CN103562724B - 用于测量内毒素的试剂 - Google Patents
用于测量内毒素的试剂 Download PDFInfo
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Abstract
提供了一种用于快速地且高灵敏度地测量内毒素的方法。使用包含下面的蛋白(1)至(3)的内毒素测量剂测量内毒素,所述蛋白质中的每一种是通过使用昆虫细胞作为宿主进行表达可得到的重组蛋白:(1) 源自东方鲎的因子C,该因子C在C‑端处不具有His‑标签序列;(2) 鲎的因子B;和(3) 鲎的前凝固酶。
Description
技术领域
本发明涉及内毒素测量剂、用于生产所述测量剂的方法、和用于测量样品中的内毒素的方法。
背景技术
内毒素是存在于革兰氏阴性细菌的细胞壁外膜上的脂多糖,且已知是强致热原。此外,已知的是,即使少量的内毒素也会造成归因于细菌感染的不同疾病状态,诸如由巨噬细胞活化引起的炎症性细胞因子的释放和内毒素性休克的诱导以及发热。因此,药物(诸如注射用药)、水、医疗设备等中的内毒素的检测是重要的。此外,内毒素被认为是革兰氏阴性细菌感染中的休克的主要原因,因此,通过测量血液中的内毒素,可以判断感染和/或药物作用是否存在。
此外,已知的是,革兰氏阴性细菌对美洲鲎(Limulus polyphemus) 的感染会造成血管内凝固,并且该现象已经被用于检测内毒素。
也就是说,已知使用鲎的血细胞提取物(鲎变形细胞裂解物;在下文中也被称作“裂解物”)测量内毒素的方法(例如,非专利文献1)。该方法被称作“鲎试验”,且使用存在于所述裂解物中的不同蛋白质的级联反应,该反应通过使内毒素与所述裂解物接触而发生。所述级联反应的示意图显示在图1中。
在使内毒素与裂解物接触后,存在于裂解物中的因子C被活化,以产生活化型因子C。该活化型因子C会活化存在于裂解物中的因子B,以产生活化型因子B。该活化型因子B然后活化存在于裂解物中的前凝固酶,以产生凝固酶。
该凝固酶会水解存在于裂解物中的凝固蛋白原分子的特定部分。由此产生凝固蛋白凝胶,以造成裂解物的凝固。因而,通过测量裂解物的凝固反应,可以测量内毒素。
此外,通过使凝固酶与合成底物反应以造成显色反应,也可以测量内毒素。例如,凝固酶会与合成底物叔丁氧羰基-亮氨酰基-甘氨酰基-精氨酰基-pNA (Boc-Leu-Gly-Arg-pNA)反应以水解它的酰胺键,并由此释放pNA。因而,通过最初在反应系统中包括合成底物,可以通过测量着色物质(pNA)的吸光度(405 nm) 来定量内毒素。
此外,已知的是,使用从日本鲎裂解物纯化出的因子C、因子B和前凝固酶,可以重构级联反应系统(非专利文献2)。
此外,已知这样的情况,其中使用源自东南亚鲎圆尾鲎(Carcinoscorpiusrotundicauda)的重组因子C、以及源自日本鲎东方鲎(Tachypleus tridentatus)的重组因子B和重组前凝固酶来重构级联反应系统(专利文献1)。
此外,已知用于检测内毒素的系统,其使用源自东南亚鲎圆尾鲎的重组因子C和可与活化型因子C反应以释放荧光物质的底物(专利文献2)。该系统可作为内毒素检测系统商购得到(商品名:PyroGene (注册商标);Lonza)。
但是,为了使用裂解物或从其制备的天然存在的因子C、因子B和前凝固酶,必须捕获鲎并从其收集血液。因此,考虑到生物资源的保护等,难以无限地供给这些组分。因此,已经需要容易地且快速地以低成本生产用于检测内毒素的试剂的技术。
此外,在使用重组因子C、重组因子B和重组前凝固酶的情况下,任意上述情况需要1小时或更久来进行测量,并且尚未实现在0.001 EU/mL量级的检测灵敏度。因此,已经需要快速地且高灵敏度地测量内毒素的技术。
现有技术文件
专利文献
[专利文献1] WO 2008/004674
[专利文献2] US 6,849,426 B
非专利文献。
[非专利文献1] Iwanaga S., Curr Opin Immunol. 1993 Feb; 5(1): 74-82。
[非专利文献2] Nakamura T. 等人, J Biochem. 1986 Mar; 99(3): 847-57。
发明内容
本发明目的在于,提供用于快速地且高灵敏度地测量内毒素的方法。本发明目的还在于,提供要在所述方法中使用的内毒素测量剂和用于生产所述试剂的方法。
本发明的发明人发现,通过使用源自日本鲎东方鲎并使用昆虫细胞作为宿主进行表达的重组因子C (不含His-标签)、重组因子B和重组前凝固酶,可以快速地且高灵敏度地测量内毒素,由此完成了本发明。
也就是说,本发明如下。
[1]
一种内毒素测量剂,其包含下面的蛋白(1)至(3),所述蛋白中的每一种是通过使用昆虫细胞作为宿主进行表达可得到的重组蛋白:
(1) 源自东方鲎的因子C,该因子C在C-端处不具有His-标签序列;
(2) 鲎的因子B;和
(3) 鲎的前凝固酶。
[2]
根据[1]所述的测量剂,其中所述因子B和所述前凝固酶源自东方鲎。
[3]
根据[1]或[2]所述的测量剂,其中所述因子C是下面的蛋白(A)或(B);所述因子B是下面的蛋白(C)或(D);且所述前凝固酶是下面的蛋白(E)或(F):
(A) 蛋白,其包含在SEQ ID NO:2中所示的氨基酸序列;
(B) 蛋白,其包含在SEQ ID NO:2中所示的氨基酸序列,但是其包括一个或几个氨基酸残基的置换、缺失、插入或添加,所述蛋白具有因子C活性;
(C) 蛋白,其包含在SEQ ID NO:4中所示的氨基酸序列;
(D) 蛋白,其包含在SEQ ID NO:4中所示的氨基酸序列,但是其包括一个或几个氨基酸残基的置换、缺失、插入或添加,所述蛋白具有因子B活性;
(E) 蛋白,其包含在SEQ ID NO:6中所示的氨基酸序列;
(F) 蛋白,其包含在SEQ ID NO:6中所示的氨基酸序列,但是其包括一个或几个氨基酸残基的置换、缺失、插入或添加,所述蛋白具有前凝固酶活性。
[4]
一种用于生产根据[1]至[3]中的任一项所述的测量剂的方法,所述方法包括下面的步骤(A)至(C):
(A) 将下面DNA(1)至(3)中的每一种掺入病毒DNA中的步骤:
(1) DNA,其编码源自东方鲎的因子C,该因子C在C-端处不具有His-标签序列;
(2) DNA,其编码鲎的因子B;和
(3) DNA,其编码鲎的前凝固酶;
(B) 用其中掺入了所述每种DNA的病毒感染昆虫细胞的步骤;和
(C) 使被所述每种病毒感染的昆虫细胞表达由所述每种DNA编码的蛋白的步骤。
[5]
一种用于生产根据[1]至[3]中的任一项所述的测量剂的方法,所述方法包括下面的步骤(A)至(C):
(A) 将下面DNA(1)至(3)中的每一种掺入载体中的步骤:
(1) DNA,其编码源自东方鲎的因子C,该因子C在C-端处不具有His-标签序列;
(2) DNA,其编码鲎的因子B;和
(3) DNA,其编码鲎的前凝固酶;
(B) 将其中掺入了所述每种DNA的载体引入昆虫细胞中以使所述每种DNA掺入昆虫细胞的染色体中的步骤;和
(C) 使其中掺入了所述每种DNA的昆虫细胞表达由所述每种DNA编码的蛋白的步骤。
[6]
根据[4]或[5]所述的方法,其中所述编码因子C的DNA是下面的DNA (A)或(B);所述编码因子B的DNA是下面的DNA (C)或(D);且所述编码前凝固酶的DNA是下面的DNA (E)或(F):
(A) DNA,其包含在SEQ ID NO:1中所示的核苷酸序列;
(B) DNA,其在严谨条件下与SEQ ID NO:1所示核苷酸序列的全长或一部分的互补序列杂交,且编码具有因子C活性的蛋白。
(C) DNA,其包含在SEQ ID NO:3或8中所示的核苷酸序列;
(D) DNA,其在严谨条件下与SEQ ID NO:3或8所示核苷酸序列的全长或一部分的互补序列杂交,且编码具有因子B活性的蛋白。
(E) DNA,其包含在SEQ ID NO:5或9中所示的核苷酸序列;
(F) DNA,其在严谨条件下与SEQ ID NO:5或9所示核苷酸序列的全长或一部分的互补序列杂交,且编码具有前凝固酶活性的蛋白。
[7]
一种用于测量试验样品中的内毒素的方法,所述方法包括:使根据[1]至[3]中的任一项所述的测量剂与试验样品混合的步骤,和测量级联反应的进展的步骤。
[8]
根据[7]所述的方法,所述方法包括:将用于检测级联反应的进展的底物加入反应系统中的步骤。
[9]
根据[8]所述的方法,所述方法另外包括:基于所述底物的反应计算试验样品中的内毒素水平的步骤。
通过本发明,可以快速地且高灵敏度地测量内毒素。例如,在本发明的一个实施方案中,仅测量30分钟便可以实现0.0005 EU/mL量级的检测灵敏度。此外,在本发明中,表达的重组因子C、重组因子B和重组前凝固酶可以不经过纯化就使用,并且因此,可以简单地且快速地以低成本生产包含这些重组蛋白的内毒素测量剂。
附图说明
图1的简图显示了鲎试验中的级联反应系统。
图2的简图显示了载体pIZ/V5-His的结构和每个基因的插入位置。在上部的箭头指示了基因的插入位置。
图3的照片显示了各个因子C的表达水平。
图4的简图显示了各个因子C的活性。
图5的照片显示了通过病毒方法表达的因子C的稳定性。
图6的照片显示了通过稳定表达细胞方法表达的因子C的稳定性。
