CN100408679C - 碱性蛋白酶 - Google Patents
碱性蛋白酶 Download PDFInfo
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- CN100408679C CN100408679C CNB2004100451021A CN200410045102A CN100408679C CN 100408679 C CN100408679 C CN 100408679C CN B2004100451021 A CNB2004100451021 A CN B2004100451021A CN 200410045102 A CN200410045102 A CN 200410045102A CN 100408679 C CN100408679 C CN 100408679C
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Abstract
本发明提供选自序列号1所示氨基酸序列中(a)15位、(b)16位、(c)166位、(d)167位、(e)187位、(f)346位、(g)405位或相当于所述位点的氨基酸残基是下述氨基酸残基的碱性蛋白酶及其编码基因:(a)位点:组氨酸、(b)位点:苏氨酸或谷氨酰胺、(c)位点:甘氨酸、(d)位点:缬氨酸、(e)位点:丝氨酸、(f)位点:精氨酸、(g)位点:天冬氨酸。所提供的蛋白酶不仅对复合污渍具有良好的洗净效果还提高了蛋白质的分泌量和比活性,从而提高了生产性。
Description
技术领域
本发明涉及碱性蛋白酶及其编码基因。
背景技术
蛋白酶早已在工业领域有所应用,由起初作为衣料洗涤剂到后来涉及纤维改性剂、皮革处理剂、化妆品、浴液、食品改性剂或医药用品方面的多种不同用途。其中,最大量工业化生产的是洗涤剂用蛋白酶,已知的例如:Alcalase、Savinase(注册商标;Novozymes)、Maxacal(注册商标;Genencor)、Blap(注册商标;Henkel)以及KAP(花王公司)。
向洗涤剂中混入蛋白酶的目的在于分解附着于衣料上的蛋白质污渍,实际的污渍不仅是蛋白质,还有来自皮脂的脂质和固体颗粒等以及混入了有机物和无机物的含有多种成分的复合污渍,因此需要获得对这种复合污渍具有强洗净效果的洗涤剂。
基于这样的观点,本发明人发现了数种即使在高浓度脂肪酸存在下也可保持对酪蛋白具有充分分解活性的碱性蛋白酶,所述的碱性蛋白酶不仅对蛋白质、对混有皮脂等的复合污渍也具有良好的洗净性、分子量约为43,000,并已在先申请了专利(国际公开号99/18218)。这一组碱性蛋白酶在分子量、一级结构、酶学性质,特别是对氧化剂具有很强耐性的方面与现有技术中已知来自芽孢杆菌属细菌的属于丝氨酸蛋白酶的枯草杆菌蛋白酶不同,经提议分为新的枯草杆菌蛋白酶亚科(Saeki等,Biochem.Biophys.Res.Commun.,279,313-319,2000)。
为了能对洗净效果优良的蛋白酶进行工业化大生产必须具有高生产性,有关提高生产性的方法包括突变改良生产菌株或改变蛋白酶编码基因或与表达调节相关基因提高蛋白酶的分泌量的方法。此外,也可以改变蛋白酶的编码基因以提高其比活性,基于这样的观点,本发明的发明人已经发现了蛋白质分泌能力和比活性提高的变异碱性蛋白酶(特愿平14-304230号、特愿平14-304231号、特愿平14-304232号)。
但是为了可以大量、廉价地进行酶生产,仍然需要使生产性进一步提高,用这种手段提高蛋白质的分泌量和比活性。
因此,本发明提供既对复合污渍具有良好洗净性、又提高了蛋白质分泌量、比活性且具有高生产性的碱性蛋白酶。
发明内容
本发明的发明人对既保持上述碱性蛋白酶的特性,又提高了分泌量和比活性的新的酶进行探索的过程中,发现对于某种碱性蛋白酶而言,其氨基酸序列中特定位点的特定氨基酸残基是必要的。
即,本发明提供序列号1所示氨基酸序列中(a)15位、(b)16位、(c)166位、(d)167位、(e)187位、(f)346位、(g)405位或相当于所述位点的氨基酸残基是下述氨基酸残基的碱性蛋白酶及其编码基因;
(a)位点:组氨酸、
(b)位点:苏氨酸或谷氨酰胺、
(c)位点:甘氨酸、
(d)位点:缬氨酸、
(e)位点:丝氨酸、
(f)位点:精氨酸、
(g)位点:天冬氨酸。
此外,本发明还提供含有该基因的载体、含有所述载体的转化体。
再有,本发明还提供含有该碱性蛋白酶的洗净剂组合物。
附图的简要说明
图1是与序列号1所示氨基酸序列具有80%或更高同源性的蛋白酶氨基酸序列的排列图。
本发明的最佳实施方式
如上所述,本发明的碱性蛋白酶是在序列号1所示氨基酸序列中(a)15位、(b)16位、(c)166位、(d)167位、(e)187位、(f)346位、(g)405位或相当于所述位点的氨基酸残基是下述氨基酸残基的碱性蛋白酶:(a)位点:组氨酸、(b)位点:苏氨酸或谷氨酰胺、(c)位点:甘氨酸、(d)位点:缬氨酸、(e)位点:丝氨酸、(f)位点:精氨酸、(g)位点:天冬氨酸。
也就是说,本发明的碱性蛋白酶是指:由序列号1所示的氨基酸序列组成的碱性蛋白酶中上述选自(a)~(g)位点的氨基酸残基、或其他碱性蛋白酶氨基酸序列中相应于上述位点的氨基酸残基是特定氨基酸残基的蛋白酶,野生型、野生型的突变体或人工突变体均可。
此处所述的“其他碱性蛋白酶”可以是野生型或野生型的突变体、耐氧化剂、优选通过十二烷基硫酸钠-聚丙烯酰胺电泳(SDS-PAGE)法测得的分子量为43,000±2,000,例如由与序列号1所示氨基酸序列具有80%以上同源性的氨基酸序列组成的碱性蛋白酶。特别优选与序列号1所示氨基酸序列具有80%或更高同源性的氨基酸序列组成的、能在pH8或更高的碱性环境下起作用、耐氧化剂、50℃pH10条件下处理10分钟时活性可残留80%或更高的、受二异丙基氟磷酸(DFP)和苯基甲磺酰氟化物(PMSF)的抑制、SDS-PAGE测定的分子量为43,000±2,000的酶。此处所述的耐氧化剂是指所述的碱性蛋白酶在含有50mM过氧化氢、5mM氯化钠的Britton-Robinson缓冲液(pH 10)中,30℃下放置20分钟后残留活性至少保持在50%以上。
