Leu Val Leu Ile Glu Glu Leu Leu Val Lys
275 280 285
gaa ggc atc atg gat gaa ggt gag tct ctg tac tct ccg gcc aac atc 912
Glu Gly Ile Met Asp Glu Gly Glu Ser Leu Tyr Ser Pro Ala Asn Ile
290 295 300
atg ctg atg cac cac gta acg gcg gcg ctg cgc gct cat gcg ctg ttt 960
Met Leu Met His His Val Thr Ala Ala Leu Arg Ala His Ala Leu Phe
305 310 315 320
acc cgc gac gtc gac tac atc gtt aaa gat ggt gaa gtt atc atc gtt 1008
Thr Arg Asp Val Asp Tyr Ile Val Lys Asp Gly Glu Val Ile Ile Val
325 330 335
gac gaa cac acc ggt cgt acc atg cag ggc cgt cgc tgg tcc gat ggt 1056
Asp Glu His Thr Gly Arg Thr Met Gln Gly Arg Arg Trp Ser Asp Gly
340 345 350
ctg cac cag gct gtg gaa gcg aaa gaa ggt gtg cag atc cag aac gaa 1104
Leu His Gln Ala Val Glu Ala Lys Glu Gly Val Gln Ile Gln Asn Glu
355 360 365
aac cag acg ctg gct tcg atc acc ttc cag aac tac ttc cgt ctg tat 1152
Asn Gln Thr Leu Ala Ser Ile Thr Phe Gln Asn Tyr Phe Arg Leu Tyr
370 375 380
gaa aaa ctg gcg ggg atg act ggt act gct gat acc gaa gct ttc gaa 1200
Glu Lys Leu Ala Gly Met Thr Gly Thr Ala Asp Thr Glu Ala Phe Glu
385 390 395 400
ttc agc tcc atc tat aag ctg gat act gtc gtt gtt ccg acc aac cgt 1248
Phe Ser Ser Ile Tyr Lys Leu Asp Thr Val Val Val Pro Thr Asn Arg
405 410 415
cca atg att cgt aaa gat ctg ccg gac ctg gtc tac atg act gaa gcg 1296
Pro Met Ile Arg Lys Asp Leu Pro Asp Leu Val Tyr Met Thr Glu Ala
420 425 430
gaa aaa att cag gcg atc att gaa gat atc aaa gaa cgt act gcg aaa 2344
Glu Lys Ile Gln Ala Ile Ile Glu Asp Ile Lys Glu Arg Thr Ala Lys
435 440 445
ggc cag ccg gtg ctg gtg ggt aca atc tcc atc gaa aaa tcg gag ctg 1392
Gly Gln Pro Val Leu Val Gly Thr Ile Ser Ile Glu Lys Ser Glu Leu
450 455 460
gtg tca aat gaa ctg acc aaa gcc ggt att aag cac aac gtc ctg aac 1440
Val Ser Asn Glu Leu Thr Lys Ala Gly Ile Lys His Asn Val Leu Asn
465 470 475 480
gcc aaa ttc cat gcc aac gaa gcg gcg att gtt gct cag gca ggt tat 1488
Ala Lys Phe His Ala Asn Glu Ala Ala Ile Val Ala Gln Ala Gly Tyr
485 490 495
ccg gct gcg gtg act atc gcg acc aac atg gcg ggt cgt ggt acc gat 1536
Pro Ala Ala Val Thr Ile Ala Thr Asn Met Ala Gly Arg Gly Thr Asp
500 505 510
att gtg ctc ggt ggt agc tgg cag gca gaa gtt gcc gcg ctg gaa aat 1584
Ile Val Leu Gly Gly Ser Trp Gln Ala Glu Val Ala Ala Leu Glu Asn
515 520 525
ccg act gca gag caa att gaa aaa att aaa gcc gac tgg cag gta cgt 1632
Pro Thr Ala Glu Gln Ile Glu Lys Ile Lys Ala Asp Trp Gln Val Arg
530 535 540
cac gat gcg gta ctg gca gca ggt ggc ctg cat atc atc ggt act gaa 1680
His Asp Ala Val Leu Ala Ala Gly Gly Leu His Ile Ile Gly Thr Glu
545 550 555 560
cgt cac gaa tcc cgt cgt atc gat asc cag ctg cgc ggt cgt tct ggt 1728
Arg His Glu Ser Arg Arg Ile Asp Asn Gln Leu Arg Gly Arg Ser Gly
565 570 575
cgt cag ggg gat gct ggt tct tct cgt ttc tac ctg tcg atg gaa gat 1776
Arg Gln Gly Asp Ala Gly Ser Ser Arg Phe Tyr Leu Ser Met Glu Asp
580 585 590
gcg ctg atg cgt att ttt gct tcc gac cga gta tcc ggc atg atg cgt 1824
Ala Leu Met Arg Ile Phe Ala Ser Asp Arg Val Ser Gly Met Met Arg
595 600 605
aaa ctg ggt atg aag cca ggc gaa gcc att gag cac ccg tgg gtg acc 1872
Lys Leu Gly Met Lys Pro Gly Glu Ala Ile Glu His Pro Trp Val Thr
610 615 620
aaa gcg att gcc aac gcc cag cgt aaa gtt gaa agc cgt aac ttc gac 1920
Lys Ala Ile Ala Asn Ala Gln Arg Lys Val Glu Ser Arg Asn Phe Asp
625 630 635 640
att cgt aag caa ctg ctg gaa tat gat gac gtg gct aac gat cag cgt 1968
Ile Arg Lys Gln Leu Lau Glu Tyr Asp Asp Val Ala Asn Asp Gln Arg
645 650 655
cgc gcc att tac tcc cag cgt aac gaa ctg ctg gat gtc agc gat gtg 2016
Arg Ala Ile Tyr Ser Gln Arg Asn Glu Leu Leu Asp Val Ser Asp Val
660 665 670
agc gaa acc atc aac agc att cgt gaa gat gtg ttc aaa gcg acc att 2064
Ser Glu Thr Ile Asn Ser Ile Arg Glu Asp Val Phe Lys Ala Thr Ile
675 680 685
gat gcc tac att ccg cca cag tcg ctg gaa gaa atg tgg gat att ccg 2112
Asp Ala Tyr Ile Pro Pro Gln Ser Leu Glu Glu Met Trp Asp Ile Pro
690 695 700