图7的简图显示了中空纤维膜过滤处理对通过病毒方法表达的因子的反应性的影响。
图8的简图显示了含有通过病毒方法表达的因子的内毒素测量剂的反应性。
图9的简图显示了含有通过稳定表达细胞系方法表达的因子的内毒素测量剂的反应性。(a) 在0-0.1 EU/mL的内毒素浓度时的反应性。(b) 在0-0.01 EU/mL的内毒素浓度时的反应性。
图10的照片显示了纯化的重组因子C和纯化的天然存在的因子C的纯度和浓度。
图11的校正曲线显示了带强度和BSA的量之间的关联。
图12的简图显示了纯化的重组因子C和纯化的天然存在的因子C的活性。
具体实施方式
在本发明中,下述的一系列反应可以被称作“级联反应”:其中内毒素活化因子C以产生活化型因子C;所述活化型因子C活化因子B以产生活化型因子B;和所述活化型因子B活化前凝固酶以产生凝固酶。
[1]本发明的内毒素测量剂
本发明的内毒素测量剂包含因子C、因子B和前凝固酶。在本发明的内毒素测量剂中包含的因子C、因子B和前凝固酶在下文中可以分别被称作“本发明的因子C”、“本发明的因子B”和“本发明的前凝固酶”。此外,因子C、因子B和前凝固酶可以共同地称作“因子”。
本发明的因子C、本发明的因子B和本发明的前凝固酶全部是通过使用昆虫细胞作为宿主进行表达可得到的重组蛋白。
本发明的因子C是源自日本鲎东方鲎的因子C。本发明的因子C的特征在于,它不具有在C-端处连接的His-标签。此外,本发明的因子C优选地在C-端处不具有V5-标签。此外,本发明的因子C更优选地不具有在C-端处连接的任何肽。此外,本发明的因子C特别优选地不具有在任一端处连接的任何肽。东方鲎的因子C的氨基酸序列显示在SEQ ID NO:2中。编码东方鲎的因子C的基因的核苷酸序列显示在SEQ ID NO:1中。
本发明的因子C可以是具有SEQ ID NO:2所示的氨基酸序列的蛋白的变体,只要所述变体具有因子C活性。
“因子C活性”是指,因子C在有内毒素存在下变成活化型因子C以活化因子B的活性。例如,可以如下证实本发明的因子C“具有因子C活性”的事实:使用与合适的因子B和合适的前凝固酶相组合的本发明的因子C,并在有内毒素存在下检测级联反应的进展。更具体地,SEQ ID NO:4的蛋白可以用作合适的因子B,SEQ ID NO:6的蛋白可以用作合适的前凝固酶。使用下面提及的底物进行检测,可以测量级联反应的进展。
本发明的因子C可以是这样的蛋白:其包含在SEQ ID NO:2中所示的氨基酸序列,但是其包括一个或几个氨基酸残基的置换、缺失、插入或添加,只要所述因子C具有因子C活性。术语“一个或几个”的含义随所述氨基酸残基在蛋白的三维结构中的位置和所述氨基酸残基的类型而变化,并且,更具体地,该术语优选是指1-20、更优选1-10、更优选1-5、特别优选1-3。上述的一个或几个氨基酸的置换、缺失、插入或添加是维持蛋白的正常功能的保守突变。保守突变的代表性例子是保守置换。所述保守置换是例如这样的突变:其中,如果置换位点是芳族氨基酸,那么置换在Phe、Trp和Tyr之间相互发生;如果置换位点是疏水氨基酸,那么置换在Leu、Ile和Val之间相互发生;如果置换位点是极性氨基酸,那么置换在Gln和Asn之间相互发生;如果置换位点是碱性氨基酸,那么置换在Lys、Arg和His之间相互发生;如果置换位点是酸性氨基酸,那么置换在Asp和Glu之间相互发生;如果置换位点是具有羟基的氨基酸,那么置换在Ser和Thr之间相互发生。被视作保守置换的置换的例子具体地包括:Ser或Thr对Ala的置换,Gln、His或Lys对Arg的置换,Glu、Gln、Lys、His或Asp对Asn的置换,Asn、Glu或Gln对Asp的置换,Ser或Ala对Cys的置换,Asn、Glu、Lys、His、Asp或Arg对Gln的置换,Gly、Asn、Gln、Lys或Asp对Glu的置换,Pro对Gly的置换,Asn、Lys、Gln、Arg或Tyr对His的置换,Leu、Met、Val或Phe对Ile的置换,Ile、Met、Val或Phe对Leu的置换,Asn、Glu、Gln、His或Arg对Lys的置换,Ile、Leu、Val或Phe对Met的置换,Trp、Tyr、Met、Ile或Leu对Phe的置换,Thr或Ala对Ser的置换,Ser或Ala对Thr的置换,Phe或Tyr对Trp的置换,His、Phe或Trp对Tyr,和Met、Ile或Leu对Val的置换。此外,上述的置换、缺失、插入、添加、倒位等还可以包括天然存在的突变,所述突变归因于衍生出所述基因的鲎的个体、品种或物种的差异。
此外,本发明的因子C可以是这样的蛋白:其与如上所述的因子C的全长氨基酸序列(例如,SEQ ID NO:2所示的全长氨基酸序列)具有不小于80%、优选不小于90%、更优选不小于95%、更优选不小于97%、特别优选不小于99% 的同源性或同一性,并且具有因子C活性。
编码本发明的因子C的基因没有特别限制,只要所述基因编码如上所述的本发明的因子C。编码本发明的因子C的基因可以是基于已知基因序列制备的探针,例如,这样的DNA:其在严谨条件下与SEQ ID NO:1所示核苷酸序列的全长或一部分的互补序列杂交,且编码具有因子C活性的蛋白。术语“严谨条件”在本文中是指这样的条件:在该条件下,形成所谓的特异性的杂交物,但是不形成非特异性的杂交物。所述条件的例子包括这样的条件:在该条件下,高度同源的DNA彼此杂交,例如,具有不小于80% 同源性、优选不小于90% 同源性、更优选不小于95% 同源性、更优选不小于97% 同源性、特别优选不小于99% 同源性的DNA彼此杂交,而其同源性低于上述值的DNA不会彼此杂交;以及这样的条件:在该条件下,在与60℃、1×SSC和0.1% SDS(优选60℃、0.1×SSC和0.1% SDS,更优选68℃、0.1×SSC和0.1% SDS,它们是在DNA杂交中的标准洗涤条件)相对应的盐浓度和温度,进行洗涤1次,更优选2次或3次。
此外,可以改变编码本发明的因子C的基因中的密码子组合,从而为在昆虫细胞中的表达而优化所述基因。所述优化可以如下进行,例如,使用通常可得到的协议服务。编码本发明的因子C的基因可以是DNA变体,其密码子组合为在昆虫细胞中的表达进行了优化。
上面关于基因和蛋白的变体的描述类似地适用于本发明的因子B和前凝固酶,并适用于编码它们的基因。
本发明的因子B是源自鲎的因子B。此外,本发明的前凝固酶是源自鲎的前凝固酶。鲎的例子包括日本鲎东方鲎、美洲鲎美洲鲎、东南亚鲎圆尾鲎和东南亚鲎马来鲎(Tachypleus gigas)。在这些鲎中,上述因子优选地源自日本鲎东方鲎。
东方鲎的因子B和前凝固酶的氨基酸序列分别显示在SEQ ID NO:4和6中。编码东方鲎的因子B和前凝固酶的基因的核苷酸序列分别显示在SEQ ID NO:3和5中。
本发明的因子B可以是上述任一种鲎的因子B的变体,例如,具有SEQ ID NO:4所示氨基酸序列的蛋白的变体,只要本发明的因子B具有因子B活性。此外,编码本发明的因子B的基因没有特别限制,只要所述基因编码如上所述的本发明的因子B。上面关于因子C的描述在细节上做必要的修正后也适用于基因和蛋白的变体。
“因子B活性”是指,因子B在活化型因子C存在下变成活化型因子B以将前凝固酶变成它的活性形式凝固酶的活性。例如,可以如下证实本发明的因子B“具有因子B活性”的事实:使用与合适的因子C和合适的前凝固酶相组合的本发明的因子B,并在内毒素存在下检测级联反应的进展。更具体地,SEQ ID NO:2的蛋白可以用作合适的因子C,SEQ ID NO:6的蛋白可以用作合适的前凝固酶。使用下面提及的底物进行检测,可以测量级联反应的进展。
本发明的前凝固酶可以是上述任一种鲎的前凝固酶的变体,例如,具有SEQ IDNO:6所示氨基酸序列的蛋白的变体,只要本发明的前凝固酶具有前凝固酶活性。此外,编码本发明的前凝固酶的基因没有特别限制,只要所述基因编码如上所述的本发明的前凝固酶。上面关于因子C的描述在细节上做必要的修正后也适用于基因和蛋白的变体。
“前凝固酶活性”是指,前凝固酶在活化型因子B存在下变成凝固酶以与下面提及的用于检测的底物反应的活性。“与用于检测的底物反应的活性”是指,例如,与凝固蛋白原反应以造成凝固的活性,和与Boc-Leu-Gly-Arg-pNA反应以释放pNA的活性。例如,可以如下证实本发明的前凝固酶“具有前凝固酶活性”的事实:使用与合适的因子C和合适的因子B相组合的本发明的凝固酶,并在内毒素存在下检测级联反应的进展。更具体地,SEQ ID NO:2的蛋白可以用作合适的因子C,SEQ ID NO:4的蛋白可以用作合适的因子B。使用下面提及的底物进行检测,可以测量级联反应的进展。
可以向本发明的因子B和/或本发明的前凝固酶添加任意肽等,只要所述因子分别具有因子B活性和前凝固酶活性。这样的肽的例子包括标签序列诸如His-标签和V5-标签。与本发明的因子C类似地,要使用的本发明的因子B和/或本发明的前凝固酶可以属于下述的任一种:其中在C-端没有添加His-标签的那些,其中在C-端没有添加V5-标签的那些,其中在C-端根本没有添加肽的那些,和其中在任一端根本没有添加肽的那些。