此处所述的“由序列号1所示的氨基酸序列组成的碱性蛋白酶”例如KP43[来自芽孢杆菌-KSM-KP43(FERM BP-6532)国际公开号99/18218]、“由与序列号1所示氨基酸序列具有80%或更高同源性的氨基酸序列组成的碱性蛋白酶”例如,蛋白酶KP9860(GenBank登录号AB046403)[来自芽孢杆菌-KSM-9860(FERM BP-6534)、国际公开号99/18218]、蛋白酶9865(GenBank登录号AB084155)[来自芽孢杆菌-KSM-9865(FERM P-1592)、特愿2002-002653]、蛋白酶E-1(GenBank登录号AB046402)[来自芽孢杆菌No.D-6(FERMP-1592)、特开昭49-71191号公报]、蛋白酶Ya(GenBank登录号AB046404)[来自芽孢杆菌-Y(FERM BP-1029)、特开昭61-280268号公报]、蛋白酶SD521(GenBank登录号AB046405)[来自芽孢杆菌SD521(FERM P-11162)、特开平3-191781号公报]、蛋白酶A-1(GenBank登录号AB046406)[来自NCIB12289、国际公开号88/01293号]、蛋白酶A-2[来自NCIB12513、国际公开号8/56927号]、特开2002-218989号公报、特开2002-306176号公报记载的突变蛋白酶、序列号1所示的氨基酸序列中第251位分别被天冬酰胺、苏氨酸、异亮氨酸、缬氨酸、亮氨酸或谷氨酰胺替代的突变体、第256位分别被丝氨酸、谷氨酰胺、天冬酰胺、缬氨酸或丙氨酸替代的突变体(特愿2001-329472号)、序列号1所示的氨基酸序列中第65位由脯氨酸替代的突变体、101位由天冬酰胺替代的突变体、273位分别由异亮氨酸、甘氨酸、苏氨酸替代的突变体、320位分别由苯丙氨酸、缬氨酸、苏氨酸、亮氨酸、异亮氨酸或甘氨酸替代的突变体、359位分别由丝氨酸、亮氨酸、缬氨酸、异亮氨酸或谷氨酰胺替代的突变体、387分别由丙氨酸、赖氨酸、谷氨酰胺、谷氨酸、精氨酸或组氨酸替代的突变体(特愿2002-304230号)、序列号1所示氨基酸序列的第163位由组氨酸、天冬氨酸、苯丙氨酸、赖氨酸、天冬酰胺、丝氨酸、异亮氨酸、亮氨酸、谷氨酰胺、苏氨酸或缬氨酸替代的突变体、第170位由缬氨酸或亮氨酸替代的突变体、第171位由丙氨酸、谷氨酸、甘氨酸、或苏氨酸替代的突变体(特愿2002-304231号)或与以上氨基酸序列具有80%或更高、优选87%或更高、较优选90%或更高、更优选95%或更高同源性的碱性蛋白酶。
比外,氨基酸序列的同源性根据Lipman-Pearson法(Science,227,1435,1985)计算。
此外,确定“相应于该位点的氨基酸序列”的方法可以是,例如通过Lipman-Pearson法等公知的算法对氨基酸序列进行比较、得出与存在于各碱性蛋白酶氨基酸序列中的保守性氨基酸残基间的最大同源性。按上述方法排列蛋白酶氨基酸序列、不涉及氨基酸序列中的***、缺失、可以确定相同的氨基酸残基在不同蛋白酶序列中的位点。一般认为所述相同的位点也存在于三级结构中相同的位点,可以推定其具有与被研究的蛋白酶的相关特异功能类似的效果。
即,根据用上述方法排列的氨基酸序列组成的图1,(a)序列号1所示的氨基酸序列中第15位的氨基酸残基是丝氨酸残基、相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶E-1中第15位的精氨酸残基。优选该氨基酸残基是组氨酸残基。
(b)序列号1所示的氨基酸序列中第16位的氨基酸残基是丝氨酸,此处,相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶E-1中第16位的天冬酰胺残基。优选该氨基酸残基是苏氨酸残基或谷氨酰胺残基。
(c)序列号1所示的氨基酸序列中第166位的氨基酸残基是天冬酰胺残基,此处,相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶Ya中第165位的天冬酰胺残基。优选该氨基酸残基是甘氨酸残基。
(d)序列号1所示的氨基酸序列中第167位的氨基酸残基是甘氨酸残基,此处,相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶Ya中第166位的丝氨酸残基。优选所述氨基酸残基是缬氨酸残基。
(e)序列号1所示的氨基酸序列中第187位的氨基酸残基是天冬酰胺残基,此处,相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶SD-521中第186位的天冬酰胺残基。优选该氨基酸残基是丝氨酸残基。
(f)序列号1所示的氨基酸序列中第346位的氨基酸残基是赖氨酸残基,此处,相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶KP9860中第346位的赖氨酸残基。优选该氨基酸残基是精氨酸残基。
(g)序列号1所示的氨基酸序列中第405位的氨基酸残基是天冬酰氨残基,此处,相应于该位点的氨基酸残基用上述方法可以推定为,例如蛋白酶KP9860中第405位的天冬酰胺残基。优选该氨基酸残基是天冬氨酸残基。
(表1)显示出适用于上述“其他碱性蛋白酶”中的、相应于蛋白酶KP43的氨基酸序列(序列号1)的(a)15位、(b)16位、(c)166位、(d)167位、(e)187位、(f)346位、(g)405位的位点或相应于上述位点的氨基酸残基的位点,以及氨基酸残基的具体例子。
表1
此外,在不使酶活性及酶学特性发生变化的范围内,优选本发明的碱性蛋白酶氨基酸序列中的(a)~(g)的选择可以是上述(a)~(g)中的两个位点以上同时进行。两个位点以上同时进行的情况中的优选实例如下所示。此外,氨基酸用三字母表示,“+”表示一个氨基酸的替换附加的替换。
两个位点发生替换的例子如Ser15His+Ser16Thr、Ser15His+Ser16Gln、Lys346Arg+Asn405Asp、Asn187Ser+Lys346Arg、Asn166Gly+Gly167Val,特别优选Ser15His+Ser16Gln、Lys346Arg+Asn405Asp、Asn166Gly+Gly167Val。
三个位点发生替换的例子如Ser15His+Ser16Thr+Asn187Ser、Ser15His+Ser16Gln+Asn187Ser、Asn187Ser+Asn166Gly+Gly167Val,特别优选Ser15His+Ser16Gln+Asn187Ser、Asn187Ser+Asn166Gly+Gly167Val。
在满足本发明的条件的范围内也可以是四个位点到七个位点的替换,特别优选Ser15His+Ser16Gln+Asn166Gly+Gly167Val+Asn187Ser+Lys346Arg+Asn405Asp。
本发明的碱性蛋白酶是突变体时,作为突变前的碱性蛋白酶(往往称作亲代碱性蛋白酶)的是“由序列号1所示的氨基酸序列组成的蛋白酶”或上述的“其他碱性蛋白酶”所表示的蛋白酶,对这些蛋白酶的目的部位进行突变可得到本发明的碱性蛋白酶。例如蛋白酶KP43序列号1所示的氨基酸序列中前述(a)~(g)位点的氨基酸残基、或是碱性蛋白酶氨基酸序列中相应于上述位点的氨基酸残基被其他的氨基酸残基替代所得。