ggg ctg cag gaa cgt ctg aag aac gat ttc gac ctc gat ttg cca att 2160
Gly Leu Gln Glu Arg Leu Lys Asn Asp Phe Asp Leu Asp Leu Pro Ile
705 710 715 720
gcc gag tgg ctg gat aaa gaa cca gaa ctg cat gaa gag acg ctg cgt 2208
Ala Glu Trp Leu Asp Lys Glu Pro Glu Leu His Glu Glu Thr Leu Arg
725 730 735
gag cgc att ctg gcg cag tcc atc gaa gtg tat cag cgt aaa gaa gaa 2256
Glu Arg Ile Leu Ala Gln Ser Ile Glu Val Tyr Gln Arg Lys Glu Glu
740 745 750
gtg gtt ggt gct gag atg atg cgt cac ttc gag aaa ggc gtc atg ctg 2304
Val Val Gly Ala Glu Met Met Arg His Phe Glu Lys Gly Val Met Leu
755 760 765
caa act ctc gac tct ctg tgg aaa gag cac ctg gca gcg atg gac tat 2352
Gln Thr Leu Asp Ser Leu Trp Lys Glu His Leu Ala Ala Met Asp Tyr
770 775 780
ctg cgt cag ggt atc cac ctg cgt ggc tat gca cag aaa gat ccg aag 2400
Leu Arg Gln Gly Ile His Leu Arg Gly Tyr Ala Gln Lys Asp Pro Lys
785 790 795 800
cag gaa tac aaa cgt gaa tcg ttc tcc atg ttt gca gcg atg ctg gag 2448
Gln Glu Tyr Lys Arg Glu Ser Phe Ser Met Phe Ala Ala Met Leu Glu
805 810 815
tcg ttg aaa tat gaa gtt atc agt acg ctg agc aaa gtt cag gta cgt 2496
Ser Leu Lys Tyr Glu Val Ile Ser Thr Leu Ser Lys Val Gln Val Arg
820 825 830
atg cct gaa gag gtt gag gag ctg gaa caa cag cgt cgt atg gaa gcc 2544
Met Pro Glu Glu Val Glu Glu Leu Glu Gln Gln Arg Arg Met Glu Ala
835 840 845
gag cgt tta gcg caa atg cag cag ctt agc cat cag gat gac gac tct 2592
Glu Arg Leu Ala Gln Met Gln Gln Leu Ser His Gln Asp Asp Asp Ser
850 855 860
gca gcc gca gct gca ctg gcg gcg caa acc ggt gaa cgc aaa gta gga 2640
Ala Ala Ala Ala Ala Leu Ala Ala Gln Thr Gly Glu Arg Lys Val Gly
865 870 875 880
cgt aac gat cct tgc ccg tgt ggt tct ggt aaa aaa tac aag cag tgc 2688
Arg Asn Asp Pro Cys Pro Cys Gly Ser Gly Lys Lys Tyr Lys Gln Cys
885 890 895
cat ggc cgc ctg caa taa 2706
His Gly Arg Leu Gln
900
<210>4
<211>901
<212>PRT
<213>Escherichia coli
<400>4
Met Leu Ile Lys Leu Leu Thr Lys Val Phe Gly Ser Arg Asn Asp Arg
1 5 10 15
Thr Leu Arg Arg Met Arg Lys Val Val Asn Ile Ile Asn Ala Met Glu
20 25 30
Pro Glu Met Glu Lys Leu Ser Asp Glu Glu Leu Lys Gly Lys Thr Ala
35 40 45
Glu Phe Arg Ala Arg Leu Glu Lys Gly Glu Val Leu Glu Asn Leu Ile
50 55 60
Pro Glu Ala Phe Ala Val Val Arg Glu Ala Ser Lys Arg Val Phe Gly
65 70 75 80
Met Arg His Phe Asp Val Gln Leu Leu Gly Gly Met Val Leu Asn Glu
85 90 95
Arg Cys Ile Ala Glu Met Arg Thr Gly Glu Gly Lys Thr Leu Thr Ala
100 105 110
Thr Leu Pro Ala Tyr Leu Asn Ala Leu Thr Gly Lys Gly Val His Val
115 120 125
Val Thr Val Asn Asp Tyr Leu Ala Gln Arg Asp Ala Glu Asn Asn Arg
130 135 140
Pro Leu Phe Glu Phe Leu Gly Leu Thr Val Gly Ile Asn Leu Pro Gly
145 150 155 160
Met Pro Ala Pro Ala Lys Arg Glu Ala Tyr Ala Ala Asp Ile Thr Tyr
165 170 175
Gly Thr Asn Asn Glu Tyr Gly Phe Asp Tyr Leu Arg Asp Asn Met Ala
180 185 190
Phe Ser Pro Glu Glu Arg Val Gln Arg Lys Leu His Tyr Ala Leu Val
195 200 205
Asp Glu Val Asp Ser Ile Leu Ile Asp Glu Ala Arg Thr Pro Leu Ile
210 215 220
Ile Ser Gly Pro Ala Glu Asp Ser Ser Glu Met Tyr Lys Arg Val Asn
225 230 235 240
Lys Ile Ile Pro His Leu Ile Arg Gln Glu Lys Glu Asp Ser Glu Thr
245 250 255
Phe Gln Gly Glu Gly His Phe Ser Val Asp Glu Lys Ser Arg Gln Val
260 265 270
Asn Leu Thr Glu Arg Gly Leu Val Leu Ile Glu Glu Leu Leu Val Lys
275 280 285
Glu Gly Ile Met Asp Glu Gly Glu Ser Leu Tyr Ser Pro Ala Asn Ile
290 295 300
Met Leu Met His His Val Thr Ala Ala Leu Arg Ala His Ala Leu Phe
305 310 315 320
Thr Arg Asp Val Asp Tyr Ile Val Lys Asp Gly Glu Val Ile Ile Val
325 330 335
Asp Glu His Thr Gly Arg Thr Met Gln Gly Arg Arg Trp Ser Asp Gly
340 345 350
Leu His Gln Ala Val Glu Ala Lys Glu Gly Val Gln Ile Gln Asn Glu
355 360 365
Asn Gln Thr Leu Ala Ser Ile Thr Phe Gln Asn Tyr Phe Arg Leu Tyr
370 375 380
Glu Lys Leu Ala Gly Met Thr Gly Thr Ala Asp Thr Glu Ala Phe Glu
385 390 395 400
Phe Ser Ser Ile Tyr Lys Leu Asp Thr Val Val Val Pro Thr Asn Arg
405 410 415