此外,可以改变编码本发明的因子B的基因和/或编码本发明的前凝固酶的基因中的密码子组合,从而为在昆虫细胞中的表达而优化所述基因。编码SEQ ID NO:4的因子B且具有为在昆虫细胞中的表达而优化的密码子组合的DNA的例子包括SEQ ID NO:8的DNA。编码SEQ ID NO:6的前凝固酶且具有为在昆虫细胞中的表达而优化的密码子组合的DNA的例子包括SEQ ID NO:9的DNA。每一个编码本发明的因子B的基因和/或编码本发明的前凝固酶的基因可以是DNA变体,其密码子组合为在昆虫细胞中的表达进行了优化。
本发明的内毒素测量剂可以由本发明的因子C、本发明的本发明的因子B和本发明的前凝固酶组成。
本发明的内毒素测量剂可以包含用于检测级联反应的进展的底物。在本发明中,这样的底物可以被称作“用于检测的底物”。
用于检测的底物的例子包括凝固蛋白原。由于凝固蛋白原与凝固酶的接触,发生凝固从而产生凝固蛋白。通过测量反应溶液的浊度,可以测定凝固反应的进程。可以从鲎血细胞提取物(裂解物)回收凝固蛋白原。并且,因为已经公开了编码凝固蛋白原的基因的核苷酸序列(Miyata, 等人, PROTEIN, NUCLEIC ACID AND ENZYME, 增刊, 第29期, 第30-43页(1986)),可以根据常规方法通过基因工程生产凝固蛋白原。
还可以使用合成底物作为用于检测的底物。所述合成底物没有特别限制,只要所述底物具有适合用于检测的性质,诸如使凝固酶的催化反应造成显色或发荧光的性质。合成底物的例子包括由通式X-Y-Z (其中X代表保护基,Y代表肽,且Z代表经由酰胺键与Y结合的染料)代表的底物。在内毒素存在于反应系统中的情况下,凝固酶(其作为级联反应的结果而产生)的催化反应会切割Y和Z之间的酰胺键,以释放染料Z,从而导致显色或发荧光。保护基X没有特别限制,可以适当地使用肽的已知保护基。这样的保护基的例子包括叔丁氧羰基和苯甲酰基。染料Z没有特别限制,且可以是在可见光下可检测的染料或荧光染料。染料Z的例子包括pNA (对-硝基苯胺)、MCA (7-甲氧基香豆素-4-乙酸)、DNP (2,4-二硝基苯胺)和丹磺酰基染料。肽Y的例子包括Leu-Gly-Arg (LGR)、Ile-Glu-Gly-Arg (IEGR) (SEQ IDNO:12)和Val-Pro-Arg (VPR)。通过根据染料的性质选择的方法,可以测量释放的染料Z。
此外,本发明的内毒素测量剂还可以包含除了因子和用于检测的底物以外的组分,只要所述试剂可以用于测量内毒素。这样的组分没有特别限制,且可以考虑因子和用于检测的底物的储存性、操作容易度以及稳定性来选择。本发明的内毒素测量剂可以包含,例如,pH-缓冲剂和/或盐。pH-缓冲剂的例子包括HEPES缓冲剂、MES缓冲剂、Tris缓冲剂和GTA宽范围缓冲剂。在本发明的内毒素测量剂中还可以包含诸如醇、酯、酮和酰胺等有机溶剂。
本发明的内毒素测量剂可以配制成任意形式,包括例如,固体形式、液体形式和凝胶形式。就制剂而言,可以使用通常用作制剂载体诸如媒介物、粘合剂、崩解剂、润滑剂、稳定剂、矫味剂、稀释剂、表面活性剂和溶剂的添加剂。本发明的内毒素测量剂可以原样用于测量内毒素,或者在水、生理盐水、缓冲液等中进行稀释、分散或溶解。不言而喻,通过这样的稀释、分散或溶解得到的生成制剂也在本发明的内毒素测量剂的范围内。
在本发明的内毒素测量剂中,所述因子和所述其它组分可以作为混合物存在,或者可以分开存在。例如,所述因子可以以要配制的任意比例混合,或者可以分开配制。
在本发明的内毒素测量剂中的所述因子和所述其它组分的浓度没有特别限制,且优选地经过调节,使得当测量内毒素时,所述浓度是在下面提及的优选范围内。在本发明的内毒素测量剂(以在与试验样品接触之前制备的溶液的方式) 中的每种因子的浓度是,例如,优选20-100 μg/mL、更优选40-80 μg/mL、特别优选约60 μg/mL。
本发明的内毒素测量剂可以作为内毒素测量试剂盒来提供。内毒素测量试剂盒没有特别限制,只要所述试剂盒含有本发明的内毒素测量剂。
(2)用于生产本发明的内毒素测量剂的方法
通过使用昆虫细胞作为宿主进行表达,可以生产在本发明的内毒素测量剂中包含的因子。
所述昆虫细胞没有特别限制,只要所述细胞可以表达所述因子,并且可以适当地使用通常用于表达异源蛋白的细胞。这样的昆虫细胞的例子包括Sf9、Sf21、SF+和High-Five。所述昆虫细胞优选地是Sf9。
用于培养昆虫细胞的培养条件没有特别限制,只要在所述条件下可以培养昆虫细胞,并且如果必要的话,可以在适当地修改后使用通常用于培养昆虫细胞的培养条件。例如,可以使用通常用于培养昆虫细胞的培养基作为培养基。这样的培养基的例子包括商购可得的用于昆虫细胞的无血清培养基。更具体地,可以适当地使用Sf900 II培养基(Invitrogen)等。例如,可以在27℃至28℃在摇动下进行培养。
使用昆虫细胞作为宿主来表达因子的方法没有特别限制,只要通过该方法可以表达所述因子,并且可以适当地使用通常用于表达异源蛋白的方法。例如,通过用其中掺入了编码所述因子的基因的病毒感染昆虫细胞,可以表达每种因子(病毒方法)。可替换地,通过将其中掺入了编码所述因子的基因的载体引入昆虫细胞中,由此将所述基因掺入宿主染色体中,可以表达每种因子(稳定表达细胞系方法)。
<病毒方法>
要在病毒方法中使用的病毒没有特别限制,只要该病毒可以感染昆虫细胞,并且由此可以表达所述因子,并且可以适当地使用通常用于在昆虫细胞中表达蛋白的病毒。这样的病毒的例子包括杆状病毒。所述杆状病毒优选地是核多角体病毒属(NPV)。NPV的例子包括AcNPV (苜蓿银纹夜蛾NPV)和BmNPV (家蚕NPV)。NPV优选地是AcNPV。
通过常规方法,例如,通过使用转移载体的同源重组,可以将核酸引入病毒中。转移载体的例子包括pPSC8 (Protein Sciences)、pFastBac (Invitrogen)和pVL1393(Pharmingen)。转移载体优选地是pPSC8。
通过常规方法用其中掺入了编码每种因子的基因的病毒感染昆虫细胞,可以得到携带所述病毒并表达所述因子的昆虫细胞。
<稳定表达细胞系方法>
通过将编码每种因子的基因掺入昆虫细胞的染色体中,可以得到稳定表达细胞系,其稳定地表达所述因子。稳定表达细胞系的构建方法没有特别限制,并且可以通过常规方法进行构建。例如,根据手册使用pIZ/V5-His载体(Invitrogen),可以构建稳定表达细胞系。
在任何情况下,构建表达细胞,使得表达的因子C具有没有连接His标签的C-端。此外,在没有添加任何肽(其不限于在因子C的C-端处的His-标签)而表达每种因子的情况下,可以构建表达细胞,使得不添加肽。
在任何情况下,所述因子可以由单一类型的表达细胞一起表达,或者可以为每种因子构建表达细胞以分别表达各种因子。
通过测量因子的活性,可以证实每种因子是否被表达。通过测量从编码因子的基因转录的mRNA的量,或者通过使用抗体通过蛋白质印迹法而检测因子,也可以证实每种因子是否被表达。
每种表达的因子可以作为含有因子的溶液回收,以用作本发明的内毒素测量剂的组分。含有因子的溶液可以是,例如,培养液、培养物上清液、或细胞提取物、或其混合物。每种因子可以在纯化后或不经过纯化地使用。在本发明中,即使不经过因子纯化而原样使用含有每种表达的因子的细胞培养物上清液,也可以提供具有足够高性能的内毒素测量剂。在要纯化每种因子的情况下,可以通过例如用于蛋白纯化的已知方法进行纯化。这样的方法的例子包括硫酸铵沉淀、凝胶过滤色谱法、离子交换色谱法、疏水相互作用色谱法和羟磷灰石色谱法。在将诸如His-标签等标签与每种因子连接的情况下,使用针对所述标签的亲和力,通过亲和色谱法也可以纯化所述因子。
在通过病毒方法生产每种因子的情况下,优选地消除病毒。消除病毒的方法没有特别限制,并且可以通过常规方法进行消除。例如,通过具有500 kDa孔径的中空纤维过滤膜,可以消除病毒。
(3)本发明的测量内毒素的方法
通过将本发明的内毒素测量剂与试验样品混合,在试验样品含有内毒素的情况下,发生级联反应。通过测量级联反应的进展,可以测量试验样品中的内毒素。也就是说,本发明提供了一种用于测量试验样品中的内毒素的方法,所述方法包括:将本发明的内毒素测量剂与试验样品混合的步骤,和测量级联反应的进展的步骤(在下文中被称作“第一实施方案”)。
在所述第一实施方案中,从将本发明的内毒素测量剂与试验样品混合的步骤开始,在本发明的内毒素测量剂中含有的每种因子可以已经被包含在反应系统中,或者可以顺序地加入反应系统中。
例如,将本发明的内毒素测量剂与试验样品混合的步骤可以包括下述步骤(A)至(C):
(A) 将本发明的因子C加入反应系统中的步骤;
(B) 将本发明的因子B加入反应系统中的步骤;和
(C) 将本发明的前凝固酶加入反应系统中的步骤。
步骤(A)至(C) 可以分开地、部分同时地或完全同时地进行。步骤(A)至(C) 可以以任意次序进行。例如,步骤(A)之后进行步骤(B),然后进行步骤(C)。
在所述第一实施方案中,通过将用于检测的底物加入反应系统中,然后测量底物的反应(着色、凝固等),可以测量级联反应的进展。从将本发明的内毒素测量剂与试验样品混合的步骤开始,用于检测的底物可以已经被包含在反应系统中,或者可以在进展过程中或在该步骤结束以后加入反应系统中。当然,所述第一实施方案包括这样的情况:其中采用预先含有用于检测的底物的本发明的内毒素测量剂。