本发明的碱性蛋白酶也可由下述方法获得。即对所克隆的亲代碱性蛋白酶编码基因(序列号2:成熟酶区域,即序列号1的编码基因第619号密码子之后的部分所示的)进行突变,用所得的突变基因转化适当的宿主菌,培养经转化的宿主菌,再从培养物中收集所得。克隆亲代碱性蛋白酶的编码基因可以使用常规的基因转化技术,例如可以使用在国际公开号99/18218号、国际公开号第98/56927号中记载的方法。
有关对亲代碱性蛋白酶的编码基因的突变手段,通常应用的随机突变和定点诱变方法均可使用。更具体说来,可以使用例如“定点诱变***超突变表达Km试剂盒(Site-Directed Mutagenesis System Mutan-Super Express Km kit)”(Takara)。此外,也可以用重组体PCR(聚合酶链式反应)法(PCR方法,科学出版社,纽约,1990(PCRprotocols,Academic press,NewYork,1990))、可将基因的任意序列用其他基因中与该任意序列相应的序列替代。
用所得的突变基因生产本发明的蛋白酶的方法,例如可采用将所述的突变基因与可使其稳定扩增的DNA载体相连,转化宿主菌,或将所述的突变体基因导入可使其稳定存在的宿主菌染色体DNA上等方法。满足上述条件的宿主菌例如:芽孢杆菌属的细菌、大肠杆菌、霉菌、酵母、放线菌等,将这些菌株接种到含同化碳源、氮源及其他必需营养元素的培养基中,通过常规方法培养。
按照常规的酶提取纯化方法从上述培养液中收集、纯化碱性蛋白酶。例如,将所述培养液离心分离、或过滤去除菌体,利用常规的纯化方法从上清液中收集目的酶。由上述方法所得的酶液可以直接使用,也可以通过公知的方法纯化、结晶化、粉末化或颗粒化。
所得的本发明的碱性蛋白酶具有耐氧化剂、对酪蛋白的分解活性不受高浓度的脂肪酸的抑制、SDS-PAGE测得的分子量43,000±2,000,在碱性环境下具有活性的同时,与亲代碱性蛋白酶相比获得了比活性提高、蛋白分泌量提高的新性质。
因此,本发明的碱性蛋白酶可作为与各种洗涤剂组合物混合使用的酶。
向洗涤剂组合物中加入的本发明的碱性蛋白酶的混合量,只要可以显示出碱性蛋白酶活性,对所述的量没有特别地限制,每1kg洗涤剂组合物混合0.1~5000PU,从经济性角度考虑优选00PU以下。
可将本发明的蛋白酶与其他的各种蛋白酶一起应用于本发明的洗涤剂组合物。例如水解酶、氧化酶、还原酶、转移酶、裂解酶、异构酶、连接酶、合成酶等。其中,优选本发明以外的蛋白酶、纤维素酶、角蛋白酶、酯酶、角质酶、淀粉酶、脂酶、支链淀粉酶、果胶酶、甘露聚糖酶、葡萄糖苷酶、葡聚糖酶、胆固醇氧化酶、过氧化物酶、漆酶等,特别优选蛋白酶、纤维素酶、淀粉酶、脂酶。作为蛋白酶,例如市售的Alcalase、Esperase、Savinase、Everlase、Kannase(注册商标;Novozymes公司)、Properase、Purafect(注册商标;Genencor公司)以及KAP(花王公司)等。作为纤维素酶,例如Celluzyme、Carezyme(注册商标;Novozymes公司)、以及KAC、特开平10-313859号公报记载的芽孢杆菌种-KSM-S237菌株生产的碱性蛋白酶、特愿2002-116553号公报记载的突变碱性蛋白酶(以上为花王公司产品)。作为淀粉酶,例如Termamyl、Duramyl(注册商标;Novozymes公司)、Purastar(注册商标;Genencor公司)、以及KAM(花王公司)等。作为脂酶,例如Lipolase、Lipolase Ultra(注册商标;Novozymes公司)。
洗涤剂组合物中,与本发明的蛋白酶一起使用的本发明的蛋白酶之外的蛋白酶的混合量优选是每1kg洗涤剂组合物0.1~500PU。与纤维素酶共用时,根据特开平10-313859号公报第[0020]段中记载的酶活性测定方法确定的单位(KU),优选每1kg洗涤剂组合物300~3000000KU。
与淀粉酶共用时,根据特开平11-43690号公报第[0040]段中记载的淀粉酶活性测定方法确定的单位(IU)、优选每1kg洗涤剂组合物50~500000IU。
与脂酶共用时,根据特表平8-500013号公报实施例1中记载的脂酶活性测定方法确定的单位(LU),优选每1kg洗涤剂组合物10000~1000000LU。
可向本发明的洗涤剂组合物中混合公知的洗涤剂组分,所述的公知洗涤剂组分例如下述的物质。
(1)表面活性剂
向洗涤剂组合物中混入0.5~60质量%的表面活性剂、特别对粉末状洗涤剂组合物优选混入10~45质量%、对液体洗涤剂组合物优选混入20~50质量%。本发明的洗涤剂组合物作为漂白剂或自动餐具洗净机用洗涤剂时,其中的表面活性剂通常占1~10质量%,优选占1~5质量%。
作为用于本发明的洗涤剂组合物的表面活性剂可以是阴离子表面活性剂、非离子表面活性剂、两性表面活性剂、阳离子表面活性剂中的一种或其组合,优选是阴离子表面活性剂、非离子表面活性剂。
作为阴离子表面活性剂优选碳原子数10~18的醇的硫酸酯盐、碳原子数8~20的醇的烷氧基化物的硫酸酯盐、烷基苯磺酸盐、链烷烃磺酸盐、α-链烯烃磺酸盐、α-磺基脂肪酸盐、α-磺基脂肪酸烷基酯盐或脂肪酸盐。在本发明中特别是,烷基链的碳原子数为10~14、优选12~14的直链烷基苯磺酸盐,作为抗衡离子优选碱金属盐或胺类、特别优选钠和/或钾、一乙醇胺、二乙醇胺。
作为非离子表面活性剂优选聚氧化烯烷基(碳原子数8~20)醚、烷基聚糖苷、聚氧化烯烷基(碳原子数8~20)苯基醚、聚氧化烯山梨糖醇酐脂肪酸(碳原子数8~22)酯、聚氧化烯二醇脂肪酸(碳原子数8~22)酯、聚氧乙烯聚丙烯嵌段聚合物。特别地,作为非离子表面活性剂,碳原子数10~18的醇和4~20摩尔环氧乙烷、环氧丙烷等环氧化物加成[HLB值(Griffin法计算所得)10.5~15.0,优选11.0~14.5]所得的聚氧化烯基烷基醚。
(2)二价金属离子捕获剂
二价金属离子捕获剂的混合量为0.01~50质量%,优选5~40质量%。用于本发明洗涤剂组合物的二价金属离子捕获剂例如,三聚磷酸盐、焦磷酸盐、正磷酸盐等缩合磷酸盐、沸石等铝硅酸盐、合成层状结晶性硅酸盐、次氮基三乙酸盐、乙二胺四乙酸盐、柠檬酸盐、异柠檬酸盐、聚醛缩羧酸盐等。其中特别优选结晶性铝硅酸盐(合成沸石),A型、X型、P型沸石中特别优选A型。适于使用的合成沸石平均原始粒径0.1~10μm、特别适用的是0.1~5μm。
(3)碱性试剂