Pro Met Ile Arg Lys Asp Leu Pro Asp Leu Val Tyr Met Thr Glu Ala
420 425 430
Glu Lys Ile Gln Ala Ile Ile Glu Asp Ile Lys Glu Arg Thr Ala Lys
435 440 445
Gly Gln Pro Val Leu Val Gly Thr Ile Ser Ile Glu Lys Ser Glu Leu
450 455 460
Val Ser Asn Glu Leu Thr Lys Ala Gly Ile Lys His Asn Val Leu Asn
465 470 475 480
Ala Lys Phe His Ala Asn Glu Ala Ala Ile Val Ala Gln Ala Gly Tyr
485 490 495
Pro Ala Ala Val Thr Ile Ala Thr Asn Met Ala Gly Arg Gly Thr Asp
500 505 510
Ile Val Leu Gly Gly Ser Trp Gln Ala Glu Val Ala Ala Leu Glu Asn
515 520 525
Pro Thr Ala Glu Gln Ile Glu Lys Ile Lys Ala Asp Trp Gln Val Arg
530 535 540
His Asp Ala Val Leu Ala Ala Gly Gly Leu His Ile Ile Gly Thr Glu
545 550 555 560
Arg His Glu Ser Arg Arg Ile Asp Asn Gln Leu Arg Gly Arg Ser Gly
565 570 575
Arg Gln Gly Asp Ala Gly Ser Ser Arg Phe Tyr Leu ser Met Glu Asp
580 585 590
Ala Leu Met Arg Ile Phe Ala Ser Asp Arg Val Ser Gly Met Met Arg
595 600 605
Lys Leu Gly Met Lys Pro Gly Glu Ala Ile Glu His Pro Trp Val Thr
610 615 620
Lys Ala Ile Ala Asn Ala Gln Arg Lys Val Glu Ser Arg Asn Phe Asp
625 630 635 640
Ile Arg Lys Gln Leu Leu Glu Tyr Asp Asp Val Ala Asn Asp Gln Arg
645 650 655
Arg Ala Ile Tyr Ser Gln Arg Asn Glu Leu Leu Asp Val Ser Asp Val
660 665 670
Ser Glu Thr Ile Asn Ser Ile Arg Glu Asp Val Phe Lys Ala Thr Ile
675 680 685
Asp Ala Tyr Ile Pro Pro Gln Ser Leu Glu Glu Met Trp Asp Ile Pro
690 695 700
Gly Leu Gln Glu Arg Leu Lys Asn Asp Phe Asp Leu Asp Leu Pro Ile
705 710 715 720
Ala Glu Trp Leu Asp Lys Glu Pro Glu Leu His Glu Glu Thr Leu Arg
725 730 735
Glu Arg Ile Leu Ala Gln Ser Ile Glu Val Tyr Gln Arg Lys Glu Glu
740 745 750
Val Val Gly Ala Glu Met Met Arg His Phe Glu Lys Gly Val Met Leu
755 760 765
Gln Thr Leu Asp Ser Leu Trp Lys Glu His Leu Ala Ala Met Asp Tyr
770 775 780
Leu Arg Gln Gly Ile His Leu Arg Gly Tyr Ala Gln Lys Asp Pro Lys
785 790 795 800
Gln Glu Tyr Lys Arg Glu Ser Phe Ser Met Phe Ala Ala Met Leu Glu
805 810 815
Ser Leu Lys Tyr Glu Val Ile Ser Thr Leu Ser Lys Val Gln Val Arg
820 825 830
Met Pro Glu Glu Val Glu Glu Leu Glu Gln Gln Arg Arg Met Glu Ala
835 840 845
Glu Arg Leu Ala Gln Met Gln Gln Leu Ser His Gln Asp Asp Asp Ser
850 855 860
Ala Ala Ala Ala Ala Leu Ala Ala Gln Thr Gly Glu Arg Lys Val Gly
865 870 875 880
Arg Asn Asp Pro Cys Pro Cys Gly Ser Gly Lys Lys Tyr Lys Gln Cys
885 890 895
His Gly Arg Leu Gln
900
<210>5
<211>2706
<212>DNA
<213>Bacillus licheniformis
<220>
<221>CDS
<222>(154)..(2679)
<400>5
gatccccctc ccggatcttc cgcagagggg attttttccg ttcccccgcg gtaaattgtt 60
tggaaatgac aaaaggtatg atatgatatt gcatatataa aaattactgt ttactcatgc 120
ttaaacaagg aaattaaaga ggagcgttat tct atg ctt gga att tta aat aaa 174
Met Leu Gly Ile Leu Asn Lys
1 5
gtg ttt gat ccg aca aaa cgc acg ctc agc cgt tat gaa aag aaa gcg 222
Val Phe Asp Pro Thr Lys Arg Thr Leu Ser Arg Tyr Glu Lys Lys Ala
10 15 20
aac gag att gat gcg ctc aag gca gat ata gag aag ctt tca gac gaa 270
Asn Glu Ile Asp Ala Leu Lys Ala Asp Ile Glu Lys Leu Ser Asp Glu
25 30 35
gct ttg aag caa aag acg atc gag ttc aaa gag cgc ctt gaa aaa ggc 318
Ala Leu Lys Gln Lys Thr Ile Glu Phe Lys Glu Arg Leu Glu Lys Gly
40 45 50 55
gaa acg gtt gac gat ctt ttg gtt gaa gcg ttt gcc gtt gtc agg gaa 366
Glu Thr Val Asp Asp Leu Leu Val Glu Ala Phe Ala Val Val Arg Glu
60 65 70
gct tcc cgg cgc gtg aca ggc atg ttt ccg ttt aag gtt cag ctg atg 414
Ala Ser Arg Arg Val Thr Gly Met Phe Pro Phe Lys Val Gln Leu Met
75 80 85
ggg ggc gtc gcc ctt cat gaa ggg aat atc gcc gaa atg aaa acg ggg 462
Gly Gly Val Ala Leu His Glu Gly Asn Ile Ala Glu Met Lys Thr Gly
90 95 100
gaa ggt aaa acg ctg act tcc aca atg ccc gtt tac ttg aac gct ctg 510
Glu Gly Lys Thr Leu Thr Ser Thr Met Pro Val Tyr Leu Asn Ala Leu
105 110 115
tca ggg aaa ggc gtt cac gtc gtg acg gtc aac gaa tac ctg gcg agc 558
Ssr Gly Lys Gly Val His Val Val Thr Val Asn Glu Tyr Leu Ala Ser
120 125 130 135