只要在试验物含有内毒素的情况下发生级联反应,本发明的因子B和前凝固酶本身可以不必与试验样品接触。也就是说,本发明的用于测量内毒素的方法的另一个实施方案(在下文中被称作“第二实施方案”)是,用于测量试验物中的内毒素的方法,该方法包括下面的步骤(A)至(D)。
(A)将本发明的因子C与试验样品混合的步骤;
(B) 在步骤A中混合因子C以后,将本发明的因子B与因子C混合的步骤;
(C) 在步骤B中混合因子B以后,将本发明的前凝固酶与因子B混合的步骤;和
(D) 测量级联反应的进展的步骤。
在所述第二实施方案中,步骤(A)至(D)可以分开地、部分同时地或完全同时地进行。例如,在开始步骤A之后,可以在进展过程中或在该步骤结束以后将因子B和/或前凝固酶加入反应系统中。可替换地,在开始步骤B之后,可以在进展过程中或在该步骤结束以后将前凝固酶加入反应系统中。可替换地,从步骤A开始时,所有3种因子可以都被包含在反应系统中。可替换地,例如,可以回收在步骤A中的接触以后的因子C用于步骤B,且可以回收在步骤B中的接触以后的因子B用于步骤C。
在所述第二实施方案中,通过将用于检测的底物加入反应系统中,然后测量底物的反应(着色、凝固等),可以测量级联反应的进展。从步骤A开始,用于检测的底物可以被包含在反应系统中,或者可以在进展过程中或在每个步骤结束以后加入反应系统中。
本发明的测量内毒素的方法可以包含其它任意步骤,只要在试验样品含有内毒素的情况下会发生级联反应即可。例如,本发明的测量内毒素的方法可以包括:将用于检测的底物加入反应系统中的步骤,或将由级联反应产生的凝固酶与用于检测的底物混合的步骤。此外,例如,本发明的测量内毒素的方法可以包括:基于用于检测的底物的反应,计算试验样品中的内毒素水平的步骤。
在本发明的测量内毒素的方法中,所述反应优选地在水性溶剂诸如水或缓冲液中进行。
在本发明的测量内毒素的方法中,反应溶液中的每种因子的浓度没有特别限制,只要在试验样品中含有内毒素的情况下会发生级联反应即可,并且可以根据因子的性质和/或类似因素适当地设定。例如,以终浓度的方式,每种因子的浓度通常是10-50 μg/mL、优选20-40 μg/mL、更优选约30 μg/mL。
在本发明的测量内毒素的方法中,反应溶液中的用于检测的底物的浓度没有特别限制,只要在试验样品中含有内毒素的情况下会发生级联反应即可,并且可以根据用于检测的底物的性质和/或类似因素适当地设定。例如,在用于检测的底物是合成底物的情况下,以终浓度的方式,用于检测的底物的浓度通常是0.001 mM-100 mM、优选0.01 mM-10mM。
在任何实施方案中,反应系统可以含有除了内毒素测量剂(在第一实施方案中)或因子(在第二实施方案中)、用于检测的底物和试验样品以外的一种或多种任意组分,只要在试验样品中含有内毒素的情况下会发生级联反应即可。例如,反应系统可以含有pH-缓冲剂和/或盐。pH-缓冲剂的例子包括HEPES缓冲剂、MES缓冲剂、Tris缓冲剂和GTA宽范围缓冲剂。在反应系统中还可以包含诸如醇、酯、酮和酰胺等有机溶剂。
反应溶液的pH没有特别限制,只要在试验样品中含有内毒素的情况下会发生级联反应即可,且可以根据每种因子的性质适当地设定。例如,反应溶液的pH通常是5-10、优选7-8.5。
反应温度没有特别限制,只要在试验样品中含有内毒素的情况下会发生级联反应即可,且可以根据每种因子的性质适当地设定。反应温度通常是,例如,10℃至80℃、优选20℃至50℃。例如,反应温度可以是室温。
反应时间没有特别限制,且可以根据诸如每种因子的性质和反应温度等条件适当地设定。反应时间通常是,例如,5分钟至1小时、优选15分钟至45分钟。例如,反应时间可以是30分钟。
在任何实施方案中,在反应过程中,可以向反应系统中额外地单独地或以任意组合加入试验样品、因子和其它组分。这些组分可以一次性加入,或者分多次加入,或者可以连续加入。从反应开始至反应结束可以采用恒定条件,或者可以在反应过程中改变条件。
通过测量用于检测的底物的反应(着色、凝固等),可以测量由内毒素的存在引起的级联反应的进展,并因此可以测量试验物中的内毒素。通过依赖于采用的用于检测的底物的方法,可以测量用于检测的底物的反应(着色、凝固等)。
在定量测量内毒素的情况下,可以使用已知其浓度的内毒素标准样品来得到内毒素水平和用于检测的底物的反应程度(着色、凝固等的程度)之间的关联数据,并且,基于关联数据,可以定量在试验样品中存在的内毒素。关联数据可以是,例如,校正曲线。定量可以通过动力学方法或通过终点法来进行。
要进行内毒素测量的试验样品没有特别限制,其例子包括医用水、药物、输注溶液、血液制品、医疗设备、医疗仪器、化妆品、食品和饮料、环境样品(例如,空气、河水和土壤)、生物组分(例如,血液、体液和组织)、天然存在的蛋白、重组蛋白、核酸和碳水化合物。通过在反应系统中混合、分散或溶解试验样品原样或试验样品的提取物或洗涤溶液,可以对试验样品进行内毒素测量。
实施例
现在将通过实施例更具体地描述本发明。但是,这些仅仅是本发明的实施例,并且本发明的范围不限于这些。
实施例1: 本发明的内毒素测量剂的生产
(1-1) 使用病毒的方法(在下文中被称作“病毒方法”)
在本实施例中,使用其中掺入了编码每种因子C、因子B和前凝固酶的基因的重组杆状病毒在昆虫细胞中表达所述因子,并由此生产内毒素测量剂。
(1-1-1)重组杆状病毒的制备
使用通常可得到的协议服务(TAKARA BIO INC.),完全合成了SEQ ID NO:7的DNA,作为编码His-标签连接的因子C的DNA(His-标签连接的因子C基因)。His-标签连接的因子C是在SEQ ID NO:2中显示的日本鲎的因子C,其中6×His-标签连接至C-端。将所述DNA插入在转移载体pPSC8 (Protein Sciences)的限制性酶NruI和SmaI的识别位点之间,以得到用于重组的载体。使用用于重组的载体,将His-标签连接的因子C基因掺入杆状病毒AcNPV中,以制备重组杆状病毒。
此外,使用引物FC-N-Pst (SEQ ID NO:10)和引物FC-notag-R-Bam (SEQ ID NO:11)并使用上述的编码His-标签连接的因子C的DNA作为模板,进行PCR以制备编码因子C的DNA,其中编码在3'-末端处的His-标签序列的核苷酸序列被除去(不含His-标签的因子C基因)。该DNA编码在SEQ ID NO:2中显示的日本鲎因子C,其中在C-端处没有连接His标签。对于不含His-标签的因子C基因,也通过如上所述的相同方法制备重组杆状病毒。
使用通常可得到的协议服务(TAKARA BIO INC.),完全合成了SEQ ID NO:8的DNA,作为编码因子B的DNA(因子B基因)。该DNA编码在SEQ ID NO:4中显示的日本鲎因子B (不含His-标签),并且它的密码子组合为在昆虫细胞中的表达进行了优化。对于因子B基因,也通过如上所述的相同方法制备重组杆状病毒。但是,在pPSC8载体中的插入位置是在限制性酶PstI和KpnI的识别位点之间。
使用通常可得到的协议服务(TAKARA BIO INC.),完全合成了SEQ ID NO:9的DNA,作为编码前凝固酶的DNA(前凝固酶基因)。该DNA编码在SEQ ID NO:6中显示的日本鲎前凝固酶(不含His-标签),并且它的密码子组合为在昆虫细胞中的表达进行了优化。对于前凝固酶基因,也通过如上所述的相同方法制备重组杆状病毒。但是,在pPSC8载体中的插入位置是在限制性酶XbaI和BglII的识别位点之间。
(1-1-2)用重组杆状病毒感染昆虫细胞(Sf9细胞)
以1.5×106细胞/mL,将Sf9细胞(Novagen) 接种在培养基中,并将在其中引入了编码His-标签连接的因子C的DNA的重组杆状病毒加入培养基中,以用所述病毒感染所述细胞。使用补充了抗生素(抗生素-抗真菌剂(×100);Invitrogen) (终浓度, ×1) 的Sf900II培养基(Invitrogen) (1 L),作为Sf9细胞的培养基。将病毒的感染复数(MOI)设定为1.0。此后,将得到的细胞在摇动下在28℃培养48小时。
类似地,用在其中引入了编码不含His-标签的因子C的DNA的病毒感染Sf9细胞。
此外,还用下述每种病毒感染Sf9细胞:向其中引入了编码因子B的DNA的病毒,和向其中引入了编码前凝固酶的DNA的病毒。在这些情况下,将MOI设定为0.5,培养时间为72小时。
(1-1-3)表达的重组蛋白的溶液的回收
将上述培养以后得到的每种培养液在4℃在3000×g离心30分钟以得到上清液,然后将上清液在-80℃保存。
(1-1-4)从重组蛋白溶液除去杂质和病毒
将已经如上所述冷冻保存的每种上清液融化,并应用于具有0.1 μm孔径的滤器(Cup Filter (Millipore))。在抽吸下进行过滤,并回收已经穿滤器的溶液。将每种回收的上清液应用于具有500 kDa孔径的中空纤维过滤膜(聚醚砜中空纤维膜; Spectrum Labs),并使用Kros Flow TFF泵过滤系统(Spectrum Labs)过滤。回收已经穿过膜的每种溶液。
(1-1-5)试剂的制备
在4℃,将560 mL在上面(1-1-4)得到的每种溶液(其中含有因子C、因子B或前凝固酶)、134 mL蒸馏水、126 mL 6.66 mM的合成底物(Boc-Leu-Gly-Arg-pNA)的水溶液(终浓度, 0.3 mM)和560 mL 15%的葡聚糖水溶液(终浓度, 3%)混合到一起。将该混合物以5 mL体积等分分进管形瓶中并冷冻干燥,以得到内毒素测量剂1。