混合0.01~80%质量%、优选1~40质量%的碱性试剂。在粉末洗涤剂的情况下,可举出的例子如,统称为浓灰(dense ash)、轻灰的碳酸钠等碱金属碳酸盐,以及JIS1号、2号、3号等非晶体碱金属硅酸盐。这些无机碱性试剂在洗涤剂干燥时对颗粒成形起作用,可以得到相对硬的流动性良好的洗涤剂。除此之外的碱例如,倍半碳酸钠、碳酸氢钠等。此外,三聚磷酸盐等也具有作为碱性试剂的作用。此外,作为用于液体洗涤剂的碱性试剂除上述之外也可以用氢氧化钠、以及单、二和三乙醇胺,也可以用作活性剂的抗衡离子。
(4)再污染抑制剂
混合0.001~10%质量%、优选1~5质量%的再污染抑制剂。用于本发明的洗涤剂组合物的再污染抑制剂可举出的例如,聚乙二醇、羧酸类聚合物、聚乙烯醇、聚乙烯吡咯烷酮等。其中羧酸类聚合物除能防止再污染之外,还具有金属离子捕获功能,以及使固体颗粒污渍从衣料分散到洗涤液中的作用。适用的羧酸类聚合物是丙烯酸、异丁烯酸、衣康酸等的均聚物或共聚物,适用的共聚物是上述的单体和顺丁烯二酸的共聚物,分子量优选几千~10万。除上述的羧酸类聚合物之外,由于聚缩水甘油酸盐等聚合物、羟甲基纤维素等纤维素衍生物、以及聚天冬氨酸等氨基羧酸类聚合物也具有金属离子捕获剂、分散剂和防止再污染的功能,因此也是优选的。
(5)漂白剂
优选混入例如1~10质量%的过氧化氢、过碳酸盐等漂白剂。使用漂白剂时可混入0.01~10质量%的四乙酰乙二胺(TAED)、特开平6-316700中记载的漂白活化剂(活化因子)。
(6)荧光剂
可用于本发明洗涤剂组合物的荧光剂例如联苯型荧光剂(例如,TinopalCBS-X等)或二苯乙烯型荧光剂(例如DM型荧光染料等)。优选混入0.001~2质量%的荧光剂。
(7)其他组分
在本发明的洗涤剂组合物中可包含衣料用洗涤剂领域所公知的赋形剂、柔软剂、还原剂(亚硫酸盐等)、止泡剂(硅酮等)、香料以及其他的添加剂。
本发明的洗涤剂组合物可通过将经上述方法获得的本发明的蛋白酶与上述公知的洗净组分混合以常规的方法制造来获得。洗涤剂的形态可根据其用途来选择,例如液体、粉末、颗粒、糊浆、固体等。
所得的本发明的洗涤剂组合物可用作衣料洗涤剂、漂白剂、硬质表面用洗涤剂、排水管洗涤剂、假牙洗涤剂、医疗器具杀菌用洗涤剂。
实施例
实施例1
对2.0kb包含终止密码子的芽孢杆菌种-KSM-KP43的碱性蛋白酶结构基因,用无错误修复功能的Takara Taq(Takara)及适量的硫酸镁和二甲亚砜进行易错PCR反应引入随机突变。用引物1(序列号3)和引物2(序列号4)对上述的约2.0kbDNA进行PCR扩增反应。引物1向正义链5’末端引入BamHI接头,引物2向反义链5’末端引入XbaI接头。PCR反应条件为94℃下使模板DNA变性2分钟后,94℃1分钟、55℃1分钟、72℃2分钟的一个循环后,再进行30个循环的反应。将扩增所得的PCR片段用PCR纯化试剂盒(罗氏公司)纯化,用BamHI和XbaI切割末端限制酶接头。扩增所得的DNA与经BamHI和XbaI处理的质粒pHA64(特愿平8-323050:启动子64下游具有BamHI、XbaI切割位点)混合后,用Ligation high(东洋纺)进行连接反应。乙醇沉淀,用从连接反应液中回收的质粒转化宿主芽孢杆菌KSM9865(FERM-18566)。
9865菌株的转化子在含有脱脂牛奶的碱性琼脂培养基[脱脂牛奶(Difico)1%(w/v)、细菌用胰蛋白胨(Difico)1%、酵母抽提物(Difico)0.5%、氯化钠1%、琼脂1.5%、碳酸钠0.05%、四环素15ppm]中繁殖,根据晕圈形成的情况判断是否导入了突变碱性蛋白酶基因。将转化子接种到5mL种子培养基中[6.0%(w/v)聚胨S、0.05%酵母抽提物、1.0%麦芽糖、0.02%的7水硫酸镁、0.1%的磷酸二氢钾、0.25%碳酸钠、30ppm四环素],在30℃下振荡培养16小时。然后将1%的种子培养液(v/v)接种到30mL的主培养基[8%聚胨S、0.3%酵母抽提物、10%麦芽糖、0.04%的7水硫酸镁、0.2%的磷酸二氢钾、1.5%无水碳酸钠、30ppm四环素]在30℃下振荡培养3天。
离心分离所得的培养液,测定培养液上清中的蛋白酶活性。用以酪蛋白为基质的活性测定方法测定蛋白酶的活性,用蛋白检测试剂盒(和光纯药)测定蛋白质的量。与在相同的条件培养带有野生型酶基因的转化子的培养物上清液进行比较,选择已确认蛋白酶活性提高了的突变蛋白酶基因。
用高纯度质粒分离试剂盒(罗氏公司)从选出的转化子中回收质粒后,确定碱基序列。用300ng质粒DNA作为模板,用引物和Big染料DNA测序试剂盒(Applied Biosystems)在20μL的反应体系中进行PCR反应,用DNA测序仪377型(Applied Biosystems)进行分析。结果蛋白酶生产性提高的突变体是第15位的丝氨酸被组氨酸替代的酶、第16位的丝氨酸被苏氨酸替代的酶、第15和16位的丝氨酸分别被组氨酸、谷氨酰胺替代的二重突变体、166位的天冬酰胺被甘氨酸替代的酶、167位的甘氨酸被缬氨酸替代的酶、166位的天冬酰胺以及167位的甘氨酸分别被甘氨酸、缬氨酸替代的二重突变体、187位的天冬酰胺被丝氨酸替代的酶、346位的赖氨酸被精氨酸替代的酶、405位天冬酰胺被天冬氨酸替代的酶、346位的赖氨酸和405位的天冬酰胺分别被精氨酸和天冬氨酸替代的二重突变体。上述生产性显著提高的突变体是第15位的丝氨酸和16位的丝氨酸分别被组氨酸、谷氨酰胺替换的二重突变体、166位的天冬酰胺和167位的甘氨酸分别被甘氨酸、缬氨酸替代的二重突变体、346位的赖氨酸和第405位的天冬酰胺分别被精氨酸和天冬氨酸替代的二重突变体,以及第187位的天冬酰胺被丝氨酸替代的突变体。
将培养液的一部分进行稀释,装入含2mM氯化钙的10mM tris-HCl缓冲液(pH7.5)平衡的DEAE-Toyopearl(东ソ一)柱中回收非吸附组分,得到大致均一的蛋白酶。根据纯化酶的蛋白质的量、蛋白质的分解活性测定结果可知生产性提高的主要原因是:以野生型酶的分泌量、比活性为100%,上述导入了突变的蛋白质的分泌量提高(102-108%)、比活性提高(104-121%)(表2)。
为将各突变点进行组合用引物1~8(序列号3-10)和Pyrobest(Takara)以重组PCR方法制备多重突变体。即,以野生型基因和突变基因分别作为模板,用引物1(序列号3)和引物3(序列号5)扩增含碱性蛋白酶结构基因翻译起始点起15位和16位的约700bp的DNA片段,用引物4(序列号6)和引物5(序列号7)扩增含166位和167位的约500bp的DNA片段,用引物6(序列号8)和引物7(序列号9)扩增含187位的约400bp的DNA片段,用引物2(序列号4)和引物8(序列号10)扩增含346位和405位、且直至碱性蛋白酶结构基因终止密码子的约500bp的DNA片段,分别组合制备各种突变体。培养各突变体评价蛋白酶的生产性,确定了S15H/S16Q/K346R/N405D、S15H/S16Q/N187S/K346R/N405D和S15H/S16Q/N166G/G167V/N187S/K346R/N405D的生产性的提高。生产性提高的主要原因是:以野生型酶的蛋白质分泌量、比活性为100%时,各多重突变体的蛋白质的分泌量提高(107-112%)、比活性提高(103-115%)(表2)。