cgc gac gct gaa gag atg ggg aaa atc ttt gag ttt ctc ggg ctg acg 606
Arg Asp Ala Glu Glu Met Gly Lys Ile Phe Glu Phe Leu Gly Leu Thr
140 145 150
gtc ggc cta aac ctg aac agc ctg tca aaa gac gag aag cgt gaa gcc 654
Val Gly Leu Asn Leu Asn Ser Leu Ser Lys Asp Glu Lys Arg Glu Ala
155 160 165
tat gca gca gat att acg tat tct acg aat aat gag ctt ggc ttt gac 702
Tyr Ala Ala Asp Ile Thr Tyr Ser Thr Asn Asn Glu Leu Gly Phe Asp
170 175 180
tac ttg cgc gac aac atg gtg ctt tat aaa gag cag atg gtt cag cgc 750
Tyr Leu Arg Asp Asn Met Val Leu Tyr Lys Glu Gln Met Val Gln Arg
185 190 195
ccg ctt cat ttt gcg gtc atc gat gaa gtc gac tcc att ttg atc gat 798
Pro Leu His Phe Ala Val Ile Asp Glu Val Asp Ser Ile Leu Ile Asp
200 205 210 215
gaa gca aga acg ccg ctc atc att tct gga caa gcg gcc aaa tcc acc 846
Glu Ala Arg Thr Pro Leu Ile Ile Ser Gly Gln Ala Ala Lys Ser Thr
220 225 230
aag ctt tat gtt cag gcc aat gcg ttt gtc cgc acg cta aaa gcg gat 894
Lys Leu Tyr Val Gln Ala Asn Ala Phe Val Arg Thr Leu Lys Ala Asp
235 240 245
cag gac tac aca tac gat gtg aaa aca aaa ggc gtt cag ctg act gaa 942
Gln Asp Tyr Thr Tyr Asp Val Lys Thr Lys Gly Val Gln Leu Thr Glu
250 255 260
gag ggg atg aca aaa gct gaa aag gca ttt ggc atc gaa aac ttg ttt 990
Glu Gly Met Thr Lys Ala Glu Lys Ala Phe Gly Ile Glu Asn Leu Phe
265 270 275
gac gtc cgc cat gtc gcc tta aac cat cat att gcc cag gcg ctg aaa 1038
Asp Val Arg His Val Ala Leu Asn His His Ile Ala Gln Ala Leu Lys
280 285 290 295
gcc cat gcg gcg atg cat aaa gac gtc gac tac gtc gtc gaa gac ggt 1086
Ala His Ala Ala Met His Lys Asp Val Asp Tyr Val Val Glu Asp Gly
300 305 310
cag gtc gtt atc gtc gac tct ttt aca ggc cgt ttg atg aaa ggc cgc 1134
Gln Val Val Ile Val Asp Ser Phe Thr Gly Arg Leu Met Lys Gly Arg
315 320 325
cgc tac agc gac gga ctt cac cag gcc att gaa gcg aag gaa ggc ctt 1182
Arg Tyr Ser Asp Gly Leu His Gln Ala Ile Glu Ala Lys Glu Gly Leu
330 335 340
gag atc caa aat gag agc atg acg ctc gcg acg atc acc ttc cag aac 1230
Glu Ile Gln Asn Glu Ser Met Thr Leu Ala Thr Ile Thr Phe Gln Asn
345 350 355
tat ttc cga atg tat gaa aaa ttg gct gga atg acg ggt acc gca aaa 1278
Tyr Phe Arg Met Tyr Glu Lys Leu Ala Gly Met Thr Gly Thr Ala Lys
360 365 370 375
acg gaa gaa gaa gaa ttc cgc aac atc tac aac atg cag gtt gtt acg 1326
Thr Glu Glu Glu Glu Phe Arg Asn Ile Tyr Asn Met Gln Val Val Thr
380 385 390
att ccg acc aac aag ccg att gcc cgc gat gac cga ccg gat tta att 1374
Ile Pro Thr Asn Lys Pro Ile Ala Arg Asp Asp Arg Pro Asp Leu Ile
395 400 405
tac cgg acc atg gaa gga aaa ttt aaa gct gtt gca gag gat gtc gcc 1422
Tyr Arg Thr Met Glu Gly Lys Phe Lys Ala Val Ala Glu Asp Val Ala
410 415 420
cag cgc tat atg gtc gga cag ccg gta ctt gtc ggt acg gtt gcg gtt 1470
Gln Arg Tyr Met Val Gly Gln Pro Val Leu Val Gly Thr Val Ala Val
425 430 435
gaa aca tct gaa ttg ata tca agg ctc ctt aaa aat aaa gga atc ccg 1518
Glu Thr Ser Glu Leu Ile Ser Arg Leu Leu Lys Asn Lys Gly Ile Pro
440 445 450 455
cat cas gtg ttg aac gcg aaa aac cat gag cgg gaa gct cag att atc 1566
His Gln Val Leu Asn Ala Lys Asn His Glu Arg Glu Ala Gln Ile Ile
460 465 470
gaa gat gcc ggg caa aaa ggc gcg gtc acc atc gcg acc aac atg gcg 1614
Glu Asp Ala Gly Gln Lys Gly Ala Val Thr Ile Ala Thr Asn Met Ala
475 480 485
ggc cgc gga acg gac atc aag ctt ggc gaa ggt gta aaa gag ctt ggc 1662
Gly Arg Gly Thr Asp Ile Lys Leu Gly Glu Gly Val Lys Glu Leu Gly
490 495 500
gga ctg gcc gtc atc ggt acg gaa cgc cat gaa tca agg cgg att gac 1710
Gly Leu Ala Val Ile Gly Thr Glu Arg His Glu Ser Arg Arg Ile Asp
505 510 515
aac cag ctg cgc gga cgt tca ggc cgt cag ggg gac cct ggt atc acc 1758
Asn Gln Leu Arg Gly Arg Ser Gly Arg Gln Gly Asp Pro Gly Ile Thr
520 525 530 535
caa ttt tat ctg tcc atg gaa gat gaa tta atg aaa cgc ttc ggc gca 1806
Gln Phe Tyr Leu Ser Met Glu Asp Glu Leu Met Lys Arg Phe Gly Ala
540 545 550
gag cgg acg atg gcg atg ctt gac cgc ttc gga atg gac gat tcg acg 1854