(1-2)使用质粒的方法(在下文中也被称作“稳定表达细胞系方法”)
在本实施例中,将编码每种因子C、因子B和前凝固酶的基因掺入昆虫细胞的染色体中以构建稳定表达细胞系,然后表达每种因子,由此生产内毒素测量剂。
(1-2-1)稳定表达细胞系的制备和培养
使用pIZ载体试剂盒(Invitrogen),将在上述的病毒方法中使用的每种不含His-标签的因子C基因,因子B基因(SEQ ID NO:8)和前凝固酶基因(SEQ ID NO:9)引入Sf9细胞(Invitrogen)中。
更具体地,首先将每种DNA掺入在试剂盒所含的载体pIZ/V5-His的EcoRV和MluI识别位点之间,并将得到的每种载体与试剂盒所含的Cellfectin混合,随后将所述载体引入Sf9细胞中。DNA在pIZ/V5-His中的掺入位置等显示在图2中。在图2的顶部所示的厚箭头指示的区域中,掺入了每种DNA。使用补充了抗生素(抗生素-抗真菌剂(×100);Invitrogen)(终浓度, ×1)和Zeocin抗生素(Invitrogen) (终浓度, 50 μg/mL) 的Sf900 III培养基(Invitrogen) 作为Sf9细胞的培养基。在培养基中将如此得到的细胞系(其中引入了每种DNA)的密度调至6×105细胞/mL (1L),并将所述细胞在摇动下在28℃培养96小时。
应当指出,尽管在pIZ/V5-His中含有His标签序列,所有上述的DNA具有终止密码子,从而在没有添加His-标签的情况下表达所有因子C、因子B和前凝固酶。
(1-2-2)重组蛋白溶液的回收、杂质的除去和试剂的制备
以与关于病毒方法的“(1-1-3) 表达的重组蛋白的溶液的回收”、“(1-1-4) 从重组蛋白溶液除去杂质和病毒”和“(1-1-5) 试剂的制备”中所述的相同方式,处理在上述培养以后得到的每种培养液。但是,没有进行“(1-1-4) 从重组蛋白溶液除去杂质和病毒”中的使用中空纤维过滤膜的过滤过程。将如此得到的测量剂作为内毒素测量剂2提供。
实施例2: 表达的蛋白质的性能等
(2-1) 因子C的表达水平的对比
在通过病毒方法和稳定表达细胞系方法得到的不含His-标签的因子C和通过病毒方法得到的His-标签连接的因子C之间,对比了表达水平。
如下评价了表达水平:取0.5、1.5、5或15 μL与在实施例1中过滤以后且在制备试剂之前的溶液相对应的溶液,并对取样的溶液进行在有SDS存在下的5-20% 聚丙烯酰胺凝胶电泳(在非还原条件下),然后使用抗-因子C抗体(2C12,得自Shun-ichiro Kawabata教授, Department of Biology, Graduate School of Sciences, Kyushu University)进行蛋白质印迹法。
结果显示在图3中。结果指示,不含His-标签的因子C的表达水平低于His-标签连接的因子C的表达水平。此外,使用光密度计测量了图3中的蛋白质印迹上的带的强度,并且,基于测得的强度的相对值,计算用于得到相等因子C浓度的每种溶液的体积比。通过病毒方法得到的不含His-标签因子C的体积比为50,通过稳定表达细胞系方法得到的不含His-标签因子C的体积比为17,通过病毒方法得到的His-标签连接的因子C的体积比为7。
(2-2)因子C的活性的对比
使用等量的因子C,研究了每种因子C溶液的前凝固酶活化能力。
更具体地,将每种通过病毒方法得到的His-标签连接的因子C溶液(0.7 μL或5 μL)、通过病毒方法得到的不含His-标签的因子C溶液(5 μL)和通过稳定表达细胞系方法得到的不含His-标签的因子C溶液(1.7 μL) 放入96-孔板的孔中。此后,向每个孔中加入含有因子B的溶液(5 μL)和含有前凝固酶的溶液(5 μL) (在实施例1的病毒方法中在(1-1-4)中穿过0.1 μm滤器过滤以后得到)、以及Boc-Leu-Gly-Arg-pNA (终浓度, 0.3 mM)、Tris-HCl(pH 8.0) (终浓度, 100 mM)和50 μL内毒素(产品名“USP-参比标准内毒素”(USP-Reference Standard Endotoxin,(USP-RSE);可商购得自Seikagaku BiobusinessCorporation) (样品浓度:0、0.05或0.5 EU/mL),使得孔中的总体积变为100 μL,并混合到一起,随后在37℃温育3小时,在这期间,随着时间测量在405 nm的吸光度。使用蒸馏水作为阴性对照。吸光度的增加速率(吸光度变化速率) 反映了前凝固酶活化能力。术语“EU”是指“内毒素单位”,它是代表内毒素的量的单位(这也适用于下文中)。
结果显示在图4中。在图4中,“DW”是指蒸馏水;“病毒+ His标签(x1)”是指通过病毒方法得到的His-标签连接的因子C溶液(0.7 μL);“病毒+ His标签(x7)”是指相同的溶液(5 μL);“病毒且无标签(x1)”是指通过病毒方法得到的不含His-标签因子C溶液;和“稳定的Sf9且无标签(x1)”是指通过稳定表达细胞系方法得到的不含His-标签因子C溶液。
结果,在含有等量的因子C的His-标签连接的因子C溶液(0.7 μL) 中,并且甚至在含有约7倍量的因子C的溶液(5 μL)中,没有观察到或几乎没有观察到前凝固酶的活化。另一方面,不含His-标签的因子C表现出显著的前凝固酶活化能力,不论它是通过病毒方法得到还是通过稳定表达细胞系方法得到。
上述结果表明,与在添加His-标签序列的情况下表达的重组因子C分子相比,在没有添加His-标签序列的情况下表达的重组因子C分子具有强得多的前凝固酶活化能力。此外,表明了每种表达的蛋白质可以以在培养物上清液中含有的蛋白质的状态不经纯化地使用。
(2-3)表达的因子C的稳定性的对比
(2-3-1) 通过病毒方法表达的因子C的稳定性
在实施例1的病毒方法中在(1-1-2)中在摇动下在28℃培养病毒感染的细胞的步骤中,在培养48小时、72小时和96小时以后回收上清液,并对每种回收的上清液进行在有SDS存在下的5-20% 聚丙烯酰胺凝胶电泳(在非还原条件下),然后使用抗-因子C抗体(2C12,其与上面使用的相同) 通过蛋白质印迹法评价因子C的剩余量。此外,以相同的方式对通过在病毒感染24小时后向培养液中加入蛋白酶抑制剂(终浓度为0.5 μg/mL的亮抑酶肽+ 终浓度为0.7 μg/mL的抑胃酶肽A)得到的上清液分别进行取样和分析。
结果显示在图5中。结果表明,通过病毒方法表达的因子C在培养期间随着时间而分解。此外,表明了在加入蛋白酶抑制剂的情况下,也发生某种程度的因子C的分解。
(2-3-2)通过稳定表达细胞系方法表达的因子C的稳定性
类似地,在实施例1的稳定表达细胞系方法中在(1-2-1)中在摇动下在28℃培养稳定表达细胞系的步骤中,在培养72小时、96小时、120小时、144小时和168小时以后回收上清液,并对每种回收的上清液进行在有SDS存在下的5-20% 聚丙烯酰胺凝胶电泳(在非还原条件下),然后使用抗-因子C抗体(2C12,其与上面使用的相同) 通过蛋白质印迹法评价因子C的剩余量。此外,还将通过病毒方法培养48小时以后得到的上清液上样。
结果显示在图6中。结果,在没有蛋白酶抑制剂存在下,即使在培养168小时以后,通过稳定表达细胞系方法表达的因子C也没有分解。由此表明,稳定表达细胞系方法的应用可以防止因子C的分解。
(2-4)关于中空纤维膜过滤处理是否必要的研究
研究了在病毒方法中在(1-1-4)中的中空纤维过滤膜处理是否是必要的。使用在(1-1-4)中穿过中空纤维膜过滤之前取样的每种溶液和在(1-1-4)中穿过中空纤维膜过滤之后取样的每种溶液(3批),通过加入内毒素(USP-RSE) 至0或0.05 EU/mL的终浓度,以与上面(2-2)相同的方式测量了吸光度的增加速率(吸光度变化速率)。
结果显示在图7中。在图7中,“未过滤的溶液”是指没有过滤的保留在中空纤维膜筒中的溶液。在使用穿过中空纤维膜过滤后取样的每种溶液的情况下,当内毒素的浓度为0EU/mL时,前凝固酶的活化度较低(换而言之,在内毒素测量后的空白值较低),也就是说,得到了优良结果。相反,表明了在使用穿过中空纤维膜过滤之前取样的每种溶液(“过滤前”或“未过滤的溶液”) 的情况下,即使在0 EU/mL内毒素的情况下,前凝固酶的活化程度也较高,这会导致在内毒素测量后的高空白值。
相反,通过稳定表达细胞系方法,即使没有这样的穿过中空纤维过滤膜的过滤过程,在0 EU/mL内毒素的情况下前凝固酶的活化程度(在内毒素测量后的空白值)保持较低(图4)。
这些结果表明,尽管在使用病毒方法的情况下,穿过中空纤维过滤膜的过滤是必不可少的,但是在使用稳定表达细胞系方法的情况下,这样的过滤不是必需的。
实施例3: 使用本发明的内毒素测量剂测量内毒素
(3-1) 使用内毒素测量剂1的测量
向内毒素测量剂1 (冷冻干燥产品)中,加入3.3 mL 100 mM Tris缓冲液(pH8.0),以溶解该试剂。在该溶液中,含有因子C、因子B和前凝固酶的每种培养物上清液的蛋白浓度为约60 μg/mL。