表2
相对蛋白质分泌量(%) | 相对比活性(%) | |
野生型 | 100 | 100 |
S15H+S16T | 102 | 101 |
S15H+S16Q | 108 | 104 |
N166G+G167V | 100 | 121 |
N187S | 101 | 108 |
K346R+N405D | 102 | 107 |
S15H+S16Q+K346R+N405D | 112 | 103 |
S15H+S16Q+N187S+K346R+N405D | 107 | 113 |
S15H+S16Q+N166G+G167V+N187S+K346R+N405D | 111 | 115 |
上述本发明的碱性蛋白酶的突变体相对于酪蛋白的蛋白质分泌量提高了或比活性提高了、或者蛋白质的分泌量和比活性提高了,除此之外仍保持了亲代碱性蛋白酶的特性,即具有耐氧化性、对酪蛋白的分解活性不受高浓度脂肪酸存在的影响,根据SDS-PAGE确定的分子量为43,000±2,000,在碱性条件下具有活性。
参考例
<蛋白酶活性测定法(酪蛋白法)>
1mL含酪蛋白(Hammerstein法:Merck公司)1%(w/v)的50mM硼酸缓冲液(pH 10.5)在30℃下恒温5分钟后,添加0.1mL的酶液开始反应。反应15分钟后加入2mL的反应终止液(0.11M三氯乙酸/0.22醋酸钠/0.33M醋酸)。在室温下放置30分钟后用Waterman No1号滤纸过滤沉淀物。用Lowry等的方法对分解产物进行定量。即,向0.5mL的滤液中加入2.5mL的碱性铜溶液(1%Rochelle盐∶1%5水硫酸铜∶2%碳酸钠/0.1氢氧化钠=1∶1∶100)30℃恒温10分钟后,加0.25mL苯酚试剂(关东化学)[市售的苯酚试剂在去离子水中稀释两倍所得的溶液],充分搅拌,在30℃下放置30分钟。然后测定660nm下的吸光值。在上述反应条件下,1分钟内生成相当于1mmoL酪氨酸的酸可溶性蛋白质酸所需的酶量作为蛋白酶1单位(1PU)。
实施例2
(1)洗涤剂的配制
向带有搅拌翼的1m3混合槽中加入465kg水,当水温达到55℃后加入135g40%(w/v)的聚丙烯酸钠水溶液。搅拌15分钟后添加120kg碳酸钠、60kg硫酸钠、9kg亚硫酸钠、3kg荧光染料。再搅拌15分钟后,加入300kg沸石,再搅拌30分钟后可得到匀质的浆料(浆料中的水分为50质量%)。所述的浆料经设置于喷雾干燥塔塔顶附近的压力喷雾管嘴喷雾得到基质颗粒(向喷雾干燥塔提供的高温气体从塔下部225℃输入、从塔顶105℃排出)。
然后向Lodige mixer(松阪技研公司制造、容量20L、附套管)中投入100质量份的上述基质颗粒,在主轴搅拌下(150rpm)3分钟内投入20质量份非离子表面活性剂、22质量份的直链烷基(碳原子数10~13)苯磺酸钠、4质量份的脂肪酸钠(碳原子数14~18)、2质量份的聚乙二醇、4质量份的水的混合液,再搅拌5分钟。然后向搅拌器中投入20质量份的结晶性硅酸钠和10质量份的沸石,获得进行表面被覆的洗涤剂基质。
向99质量%的洗涤剂基质中混入0.5质量%的本发明的蛋白酶颗粒和0.5质量%的香料获得最终的颗粒状洗涤剂A。
(2)使用的原料
非离子表面活性剂:环氧乙烷平均加成摩尔数8.5的Emulgen 108KM(花王公司制造)
聚丙烯酸钠水溶液:平均分子量10000(按照特公平2-24283号公报中记载的实施例中所述方法制造)。
碳酸钠:浓灰(セントラル硝子公司制造)
沸石:平均粒径3.5μm的4A型沸石(东ソ一公司制造)
聚乙二醇:K-PEG6000(平均分子量8500,花王公司制造)
结晶性硅酸钠:粉末SKS-6(Hoechst Tokuyama公司制造)
本发明的蛋白酶颗粒:表2中记载的本发明的碱性蛋白酶的各种纯化样品按照特开昭62-257990号公报中实施例1所述的方法制备成的颗粒化物(6PU/g)。
荧光染料:Tinopal CBS-X(Ciba-Geigy公司制造)。
实施例3
(1)洗涤剂的配制
将固形物占50质量%的料浆用250℃的热风喷雾干燥,获得聚丙烯酸钠(质量平均分子量10000)7质量%、碳酸钠26质量%、硫酸钠20质量%、氯化钠6质量%、荧光染料0.5质量%、沸石40质量%、水0.5质量%的基质颗粒。
然后向Lodige mixer(松阪技研公司制造、容量20L、附套管)中投入100质量份的上述基质颗粒,在主轴搅拌下(150rpm)3分钟内投入20质量份的非离子表面活性剂、22质量份的直链烷基(碳原子数10~13)苯磺酸钠、4质量份的脂肪酸钠(碳原子数14~18)、2质量份的聚乙二醇、4质量份的水的混合液,再搅拌5分钟。然后向搅拌器中投入20质量份的结晶性硅酸钠和10质量份的沸石,获得进行表面被覆的洗涤剂基质。
向95质量%的洗涤剂基质中混入2.8质量%的漂白剂颗粒、1.2质量%的漂白活性剂颗粒、0.5质量%的本发明的蛋白酶颗粒和0.5质量%的香料获得最终的颗粒状洗涤剂B。
(2)使用的原料
非离子表面活性剂:环氧乙烷平均加成摩尔数8.5的Emulgen 108KM(花王公司制造)
聚丙烯酸钠水溶液:平均分子量10000(按照特公平2-24283号公报中记载的实施例中所述方法制造)。
碳酸钠:浓灰(セントラル硝子公司制造)
沸石:平均粒径3.5μm的4A型沸石(东ソ一公司制造)
聚乙二醇:K-PEG6000(平均分子量8500,花王公司制造)
结晶性硅酸钠:粉末SKS-6(Hoechst Tokuyama公司制造)
本发明的蛋白酶颗粒:由表2中记载的本发明的碱性蛋白酶的各种纯化样品按照特开昭62-257990号公报中实施例所述的方法制备成的颗粒化物(6PU/g)。
荧光染料:Tinopal CBS-X(Ciba-Geigy公司制造)。
实施例4
配制如表3所示的洗涤剂组合物(洗涤剂C和洗涤剂D)。
表3
成分 | 洗涤剂C(质量%) | 洗涤剂D(质量%) |
非离子表面活性剂<sup>1)</sup> | 25.0 | - |
非离子表面活性剂<sup>2)</sup> | 5.0 | - |
非离子表面活性剂<sup>3)</sup> | 10.0 | - |
非离子表面活性剂<sup>4)</sup> | - | 9.0 |
非离子表面活性剂<sup>5)</sup> | - | 9.0 |