Glu Arg Thr Met Ala Met Leu Asp Arg Phe Gly Met Asp Asp Ser Thr
555 560 565
ccg ata cag agc aag atg gtt tca aga gcg gtc gaa tct tca cag aag 1902
Pro Ile Gln Ser Lys Met Val Ser Arg Ala Val Glu Ser Ser Gln Lys
570 575 580
cgt gtg gaa ggc aac aac ttt gat gcc cgt aag cag ctt ctg caa tac 1950
Arg Val Glu Gly Asn Asn Phe Asp Ala Arg Lys Gln Leu Leu Gln Tyr
585 590 595
gat gac gtg ctc cgc cag cag cgc gaa gtc atc tat aaa cag cgc ttt 1998
Asp Asp Val Leu Arg Gln Gln Arg Glu Val Ile Tyr Lys Gln Arg Phe
600 605 610 615
gag gtc atc gat tcc gat aac ctc cgc tcc atc gtc gaa aat atg att 2046
Glu Val Ile Asp Ser Asp Asn Leu Arg Ser Ile Val Glu Asn Met Ile
620 625 630
aaa gct tca ctc gag cgg gct gtt gct tca tat acg ccg aag gaa gat 2094
Lys Ala Ser Leu Glu Arg Ala Val Ala Ser Tyr Thr Pro Lys Glu Asp
635 640 645
ctg cct gaa gag tgg aat ctt gac ggc ctt gtg gag ctt gta aat gcg 2142
Leu Pro Glu Glu Trp Asn Leu Asp Gly Leu Val Glu Leu Val Asn Ala
650 655 660
aat ttc ctt gat gaa ggt gga gtg gag aaa agc gac att ttc gga aaa 2190
Asn Phe Leu Asp Glu Gly Gly Val Glu Lys Ser Asp Ile Phe Gly Lys
665 670 675
gag ccc gag gag att aca gag ctc att tac gac cgc atc aaa acg aaa 2238
Glu Pro Glu Glu Ile Thr Glu Leu Ile Tyr Asp Arg Ile Lys Thr Lys
680 685 690 695
tac gat gag aaa gaa gag cgg tac ggc tct gaa caa atg cgc gaa ttt 2286
Tyr Asp Glu Lys Glu Glu Arg Tyr Gly Ser Glu Gln Met Arg Glu Phe
700 705 710
gag aaa gtc atc gtt ctc cgc gaa gtg gat acg aaa tgg atg gat cac 2334
Glu Lys Val Ile Val Leu Arg Glu Val Asp Thr Lys Trp Met Asp His
715 720 725
atc gat gcg atg gat cag ctg cgg caa gga att cat ctg cgc gct tat 2382
Ile Asp Ala Met Asp Gln Leu Arg Gln Gly Ile His Leu Arg Ala Tyr
730 735 740
gct cag aca aac ccg ctc cgc gag tat cag atg gaa ggc ttt gca atg 2430
Ala Gln Thr Asn Pro Leu Arg Glu Tyr Gln Met Glu Gly Phe Ala Met
745 750 755
ttt gaa aac atg atc gcg gcg att gaa gat gat gta gcc aaa ttc gtc 2478
Phe Glu Asn Met Ile Ala Ala Ile Glu Asp Asp Val Ala Lys Phe Val
760 765 770 775
atg aag gct gaa atc gaa aac aac ctt gag cgc gaa gag gtc att caa 2526
Met Lys Ala Glu Ile Glu Asn Asn Leu Glu Arg Glu Glu Val Ile Gln
780 785 790
gga cag acg aca gcc cat cag ccg aaa gaa ggc gat gag gaa aaa caa 2574
Gly Gln Thr Thr Ala His Gln Pro Lys Glu Gly Asp Glu Glu Lys Gln
795 800 805
gcg aag aaa aaa ccg gtc cgc aaa gcg gtg gat atc gga cgc aat gat 2622
Ala Lys Lys Lys Pro Val Arg Lys Ala Val Asp Ile Gly Arg Asn Asp
810 815 820
cct tgc tac tgc gga agc gga aaa aaa tat aaa aac tgc tgc gga aga 2670
Pro Cys Tyr Cys Gly Ser Gly Lys Lys Tyr Lys Asn Cys Cys Gly Arg
825 830 835
aca gaa taa aaagaggtgc acgcctcttt ttatttg 2706
Thr Glu
840
<210>6
<211>841
<212>PRT
<213>Bacillus licheniformis
<400>6
Met Leu Gly Ile Leu Asn Lys Val Phe Asp Pro Thr Lys Arg Thr Leu
1 5 10 15
Ser Arg Tyr Glu Lys Lys Ala Asn Glu Ile Asp Ala Leu Lys Ala Asp
20 25 30
Ile Glu Lys Leu Ser Asp Glu Ala Leu Lys Gln Lys Thr Ile Glu Phe
35 40 45
Lys Glu Arg Leu Glu Lys Gly Glu Thr Val Asp Asp Leu Leu Val Glu
50 55 60
Ala Phe Ala Val Val Arg Glu Ala Ser Arg Arg Val Thr Gly Met Phe
65 70 75 80
Pro Phe Lys Val Gln Leu Met Gly Gly Val Ala Leu His Glu Gly Asn
85 90 95
Ile Ala Glu Met Lys Thr Gly Glu Gly Lys Thr Leu Thr Ser Thr Met
100 105 110
Pro Val Tyr Leu Asn Ala Leu Ser Gly Lys Gly Val His Val Val Thr
115 120 125
Val Asn Glu Tyr Leu Ala Ser Arg Asp Ala Glu Glu Met Gly Lys Ile
130 135 140
Phe Glu Phe Leu Gly Leu Thr Val Gly Leu Asn Leu Asn Ser Leu Ser
145 150 155 160
Lys Asp Glu Lys Arg Glu Ala Tyr Ala Ala Asp Ile Thr Tyr Ser Thr
165 170 175
Asn Asn Glu Leu Gly Phe Asp Tyr Leu Arg Asp Asn Met Val Leu Tyr
180 185 190
Lys Glu Gln Met Val Gln Arg Pro Leu His Phe Ala Val Ile Asp Glu
195 200 205
Val Asp Ser Ile Leu Ile Asp Glu Ala Arg Thr Pro Leu Ile Ile Ser
210 215 220
Gly Gln Ala Ala Lys Ser Thr Lys Leu Tyr Val Gln Ala Asn Ala Phe
225 230 235 240
Val Arg Thr Leu Lys Ala Asp Gln Asp Tyr Thr Tyr Asp Val Lys Thr