在96-孔微孔滴定板的每个孔中,加入50 μL浓度为0、0.001、0.01或0.1 EU/mL的内毒素溶液的等分试样,并将50 μL通过溶解所述试剂制备的内毒素测量剂溶液加入每个孔中,随后混合得到的混合物。然后将混合物在37℃温育30分钟,并根据反应速率方法测量内毒素浓度,其中在温育过程中随时间测量在405 nm的吸光度。在该反应溶液中,含有因子C、因子B和前凝固酶的每种培养物上清液的蛋白浓度为约30 μg/mL。
结果显示在图8中。结果表明,在使用通过病毒方法表达的因子的情况下,吸光度变化速率随着内毒素浓度增加而在0.001-0.10 EU/mL范围内线性地增加。
(3-2)使用内毒素测量剂2的测量
向内毒素测量剂2(冷冻干燥产品)中,加入3.3 mL 100 mM Hepes缓冲液(pH7.6),以溶解该试剂。在该溶液中,含有因子C、因子B和前凝固酶的每种培养物上清液的蛋白浓度为约60 μg/mL。
在96-孔微孔滴定板的每个孔中,加入50 μL浓度为0、0.0005、0.001、0.005、0.01或0.1 EU/mL的内毒素溶液的等分试样,并将50 μL通过溶解所述试剂制备的内毒素测量剂溶液加入每个孔中,随后混合得到的混合物。然后将混合物在37℃温育30分钟,并根据反应速率方法测量内毒素浓度,其中在温育过程中随时间测量在405 nm的吸光度。在该反应溶液中,含有因子C、因子B和前凝固酶的每种培养物上清液的蛋白浓度为约30 μg/mL。
结果显示在图9中。结果表明,在使用通过稳定表达细胞方法表达的因子的情况下,吸光度变化速率随着内毒素浓度增加而在0.0005-0.1 EU/mL范围内线性地增加。
基于上述结果,利用任一种内毒素测量剂,在30分钟内可实现0.001 EU/mL浓度的内毒素的定量。此外,利用内毒素测量剂2,能够在30分钟内测量0.0005 EU/mL浓度的内毒素。因而,表明了与常规方法(其测量需要不小于1小时,且尚未实现0.001 EU/mL的检测灵敏度)相比,本发明的内毒素测量剂能够更快速地且灵敏地定量内毒素。此外,表明了在任一种情况下,表达的因子可以不经过纯化而原样用于测量剂中。
实施例4: 重组因子C蛋白和天然存在的因子C蛋白之间的活性差异
(4-1) 重组因子C蛋白和天然存在的因子C蛋白的纯化
通过使2 mg抗-因子C抗体(2C12,其与上面使用的相同) 与1ml琼脂糖柱(GEHealthcare)共价连接,制备了2个因子-C抗体柱。根据在所附的说明书中描述的方法,进行所述制备。向76 mL含有通过稳定表达细胞方法制备的重组因子C蛋白(其通过与上面“(1-2-2) 重组蛋白的回收”中所述相同的方法制备)的培养物上清液中,加入等量的20 mMTris-HCl缓冲液(pH 8.0) (其含有2 M氯化钠和2 mM EDTA)以稀释所述培养物上清液,随后将得到的稀释液应用于因子-C抗体柱之一。类似地,向76 mL鲎血细胞提取物中,加入等量的20 mM Tris-HCl缓冲液(pH 8.0) (其含有2 M氯化钠和2 mM EDTA)以稀释所述提取物,随后将得到的稀释液应用于因子-C抗体柱中的另一个。顺序地用20 mL各自含有200 mM或450 mM氯化钠的20 mM Tris-HCl缓冲液(pH 8.0)洗涤2个柱,然后用50 mM甘氨酸缓冲液(pH 2.5)进行洗脱。在预先放入了0.025 mL 1M氨丁三醇碱(Sigma)的1.5 mL试管中,收集1mL每个洗脱的级分,以使洗脱的溶液的pH恢复至中性。
(4-2)纯化的重组的和天然存在的因子C蛋白之间的浓度对比
对纯化的重组的和天然存在的因子C蛋白的洗脱级分进行在有SDS存在下的5-20%聚丙烯酰胺凝胶电泳分离(在非还原条件下)。在该过程中,已知浓度的纯化的牛血清白蛋白(=BSA)作为浓度参照物样品也在相同的凝胶上进行分离(图10)。用光密度计定量在考马斯亮蓝染色的凝胶上的BSA带的强度,并相对于BSA蛋白的浓度绘图,以制备校正曲线(图11)。基于纯化的因子C蛋白的带强度和校正曲线,估测出纯化的因子C蛋白的浓度。结果表明,关于纯化的样品,天然存在的因子C蛋白的浓度是重组因子C蛋白的浓度的约4倍。
(4-3)纯化的重组的和天然存在的因子C蛋白之间的活性对比
使用纯化的重组的和天然存在的因子C蛋白,进行了活性对比。在该对比中,基于(4-2)的结果,在纯化的因子C之间平衡蛋白浓度。在96-孔微孔滴定板的每个孔中,加入50μL浓度为0、0.05、0.1或0.5 EU/mL的内毒素溶液的等分试样。将试剂和培养物上清液加入每个孔中,使得反应溶液中含有50 mM Tris缓冲液(pH 8.0)、0.2 μg/mL的纯化的因子C蛋白、30 μg/mL的含有重组因子B和重组前凝固酶的每种培养物上清液的蛋白、和0.3 mM的合成底物Boc-Leu-Gly-Arg-pNA,通过加入注射用水将所述反应溶液的总体积调至100 μL。将反应溶液在37℃温育30分钟,并根据反应速率方法进行分析,其中在温育过程中随时间测量在405 nm的吸光度。
结果表明,纯化的重组因子C蛋白的活性是纯化的天然存在的因子C蛋白的活性的约2倍(图12)。上述结果提示,重组因子C具有比天然存在的因子C更高的比活性。
工业适用性
通过本发明,可以快速地且高灵敏度地测量内毒素。此外,通过本发明,可以简单地且快速地以低成本生产内毒素测量剂。因此,本发明可以非常有效地用于内毒素的检测。
序列表的描述
SEQ ID NO:1 日本鲎的因子C基因的DNA序列
SEQ ID NO:2 日本鲎的因子C的氨基酸序列
SEQ ID NO:3 日本鲎的因子B基因的DNA序列
SEQ ID NO:4 日本鲎的因子B的氨基酸序列
SEQ ID NO:5 日本鲎的前凝固酶基因的DNA序列
SEQ ID NO:6 日本鲎的前凝固酶的氨基酸序列
SEQ ID NO:7 His-标签连接的因子C基因的DNA序列
SEQ ID NO:8 其密码子为在昆虫细胞中的表达进行了优化的因子B基因的DNA序列
SEQ ID NO:9 其密码子为在昆虫细胞中的表达进行了优化的前凝固酶基因的DNA序列
SEQ ID NO:10 用于制备不含His-标签的因子C基因的引物
SEQ ID NO:11 用于制备不含His-标签的因子C基因的引物
SEQ ID NO:12 肽序列
CPCH1362272P
序列表
<110> SEIKAGAKU CORPORATION
<120> 用于测量内毒素的试剂
<130> OP-11070-PCT
<150> US61/447,556
<151> 2011-02-28
<160> 12
<170> PatentIn 3.1版
<210> 1
<211> 3060
<212> DNA
<213> 东方鲎
<220>
<221> CDS
<222> (1)..(3060)
<223>
<400> 1
atg gtc tta gcg tcg ttt ttg gtg tct ggt tta gtt cta ggg ata cta 48
Met Val Leu Ala Ser Phe Leu Val Ser Gly Leu Val Leu Gly Ile Leu
1 5 10 15
gcc caa caa atg cgt cca gtt cag tcc aga gga gta gat ctg ggc ttg 96
Ala Gln Gln Met Arg Pro Val Gln Ser Arg Gly Val Asp Leu Gly Leu
20 25 30
tgt gat gaa acg agg ttc gag tgt aag tgt gga gat cca ggc tat gtg 144
Cys Asp Glu Thr Arg Phe Glu Cys Lys Cys Gly Asp Pro Gly Tyr Val
35 40 45
ttc aac gtc cct atg aaa caa tgc acg tac ttc tat cga tgg agg cct 192
Phe Asn Val Pro Met Lys Gln Cys Thr Tyr Phe Tyr Arg Trp Arg Pro
50 55 60
tat tgt aaa cca tgt gat gac ctg gag gct aag gac att tgt cca aag 240
Tyr Cys Lys Pro Cys Asp Asp Leu Glu Ala Lys Asp Ile Cys Pro Lys
65 70 75 80
tac aaa cga tgt caa gag tgt aag gct ggt ctt gat agt tgt gtt act 288
Tyr Lys Arg Cys Gln Glu Cys Lys Ala Gly Leu Asp Ser Cys Val Thr
85 90 95
tgt cca cct aac aaa tat ggt act tgg tgt agc ggt gaa tgt caa tgt 336
Cys Pro Pro Asn Lys Tyr Gly Thr Trp Cys Ser Gly Glu Cys Gln Cys
100 105 110
aag aat gga ggt atc tgt gac cag agg aca gga gct tgt acc tgt cgt 384
Lys Asn Gly Gly Ile Cys Asp Gln Arg Thr Gly Ala Cys Thr Cys Arg