非离子表面活性剂<sup>6)</sup> | - | 2.5 |
阴离子表面活性剂<sup>7)</sup> | 1.0 | - |
硅酮<sup>8)</sup> | - | 0.8 |
羧酸类聚合物<sup>9)</sup> | 2.0 | - |
聚合物<sup>10)</sup> | - | 0.8 |
柠檬酸 | 0.2 | - |
氯化钙 | 0.05 | - |
单乙醇胺 | 4.0 | - |
三甘醇苯基醚 | 3.0 | - |
丙二醇 | 3.0 | - |
乙醇 | 2.0 | 2.0 |
亚硫酸钠 | 0.2 | - |
本发明的蛋白酶<sup>11)</sup> | 0.5 | 1.0 |
香料 | 0.5 | 0.5 |
水 | 剩余 | 剩余 |
合计 | 100 | 100 |
使用浓度 | 20g/30L | 40g/30L |
洗净液pH | 10.5 | 7.3 |
1)来自碳原子数12~14的仲醇的带有烷基的聚氧乙烯(平均7摩尔加成)烷基醚(Softanol 70,日本催化剂化学工业公司制造)
2)来自碳原子数12~14的仲醇的带有烷基的聚氧乙烯(平均12摩尔加成)烷基醚(Softanol 120,日本催化剂化学工业公司制造)
3)碳原子数10~14的直链伯醇与平均5摩尔EO、平均2摩尔PO、平均3摩尔EO顺次嵌段加成的产物。
4)环氧乙烯月桂基醚与平均8摩尔的EO加成的产物
5)环氧乙烯月桂基醚与平均11.5摩尔的EO加成的产物
6)Narrow range聚氧乙烯烷基(sec-C12/C13)醚
7)碳原子数10~14的直链烷基苯磺酸钠
8)酰胺/醚变性硅酮聚合物(东レ.ダウコ一ニングシリコ一ン公司制造,BY16-906)
9)按照特开平10-60476号公报的第11页第6行~13行记载的方法合成的苯氧基聚乙二醇、丙烯酸、顺丁烯二酸共聚物(质量平均分子量10000、固形物占51.2%)
10)戊烯/顺丁烯二酸(50/50摩尔比)共聚物的钠盐(质量平均分子量7000)
11)表2所记载的本发明的碱性蛋白酶的各种纯化样品(15PU/mL)
实施例5
下述表4所示的组成中,一边搅拌混合过碳酸钠和碳酸钠(浓灰),一边添加聚丙烯酸钠40%水溶液,和直链烷基苯磺酸钠、或非离子表面活性剂、或月桂酰氧基苯磺酸钠。然后添加按照特开昭62-257990号公报的实施例1中记载的方法制备的本发明的碱性蛋白酶颗粒,搅拌至全部均一的程度,配制漂白剂。
表4
成分 | 漂白剂E(质量%) | 漂白剂F(质量%) |
过碳酸钠<sup>1)</sup> | 72.0 | 72.0 |
碳酸钠(浓灰) | 20.0 | 20.0 |
阴离子表面活性剂<sup>2)</sup> | 2.0 | - |
非离子表面活性剂<sup>3)</sup> | - | 2.0 |
聚丙烯酸钠<sup>4)</sup> | 1.0 | 1.0 |
月桂酰氧基苯磺酸钠 | 4.0 | 4.0 |
本发明的碱性蛋白酶<sup>5)</sup> | 1.0 | 1.0 |
1)粒径500~700μm
2)碳原子数12~14的直链烷基苯磺酸钠
3)聚氧乙烯烷基醚(烷基的碳原子数12~14、EO的平均加成摩尔数12)
4)平均分子量8,000
5)表2中记载的本发明的碱性蛋白酶的各种纯化样品按照特开昭62-257990号公报中实施例1所述的方法制备成的颗粒化物(6PU/g)。
实施例6
配制如下述表5所示的全自动餐具清洗机用洗涤剂组合物(洗涤剂G、和H)。
表5
成分 | 洗涤剂G(质量%) | 洗涤剂H(质量%) |
Pluronic L-61<sup>1)</sup> | - | 4.0 |
Softanol EP-7085<sup>2)</sup> | 4.0 | - |
柠檬酸三钠 | - | 30.0 |
三聚磷酸钠 | 30.0 | - |
过碳酸钠 | 20.0 | 20.0 |
碳酸钠 | 20.0 | 20.0 |
非结晶硅酸盐<sup>3)</sup> | 10.0 | 10.0 |
AA-MA<sup>4)</sup> | 4.0 | 4.0 |
硫酸钠 | 10.0 | 10.0 |
α-淀粉酶<sup>5)</sup> | 1.0 | 1.0 |
本发明的碱性蛋白酶<sup>6)</sup> | 1.0 | 1.0 |
1)聚氧乙烯-聚氧丙烯共聚物(平均分子量2,000)
2)碳原子数12~14的仲醇的7摩尔环氧乙烯、和8.5摩尔的环氧丙烯加成物。
3)JIS 2号硅酸钠
4)丙烯酸-顺丁烯二酸共聚物
5)Duramyl 60T(注册商标;Novozymes公司制造)
6)表2中记载的本发明的碱性蛋白酶的各种纯化样品按照特开昭62-257990号公报中实施例所述的方法制备成的颗粒化物(6PU/g)。
实施例7
用下述表6中所示的各组分配制硬质表面用洗涤剂组合物(洗涤剂J)。
表6
成分 | 洗涤剂J(质量%) |
阴离子表面活性剂<sup>1)</sup> | 15.0 |
非离子表面活性剂<sup>2)</sup> | 5.0 |
非离子表面活性剂<sup>3)</sup> | 5.0 |
两性表面活性剂<sup>4)</sup> | 7.5 |
两性表面活性剂<sup>5)</sup> | 4.0 |
柠檬酸 | 1.0 |
聚丙二醇<sup>6)</sup> | 2.0 |
乙醇 | 5.0 |
本发明的蛋白酶<sup>7)</sup> | 1.0 |
香料、水、其他/ph调节剂 | 54.5 |
合计 | 100.0 |
1)聚氧乙烯(EOP=4)烷基(C12)醚硫酸酯钠
2)聚氧乙烯(EOP=8)烷基(C12)醚
3)烷基(C12)聚葡糖苷(缩合度1.3)
4)单长链叔烷基(C12)二甲基氧化胺
5)烷基(C12)羟基二甲基磺基甜菜碱
6)分子量10000
7)表2中记载的本发明的碱性蛋白酶的各种纯化样品(15PU/mL)。
实施例8
由上述的洗涤剂A(参照实施例2)所得的下述表7中记载的颗粒状洗涤剂。
表7
成分(质量%) | 洗涤剂K | 洗涤剂L | 洗涤剂M | 洗涤剂N |
基于实施例2的洗涤剂基质 | 98.4 | 98.3 | 98.5 | 97.2 |
香料 | 0.5 | 0.5 | 0.5 | 0.5 |
本发明的蛋白酶<sup>1)</sup> | 0.5 | 0.5 | 0.5 | 0.5 |
原有的蛋白酶<sup>2)</sup> | 0.6 | 0.6 |
纤维素酶<sup>3)</sup> | 0.7 | 0.7 | ||
脂酶<sup>4)</sup> | 0.5 | 0.5 |