245 250 255
Lys Gly Val Gln Leu Thr Glu Glu Gly Met Thr Lys Ala Glu Lys Ala
260 265 270
Phe Gly Ile Glu Asn Leu Phe Asp Val Arg His Val Ala Leu Asn His
275 280 285
His Ile Ala Gln Ala Leu Lys Ala His Ala Ala Met His Lys Asp Val
290 295 300
Asp Tyr Val Val Glu Asp Gly Gln Val Val Ile Val Asp Ser Phe Thr
305 310 315 320
Gly Arg Leu Met Lys Gly Arg Arg Tyr Ser Asp Gly Leu His Gln Ala
325 330 335
Ile Glu Ala Lys Glu Gly Leu Glu Ile Gln Asn Glu Ser Met Thr Leu
340 345 350
Ala Thr Ile Thr Phe Gln Asn Tyr Phe Arg Met Tyr Glu Lys Leu Ala
355 360 365
Gly Met Thr Gly Thr Ala Lys Thr Glu Glu Glu Glu Phe Arg Asn Ile
370 375 380
Tyr Asn Met Gln Val Val Thr Ile Pro Thr Asn Lys Pro Ile Ala Arg
385 390 395 400
Asp Asp Arg Pro Asp Leu Ile Tyr Arg Thr Met Glu Gly Lys Phe Lys
405 410 415
Ala Val Ala Glu Asp Val Ala Gln Arg Tyr Met Val Gly Gln Pro Val
420 425 430
Leu Val Gly Thr Val Ala Val Glu Thr Ser Glu Leu Ile Ser Arg Leu
435 440 445
Leu Lys Asn Lys Gly Ile Pro His Gln Val Leu Asn Ala Lys Asn His
450 455 460
Glu Arg Glu Ala Gln Ile Ile Glu Asp Ala Gly Gln Lys Gly Ala Val
465 470 475 480
Thr Ile Ala Thr Asn Met Ala Gly Arg Gly Thr Asp Ile Lys Leu Gly
485 490 495
Glu Gly Val Lys Glu Leu Gly Gly Leu Ala Val Ile Gly Thr Glu Arg
500 505 510
His Glu Ser Arg Arg Ile Asp Asn Gln Leu Arg Gly Arg Ser Gly Arg
515 520 525
Gln Gly Asp Pro Gly Ile Thr Gln Phe Tyr Leu Ser Met Glu Asp Glu
530 535 540
Leu Met Lys Arg Phe Gly Ala Glu Arg Thr Met Ala Met Leu Asp Arg
545 550 555 560
Phe Gly Met Asp Asp Ser Thr Pro Ile Gln Ser Lys Met Val Ser Arg
565 570 575
Ala Val Glu Ser Ser Gln Lys Arg Val Glu Gly Asn Asn Phe Asp Ala
580 585 590
Arg Lys Gln Leu Leu Gln Tyr Asp Asp Val Leu Arg Gln Gln Arg Glu
595 600 605
Val Ile Tyr Lys Gln Arg Phe Glu Val Ile Asp Ser Asp Asn Leu Arg
610 615 620
Ser Ile Val Glu Asn Met Ile Lys Ala Ser Leu Glu Arg Ala Val Ala
625 630 635 640
Ser Tyr Thr Pro Lys Glu Asp Leu Pro Glu Glu Trp Asn Leu Asp Gly
645 650 655
Leu Val Glu Leu Val Asn Ala Asn Phe Leu Asp Glu Gly Gly Val Glu
660 665 670
Lys Ser Asp Ile Phe Gly Lys Glu Pro Glu Glu Ile Thr Glu Leu Ile
675 680 685
Tyr Asp Arg Ile Lys Thr Lys Tyr Asp Glu Lys Glu Glu Arg Tyr Gly
690 695 700
Ser Glu Gln Met Arg Glu Phe Glu Lys Val Ile Val Leu Arg Glu Val
705 710 715 720
Asp Thr Lys Trp Met Asp His Ile Asp Ala Met Asp Gln Leu Arg Gln
725 730 735
Gly Ile His Leu Arg Ala Tyr Ala Gln Thr Asn Pro Leu Arg Glu Tyr
740 745 750
Gln Met Glu Gly Phe Ala Met Phe Glu Asn Met Ile Ala Ala Ile Glu
755 760 765
Asp Asp Val Ala Lys Phe Val Met Lys Ala Glu Ile Glu Asn Asn Leu
770 775 780
Glu Arg Glu Glu Val Ile Gln Gly Gln Thr Thr Ala His Gln Pro Lys
785 790 795 800
Glu Gly Asp Glu Glu Lys Gln Ala Lys Lys Lys Pro Val Arg Lys Ala
805 810 815
Val Asp Ile Gly Arg Asn Asp Pro Cys Tyr Cys Gly Ser Gly Lys Lys
820 825 830
Tyr Lys Asn Cys Cys Gly Arg Thr Glu
835 840
Claims (39)
1.一种选择微生物的方法,特征在于
(a)编码必需转位活性的内源性存在的基因被失活,和
(b)根据(a)的转位活性的失活通过载体消除。
2.如权利要求1的方法,特征在于
(c)根据(b)的载体携带转基因。
3.如权利要求1或2的方法,特征在于必需的转位活性是下列因子之一:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或Ffs/Scr)、FtsY/Srb、PrsA或YajC。
4.如权利要求3的方法,特征在于必需的转位活性是下列蛋白前体转位酶的亚基之一:SecA、SecY、SecE、SecD或SecF,优选SecA亚基。
5.如权利要求1-4中任一项的方法,特征在于根据(b)的消除通过作用与失活的内源性存在的必需转位活性相同的活性进行,优选通过遗传相关的活性,特别优选通过同一活性。
6.如权利要求1-5中任一项的方法,特征在于根据(b)的消除通过来自枯草芽孢杆菌(Bacillus subtili)、大肠杆菌(Escherichia coli)和地衣芽胞杆菌(Bacillus licheniformis)的Sec A基因区域恢复转位活性而进行,其分别显示于SEQ ID NO.1,SEQ ID NO.3和SEQ ID NO.5表示的序列中。
7.如权利要求2-6中任一项的方法,特征在于进行根据(a)的失活以阻止根据(a)失活的基因区域和根据(b)载体上同源区域间的重组,优选包含在有关染色体基因中的基因片段完全丢失。
8.如权利要求1-7中任一项的方法,特征在于根据(a)的失活通过删除载体进行,优选通过删除具有外源性可调控复制起点的载体进行,特别优选通过删除具有温度依赖型复制起点的载体进行。
9.如权利要求1-8中任一项的方法,特征在于根据(b)的载体是在微生物中自主复制的质粒。
10.如权利要求9的方法,特征在于所述质粒是多于一个拷贝数,优选多个拷贝数。
11.如权利要求1-10中任一项的方法,特征在于所述微生物是革兰氏阴性细菌株。
12.权利要求11的方法,特征在于涉及的是大肠杆菌(E.coli)属或克雷伯菌(Klebsiella)属的革兰氏阴性细菌株,特别是大肠杆菌K12,大肠杆菌B或植生克雷伯菌(Klebsiella planticola)的衍生物,和非常特别地是大肠杆菌株BL21(DE3),大肠杆菌RV308,大肠杆菌DH5α,大肠杆菌JM109,E.coli XL-1或植生克雷伯菌(Rf)菌株。