115 120 125
gac aga tat gaa gga gcg cac tgt gaa att ctc aaa ggt tgt cct ctt 432
Asp Arg Tyr Glu Gly Ala His Cys Glu Ile Leu Lys Gly Cys Pro Leu
130 135 140
ctt cca tcg gat tct caa gtt cag gaa gtc aga aac cca cca gat aat 480
Leu Pro Ser Asp Ser Gln Val Gln Glu Val Arg Asn Pro Pro Asp Asn
145 150 155 160
ccc caa act att gac tac agc tgt tca cca ggg ttc aag ctt aaa ggc 528
Pro Gln Thr Ile Asp Tyr Ser Cys Ser Pro Gly Phe Lys Leu Lys Gly
165 170 175
gtg gca cga att agc tgt ctc cca aat gga cag tgg agt agc ttt cca 576
Val Ala Arg Ile Ser Cys Leu Pro Asn Gly Gln Trp Ser Ser Phe Pro
180 185 190
ccc aaa tgt att cga gaa tgt gcc aag gtt tca tct cca gaa cac ggg 624
Pro Lys Cys Ile Arg Glu Cys Ala Lys Val Ser Ser Pro Glu His Gly
195 200 205
aaa gtg aat gct cct agt ggc aat atg ata gaa ggg gct act tta cgg 672
Lys Val Asn Ala Pro Ser Gly Asn Met Ile Glu Gly Ala Thr Leu Arg
210 215 220
ttc tca tgt gat agt ccc tac tac ttg att ggt caa gaa aca tta acc 720
Phe Ser Cys Asp Ser Pro Tyr Tyr Leu Ile Gly Gln Glu Thr Leu Thr
225 230 235 240
tgc cag ggt aat ggt cag tgg agt gga caa ata cca caa tgt aag aag 768
Cys Gln Gly Asn Gly Gln Trp Ser Gly Gln Ile Pro Gln Cys Lys Lys
245 250 255
ttg gtc ttc tgt cct gac ctt gat cct gta aac cat gct gaa cac cag 816
Leu Val Phe Cys Pro Asp Leu Asp Pro Val Asn His Ala Glu His Gln
260 265 270
gtt aaa att ggt gtg gaa caa aaa tat ggt cag ttt cct caa ggc act 864
Val Lys Ile Gly Val Glu Gln Lys Tyr Gly Gln Phe Pro Gln Gly Thr
275 280 285
gaa gtg acc tat acg tgt tcg ggt aac tac ttc ttg atg ggt ttt aac 912
Glu Val Thr Tyr Thr Cys Ser Gly Asn Tyr Phe Leu Met Gly Phe Asn
290 295 300
acc tta aaa tgt aac cct gat ggg tcc tgg tca gga tca cag cca tcc 960
Thr Leu Lys Cys Asn Pro Asp Gly Ser Trp Ser Gly Ser Gln Pro Ser
305 310 315 320
tgt gtt aaa gtg gca gac aga gag gtc gac tgt gac agt aaa gct gta 1008
Cys Val Lys Val Ala Asp Arg Glu Val Asp Cys Asp Ser Lys Ala Val
325 330 335
gac ttc ttg gat gat gtt ggt gaa cct gtc agg atc cac tgt cct gct 1056
Asp Phe Leu Asp Asp Val Gly Glu Pro Val Arg Ile His Cys Pro Ala
340 345 350
ggc tgt tct ttg aca gct ggt act gtg tgg ggt aca gcc ata tac cac 1104
Gly Cys Ser Leu Thr Ala Gly Thr Val Trp Gly Thr Ala Ile Tyr His
355 360 365
gaa ctt tcc tca gtg tgt cgt gca gcc atc cat gct ggc aag ctt cca 1152
Glu Leu Ser Ser Val Cys Arg Ala Ala Ile His Ala Gly Lys Leu Pro
370 375 380
aac tct gga ggg gcg gtg cat gta gtg aac aat ggc ccc tac tcg gac 1200
Asn Ser Gly Gly Ala Val His Val Val Asn Asn Gly Pro Tyr Ser Asp
385 390 395 400
ttt ctg ggt agt gac ctg aat ggg ata aaa tcg gaa gag ttg aag tct 1248
Phe Leu Gly Ser Asp Leu Asn Gly Ile Lys Ser Glu Glu Leu Lys Ser
405 410 415
ctt gcc cgc agt ttt cga ttt gat tat gtc agt tca tcc aca gca ggt 1296
Leu Ala Arg Ser Phe Arg Phe Asp Tyr Val Ser Ser Ser Thr Ala Gly
420 425 430
aga tca gga tgt cct gat gga tgg ttt gag gta gaa gag aac tgt gtg 1344
Arg Ser Gly Cys Pro Asp Gly Trp Phe Glu Val Glu Glu Asn Cys Val
435 440 445
tac gtt aca tca aaa cag aga gcc tgg gaa aga gct caa ggt gtg tgt 1392
Tyr Val Thr Ser Lys Gln Arg Ala Trp Glu Arg Ala Gln Gly Val Cys
450 455 460
acc aat atg gct gct cgt ctt gct gtg cta gac aaa gat cta att ccg 1440
Thr Asn Met Ala Ala Arg Leu Ala Val Leu Asp Lys Asp Leu Ile Pro
465 470 475 480
agt tcc ttg act gag act cta cga ggg aaa ggg tta aca acc aca tgg 1488
Ser Ser Leu Thr Glu Thr Leu Arg Gly Lys Gly Leu Thr Thr Thr Trp
485 490 495
ata gga ttg cac aga cta gat gct gag aag ccc ttt gtt tgg gag cta 1536
Ile Gly Leu His Arg Leu Asp Ala Glu Lys Pro Phe Val Trp Glu Leu
500 505 510
atg gat cgt agt aat gtg gtt ctg aat gat aac cta aca ttc tgg gcc 1584
Met Asp Arg Ser Asn Val Val Leu Asn Asp Asn Leu Thr Phe Trp Ala
515 520 525
tct ggc gaa cct gga aat gaa act aac tgt gta tat ctg gac atc cga 1632
Ser Gly Glu Pro Gly Asn Glu Thr Asn Cys Val Tyr Leu Asp Ile Arg
530 535 540
gat cag ctg cag cct gtg tgg aaa acc aag tca tgt ttt cag ccc tca 1680
Asp Gln Leu Gln Pro Val Trp Lys Thr Lys Ser Cys Phe Gln Pro Ser
545 550 555 560