1)由表2中记载的本发明的碱性蛋白酶的各种纯化样品按照特开昭62-257990号公报中实施例1所述的方法制备成的颗粒化物(6PU/g)。
2)基于特开昭62-257990号公报的实施例1中记载的方法,将特开平5-25492号公报中记载的蛋白酶K-16定为5PU/g。
3)KAC-500(注册商标;花王公司制造)
4)Lipolase 100T(注册商标;Novozymes公司制造)
本发明提供了即使在高浓度脂肪酸存在下也可保持对酪蛋白具有充分分解活性、不仅对蛋白质、对混有皮脂等的复合污渍也具有良好的洗净性、在培养基中可高效分泌、生产性高的碱性蛋白酶。
序列表
<110>花王公司
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Gly Asn Glu Gly Pro Asn Gly Gly Thr Ile Ser Ala Pro Gly Thr Ala
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Gly Ser Tyr Ala Asp Asn Ile Asn His Val Ala Gln Phe Ser Ser Arg
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Gly Pro Thr Lys Asp Gly Arg Ile Lys Pro Asp Val Met Ala Pro Gly
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atc ctt ttc gct gcc ggg aat gaa gga ccg aac ggc gga acc atc agt 1131
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KS0759(P2003-0164)
Claims (6)
1. 选自序列号1所示氨基酸序列中(a)15位、(b)16位、(c)166位、(d)167位、(e)187位、(f)346位、(g)405位的氨基酸残基是下述氨基酸残基的碱性蛋白酶:
(a)位点:组氨酸、
(b)位点:苏氨酸或谷氨酰胺、
(c)位点:甘氨酸、
(d)位点:缬氨酸、
(e)位点:丝氨酸、
(f)位点:精氨酸、
(g)位点:天冬氨酸。
2. 如权利要求1所述的碱性蛋白酶的编码基因。
3. 含有如权利要求2所述的基因的重组载体。
4. 含有如权利要求3所述载体的转化子。
5. 如权利要求4所述的转化子,其宿主是微生物。
6. 含有如权利要求1所述的碱性蛋白酶的洗净剂组合物。
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JP106709/03 | 2003-04-10 | ||
JP2003106709A JP2004305176A (ja) | 2003-04-10 | 2003-04-10 | アルカリプロテアーゼ |
JP106709/2003 | 2003-04-10 |
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CN100408679C true CN100408679C (zh) | 2008-08-06 |
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US (1) | US7429642B2 (zh) |
EP (1) | EP1466962B1 (zh) |
JP (1) | JP2004305176A (zh) |
CN (1) | CN100408679C (zh) |
DK (1) | DK1466962T3 (zh) |
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US6376227B1 (en) * | 1997-10-07 | 2002-04-23 | Kao Corporation | Alkaline protease |
US7368273B2 (en) * | 2002-03-22 | 2008-05-06 | Kao Corporation | Alkaline protease |
DK1794296T3 (da) | 2004-09-21 | 2012-07-30 | Novozymes As | Subtilaser |
ATE533843T1 (de) * | 2004-09-21 | 2011-12-15 | Novozymes As | Subtilasen |
JP4989922B2 (ja) * | 2006-06-08 | 2012-08-01 | 日本食品化工株式会社 | 変異体及びこれをコードする遺伝子 |
JP2008212084A (ja) | 2007-03-06 | 2008-09-18 | Kao Corp | アルカリプロテアーゼ |
JP2009034062A (ja) * | 2007-08-03 | 2009-02-19 | Kao Corp | アルカリプロテアーゼ |
JP2009034063A (ja) * | 2007-08-03 | 2009-02-19 | Kao Corp | アルカリプロテアーゼの安定性向上方法 |
DK3061817T3 (en) | 2009-04-30 | 2019-03-04 | Kao Corp | Alkaline protease variants |
JP2010273673A (ja) * | 2009-04-30 | 2010-12-09 | Kao Corp | アルカリプロテアーゼ変異体 |
WO2010134435A1 (ja) | 2009-05-22 | 2010-11-25 | 独立行政法人物質・材料研究機構 | 強磁性トンネル接合体およびそれを用いた磁気抵抗効果素子 |
WO2011015327A1 (de) * | 2009-08-03 | 2011-02-10 | C-Lecta Gmbh | Verfahren zur herstellung von nukleasen eines gram-negativen bakteriums unter nutzung eines gram-positiven expressionswirtes |
JP6067409B2 (ja) | 2012-04-10 | 2017-01-25 | 花王株式会社 | アルカリプロテアーゼの溶解性向上方法 |
US9969955B2 (en) | 2013-10-16 | 2018-05-15 | Melaleuca, Inc. | Powdered automatic dishwashing detergent |