13.如权利要求1-10中任一项的方法,特征在于微生物是***。
14.如权利要求13的方法,其特征在于***株是葡萄球菌(Staphylococcus),棒状杆菌(Corynebacteria)或芽孢杆菌(Bacillus)属,特别地是肉葡萄球菌(Staphylococcus carnosus),谷氨酸棒状杆菌(Corynebacterium glutamicum),枯草芽孢杆菌,地衣芽孢杆菌,解淀粉芽孢杆菌(B.amyloliquefaciens),克鲁伯氏芽孢杆菌(B.globigii)或缓慢芽孢杆菌(B.lentus),和非常特别地是地衣芽孢杆菌或解淀粉芽孢杆菌菌株的衍生物。
15.如权利要求2-14中任一项的方法,特征在于根据(c)的转基因是编码非酶蛋白的转基因,特别地是编码药物相关蛋白,非常特别地是编码胰岛素或降钙素的转基因。
16.如权利要求2-14中任一项的方法,特征在于根据(c)的转基因是编码酶的转基因,优选编码水解酶或氧化还原酶,特别优选编码蛋白酶、淀粉酶、半纤维素酶、纤维素酶、脂肪酶、角质素分解酶(cutinase)、氧化酶、过氧化物酶或漆酶。
17.一种通过培养微生物菌株细胞制备蛋白的方法,特征在于权利要求1-16中任一项的选择方法。
18.如权利要求17的方法,特征在于权利要求2-16中任一项的选择方法,根据(c)的转基因编码通过该方法制备的蛋白。
19.如权利要求17或18的方法,特征在于微生物的培养在液体培养基中进行,优选在发酵罐中进行。
20.如权利要求17-19中任一项的方法,特征在于所述的蛋白被分泌到周围培养基中。
21.一种微生物,通过权利要求1-16中任一项的方法获得。
22.如权利要求21的微生物,其特征在于转基因被表达。
23.如权利要求22的微生物,其特征在于转基因被分泌。
24.编码必需转位活性的基因在微生物选择中的应用,特征在于
(a)内源性存在于微生物中所述的必需转位活性被失活,和
(b)根据(a)被失活的必需转位活性通过载体消除。
25.如权利要求24的应用,特征在于
(c)根据(b)的载体携带转基因。
26.如权利要求24或25的应用,特征在于必需的转位活性是下列因子之一:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或Ffs/Scr)、FtsY/Srb、PrsA或YajC。
27.如权利要求26的应用,特征在于必需的转位活性是下列蛋白前体转位酶的亚基之一:SecA、SecY、SecE、SecD或SecF,优选为SecA亚基。
28.如权利要求24-27中任一项的应用,特征在于根据(b)的消除通过作用与失活的内源必需转位活性相同的活性进行,优选通过遗传相关的活性,特别优选通过同一活性。
29.如权利要求24-28中任一项的应用,特征在于根据(b)的消除通过来自枯草芽孢杆菌、大肠杆菌和地衣芽孢杆菌的Sec A基因区域恢复转位活性而进行,其分别显示于SEQ ID NO.1,SEQ ID NO.3和SEQ ID NO.5表示的序列中。
30.如权利要求24-29中任一项的应用,特征在于根据(b)的载体是在微生物中自主复制的质粒。
31.如权利要求30的应用,特征在于该质粒是多于一个拷贝数的质粒,优选是多拷贝数的。
32.一种携带必需转位活性基因和转基因的载体,如果其是唯一的转基因,则不编码抗生素抗性。
33.如权利要求32的载体,特征在于转基因编码药物相关的非酶蛋白或水解酶或氧化还原酶。
34.如权利要求32或33的载体,特征在于其编码的转位活性能消除失活的必需内源性存在于微生物菌株中的转位活性,优选通过遗传相关的活性,特别优选通过同一活性。
35.如权利要求32-34中任一项的载体,特征在于必需的转位活性是下列因子之一:SecA、SecY、SecE、SecD、SecF、信号肽酶、b-SRP(Ffh或Ffs/Scr)、FtsY/Srb、PrsA或YajC。
36.如权利要求35的载体,特征在于必需的转位活性是下列蛋白前体转位酶的亚基之一:SecA、SecY、SecE、SecD或SecF,优选为SecA亚基。
37.如权利要求32-36之一的载体,特征在于必需的转位活性是来自枯草芽孢杆菌、大肠杆菌和地衣芽孢杆菌的secA基因之一的基因,其分别显示于SEQ ID NO.1,SEQ ID NO.3和SEQ ID NO.5的序列中。
38.如权利要求32-37中任一项的载体,特征在于涉及的是在微生物中自主复制的质粒。
39.如权利要求38的载体,特征在于所述的质粒超过一个拷贝数,优选为多拷贝数。
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CNA2004800057644A Pending CN1756835A (zh) | 2003-03-04 | 2004-02-27 | 用作选择标记的转位酶 |
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US (1) | US20060057674A1 (zh) |
EP (1) | EP1599579B1 (zh) |
JP (1) | JP2006519022A (zh) |
CN (1) | CN1756835A (zh) |
AT (1) | ATE391172T1 (zh) |
DE (2) | DE10309557A1 (zh) |
DK (1) | DK1599579T3 (zh) |
ES (1) | ES2303058T3 (zh) |
WO (1) | WO2004078953A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102004040134A1 (de) * | 2004-08-19 | 2006-02-23 | Henkel Kgaa | Neue essentielle Gene von Bacillus licheniformis und darauf aufbauende verbesserte biotechnologische Produktionsverfahren |
JP5140285B2 (ja) * | 2006-02-16 | 2013-02-06 | 花王株式会社 | 組換え微生物 |
DK1985695T3 (da) | 2006-02-16 | 2013-03-11 | Kao Corp | Rekombinant mikroorganisme |
WO2008066931A2 (en) * | 2006-11-29 | 2008-06-05 | Novozymes, Inc. | Bacillus licheniformis chromosome |
JP5140307B2 (ja) * | 2007-04-10 | 2013-02-06 | 花王株式会社 | 組換え微生物 |
DE102007021001A1 (de) | 2007-05-04 | 2008-11-06 | Ab Enzymes Gmbh | Expressionssystem zur antibiotikafreien Produktion von Polypeptiden |
FI3655422T3 (fi) * | 2017-07-21 | 2023-06-13 | Basf Se | Heterologisen ilmentymisen promoottori |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0251579A3 (en) * | 1986-06-24 | 1989-03-22 | Enterovax Research Pty. Ltd. | Non-antibiotic marker system |
AU5170896A (en) * | 1995-02-22 | 1996-09-11 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Seca gene of mycobacterium tuberculosis and related methods and compositions |
US5919999A (en) * | 1996-11-14 | 1999-07-06 | Queen's University At Kingston | Enhanced transport with a plastid membrane transport protein |
EP0894857A3 (en) * | 1997-08-01 | 2001-09-26 | Smithkline Beecham Corporation | SecA gene from Streptococcus pneumoniae |
EP0972838B1 (en) * | 1998-07-15 | 2004-09-15 | Roche Diagnostics GmbH | Escherichia coli host/vector system based on antibiotic-free selection by complementation of an auxotrophy |
DE50107849D1 (de) * | 2000-07-28 | 2005-12-01 | Henkel Kgaa | Neues amylolytisches enzym aus bacillus sp. a 7-7 (dsm 12368) sowie wasch- und reinigungsmittel mit diesem neuen amylolytischen enzym |
EP2311855A3 (en) * | 2000-10-06 | 2011-05-11 | Novozymes Inc. | Bacillus licheniformis YvnA negative strain |
US6872547B1 (en) * | 2000-10-11 | 2005-03-29 | Washington University | Functional balanced-lethal host-vector systems |
DK1337648T3 (da) * | 2000-11-28 | 2008-01-07 | Henkel Kgaa | Ny cyclodextrin-glucanotransferase (CGTase) fra Bacillus agaradherens (DSM 9948) samt vaske- og rengöringsmidler med denne nye cyclodextrin-glucanotransferase |
WO2002077183A2 (en) * | 2001-03-21 | 2002-10-03 | Elitra Pharmaceuticals, Inc. | Identification of essential genes in microorganisms |
DE10121463A1 (de) * | 2001-05-02 | 2003-02-27 | Henkel Kgaa | Neue Alkalische Protease-Varianten und Wasch- und Reinigungsmittel enthaltend diese neuen Alkalischen Protease-Varianten |
DE10131441A1 (de) * | 2001-06-29 | 2003-01-30 | Henkel Kgaa | Eine neue Gruppe von alpha-Amylasen sowie ein Verfahren zur Identifizierung und Gewinnung neuer alpha-Amylasen |
DE10138753B4 (de) * | 2001-08-07 | 2017-07-20 | Henkel Ag & Co. Kgaa | Wasch- und Reinigungsmittel mit Hybrid-Alpha-Amylasen |
DE10153792A1 (de) * | 2001-10-31 | 2003-05-22 | Henkel Kgaa | Neue Alkalische Protease-Varianten und Wasch- und Reinigungsmittel enthaltend diese neuen Alkalischen Protease-Varianten |
DE10162728A1 (de) * | 2001-12-20 | 2003-07-10 | Henkel Kgaa | Neue Alkalische Protease aus Bacillus gibsonii (DSM 14393) und Wasch-und Reinigungsmittel enthaltend diese neue Alkalische Protease |
DE10162727A1 (de) * | 2001-12-20 | 2003-07-10 | Henkel Kgaa | Neue Alkalische Protease aus Bacillus gibsonii (DSM 14391) und Wasch-und Reinigungsmittel enthaltend diese neue Alkalische Protease |
DE10163748A1 (de) * | 2001-12-21 | 2003-07-17 | Henkel Kgaa | Neue Glykosylhydrolasen |
DE10163884A1 (de) * | 2001-12-22 | 2003-07-10 | Henkel Kgaa | Neue Alkalische Protease aus Bacillus sp. (DSM 14392) und Wasch- und Reinigungsmittel enthaltend diese neue Alkalische Protease |
DE10163883A1 (de) * | 2001-12-22 | 2003-07-10 | Henkel Kgaa | Neue Alkalische Protease aus Bacillus sp. (DSM 14390) und Wasch- und Reinigungsmittel enthaltend diese neue Alkalische Protease |
-
2003
- 2003-03-04 DE DE10309557A patent/DE10309557A1/de not_active Withdrawn
-
2004
- 2004-02-27 EP EP04715290A patent/EP1599579B1/de not_active Expired - Lifetime
- 2004-02-27 ES ES04715290T patent/ES2303058T3/es not_active Expired - Lifetime
- 2004-02-27 CN CNA2004800057644A patent/CN1756835A/zh active Pending
- 2004-02-27 JP JP2006504478A patent/JP2006519022A/ja not_active Withdrawn
- 2004-02-27 DE DE502004006718T patent/DE502004006718D1/de not_active Expired - Fee Related
- 2004-02-27 AT AT04715290T patent/ATE391172T1/de not_active IP Right Cessation
- 2004-02-27 DK DK04715290T patent/DK1599579T3/da active
- 2004-02-27 WO PCT/EP2004/001949 patent/WO2004078953A1/de active IP Right Grant
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2005
- 2005-08-31 US US11/216,333 patent/US20060057674A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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US20060057674A1 (en) | 2006-03-16 |
EP1599579A1 (de) | 2005-11-30 |
DE502004006718D1 (de) | 2008-05-15 |
DE10309557A1 (de) | 2004-09-23 |
WO2004078953A1 (de) | 2004-09-16 |
ATE391172T1 (de) | 2008-04-15 |
JP2006519022A (ja) | 2006-08-24 |
WO2004078953A9 (de) | 2005-08-04 |
DK1599579T3 (da) | 2008-08-04 |
ES2303058T3 (es) | 2008-08-01 |
EP1599579B1 (de) | 2008-04-02 |
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