WO2017213168A1 (ja) * | 2016-06-09 | 2017-12-14 | 花王株式会社 | 変異アルカリプロテアーゼ |
JP6289711B2 (ja) | 2016-06-09 | 2018-03-07 | 花王株式会社 | 変異アルカリプロテアーゼ |
CN108384771B (zh) * | 2018-02-06 | 2020-06-09 | 珠海市双指环投资有限公司 | 一种提高比活力的碱性蛋白酶突变体及其编码基因 |
DK3754026T3 (da) | 2018-02-13 | 2022-10-31 | Kao Corp | Fremgangsmåde til fremstilling af fermenteringsprodukt |
JP7245676B2 (ja) | 2019-03-11 | 2023-03-24 | 花王株式会社 | 変異プロテアーゼ |
CN110819612A (zh) * | 2019-11-29 | 2020-02-21 | 天津科技大学 | 新型抗自切碱性蛋白酶的筛选 |
JP7233596B1 (ja) | 2022-10-21 | 2023-03-06 | 株式会社アルボース | 自動食器洗浄機用洗浄剤組成物および自動食器洗浄機による食器の洗浄方法 |
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CN1113953A (zh) * | 1994-06-01 | 1995-12-27 | 中国科学院生物物理研究所 | 枯草杆菌碱性蛋白酶第118位的突变及其热稳定酶 |
WO1998056927A2 (en) * | 1997-06-12 | 1998-12-17 | Novo Nordisk Biotech, Inc. | Nucleic acids encoding polypeptide having protease activity |
EP1209233A2 (en) * | 2000-11-22 | 2002-05-29 | Kao Corporation | Alkaline proteases |
WO2002088340A2 (de) * | 2001-05-02 | 2002-11-07 | Henkel Kommanditgesellschaft Auf Aktien | Alkalische protease-varianten und wasch- und reinigungsmittel enthaltend diese alkalischen protease-varianten |
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US6376227B1 (en) | 1997-10-07 | 2002-04-23 | Kao Corporation | Alkaline protease |
JP4324363B2 (ja) | 2002-06-06 | 2009-09-02 | 花王株式会社 | 変異アルカリプロテアーゼ |
JP2004000122A (ja) | 2002-03-22 | 2004-01-08 | Kao Corp | アルカリプロテアーゼ |
JP4210548B2 (ja) | 2002-06-26 | 2009-01-21 | 花王株式会社 | アルカリプロテアーゼ |
US7101698B2 (en) * | 2002-06-26 | 2006-09-05 | Kao Corporation | Alkaline protease |
-
2003
- 2003-04-10 JP JP2003106709A patent/JP2004305176A/ja active Pending
-
2004
- 2004-04-08 EP EP04008604A patent/EP1466962B1/en not_active Expired - Lifetime
- 2004-04-08 DK DK04008604.3T patent/DK1466962T3/da active
- 2004-04-09 US US10/820,714 patent/US7429642B2/en active Active
- 2004-04-09 CN CNB2004100451021A patent/CN100408679C/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1113953A (zh) * | 1994-06-01 | 1995-12-27 | 中国科学院生物物理研究所 | 枯草杆菌碱性蛋白酶第118位的突变及其热稳定酶 |
WO1998056927A2 (en) * | 1997-06-12 | 1998-12-17 | Novo Nordisk Biotech, Inc. | Nucleic acids encoding polypeptide having protease activity |
EP1209233A2 (en) * | 2000-11-22 | 2002-05-29 | Kao Corporation | Alkaline proteases |
WO2002088340A2 (de) * | 2001-05-02 | 2002-11-07 | Henkel Kommanditgesellschaft Auf Aktien | Alkalische protease-varianten und wasch- und reinigungsmittel enthaltend diese alkalischen protease-varianten |
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EP1466962A1 (en) | 2004-10-13 |
DK1466962T3 (da) | 2011-11-21 |
JP2004305176A (ja) | 2004-11-04 |
EP1466962B1 (en) | 2011-10-12 |
US7429642B2 (en) | 2008-09-30 |
US20050214922A1 (en) | 2005-09-29 |
CN1539966A (zh) | 2004-10-27 |
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