agc ttt gct tgc atg atg gat ttg tca gac aga aat aaa gcc aaa tgc 1728
Ser Phe Ala Cys Met Met Asp Leu Ser Asp Arg Asn Lys Ala Lys Cys
565 570 575
gat gac cct gga cca ctg gaa aat gga cac gcc aca ctt cat gga caa 1776
Asp Asp Pro Gly Pro Leu Glu Asn Gly His Ala Thr Leu His Gly Gln
580 585 590
agt att gat ggg ttc tat gct ggt tct tct ata agg tac agc tgt gag 1824
Ser Ile Asp Gly Phe Tyr Ala Gly Ser Ser Ile Arg Tyr Ser Cys Glu
595 600 605
gtt ctc cac tac ctc agt gga act gag acc gta act tgt aca aca aat 1872
Val Leu His Tyr Leu Ser Gly Thr Glu Thr Val Thr Cys Thr Thr Asn
610 615 620
ggc aca tgg agt gct cct aaa cct cga tgt atc aaa gtc atc acc tgc 1920
Gly Thr Trp Ser Ala Pro Lys Pro Arg Cys Ile Lys Val Ile Thr Cys
625 630 635 640
caa aac cct cct gta cca tca tat ggt tct gtg gaa atc aaa ccc cca 1968
Gln Asn Pro Pro Val Pro Ser Tyr Gly Ser Val Glu Ile Lys Pro Pro
645 650 655
agt cgg aca aac tcg atc agt cgt gtt ggg tca cct ttc ttg agg ttg 2016
Ser Arg Thr Asn Ser Ile Ser Arg Val Gly Ser Pro Phe Leu Arg Leu
660 665 670
cca cgg tta ccc ctc cca tta gcc aga gca gcc aaa cct cct cca aaa 2064
Pro Arg Leu Pro Leu Pro Leu Ala Arg Ala Ala Lys Pro Pro Pro Lys
675 680 685
cct aga tcc tca caa ccc tct act gtg gac ttg gct tct aaa gtt aaa 2112
Pro Arg Ser Ser Gln Pro Ser Thr Val Asp Leu Ala Ser Lys Val Lys
690 695 700
cta cct gaa ggt cat tac cgg gta ggg tct cga gcc att tac acg tgc 2160
Leu Pro Glu Gly His Tyr Arg Val Gly Ser Arg Ala Ile Tyr Thr Cys
705 710 715 720
gag tcg aga tac tac gaa cta ctt gga tct caa ggc aga aga tgt gac 2208
Glu Ser Arg Tyr Tyr Glu Leu Leu Gly Ser Gln Gly Arg Arg Cys Asp
725 730 735
tct aat gga aac tgg agt ggt cgg ccc gct agc tgt att cca gtt tgt 2256
Ser Asn Gly Asn Trp Ser Gly Arg Pro Ala Ser Cys Ile Pro Val Cys
740 745 750
gga cgg tca gac tct cct cgt tct cct ttc atc tgg aat ggg aat tct 2304
Gly Arg Ser Asp Ser Pro Arg Ser Pro Phe Ile Trp Asn Gly Asn Ser
755 760 765
aca gaa ata ggt cag tgg ccg tgg cag gca gga atc tct cga tgg ctt 2352
Thr Glu Ile Gly Gln Trp Pro Trp Gln Ala Gly Ile Ser Arg Trp Leu
770 775 780
gca gac cac aat atg tgg ttt ctc cag tgt gga gga tcc cta ttg aat 2400
Ala Asp His Asn Met Trp Phe Leu Gln Cys Gly Gly Ser Leu Leu Asn
785 790 795 800
gag aaa tgg atc gtc act gct gcc cac tgt gtc acc tac tct gct act 2448
Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Thr Tyr Ser Ala Thr
805 810 815
gct gag ata att gat ccc agt cag ttt aaa atc tat ctg ggc aag tac 2496
Ala Glu Ile Ile Asp Pro Ser Gln Phe Lys Ile Tyr Leu Gly Lys Tyr
820 825 830
tac cgt gat gac agt aga gac gat gac tac gta caa gta aga gag gct 2544
Tyr Arg Asp Asp Ser Arg Asp Asp Asp Tyr Val Gln Val Arg Glu Ala
835 840 845
ctc gag atc cac gta aat cct aac tac gac ccc ggc aat ctc aac ttt 2592
Leu Glu Ile His Val Asn Pro Asn Tyr Asp Pro Gly Asn Leu Asn Phe
850 855 860
gac ata gcc cta att caa ctg aaa act cct gtt act ttg aca aca cga 2640
Asp Ile Ala Leu Ile Gln Leu Lys Thr Pro Val Thr Leu Thr Thr Arg
865 870 875 880
gtc caa cca atc tgt ctg cct act gac atc aca aca aga gaa cac ttg 2688
Val Gln Pro Ile Cys Leu Pro Thr Asp Ile Thr Thr Arg Glu His Leu
885 890 895
aag gag gga aca tta gca gtg gtg aca ggt tgg ggt ttg aat gaa aac 2736
Lys Glu Gly Thr Leu Ala Val Val Thr Gly Trp Gly Leu Asn Glu Asn
900 905 910
aac aca tat tca gag atg att caa caa gct gtg cta cct gtt gtt gca 2784
Asn Thr Tyr Ser Glu Met Ile Gln Gln Ala Val Leu Pro Val Val Ala
915 920 925
gca agc acc tgt gaa gag ggg tac aag gaa gca gac tta cca ctg aca 2832
Ala Ser Thr Cys Glu Glu Gly Tyr Lys Glu Ala Asp Leu Pro Leu Thr
930 935 940
gta aca gag aac atg ttc tgt gca ggt tac aag aag gga cgt tat gat 2880
Val Thr Glu Asn Met Phe Cys Ala Gly Tyr Lys Lys Gly Arg Tyr Asp
945 950 955 960
gcc tgc agt ggg gac agt gga gga cca tta gtg ttt gct gat gat tcc 2928
Ala Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Phe Ala Asp Asp Ser
965 970 975
cgt acc gaa agg cgg tgg gtc ttg gaa ggg att gtc agc tgg ggc agt 2976
Arg Thr Glu Arg Arg Trp Val Leu Glu Gly Ile Val Ser Trp Gly Ser
980 985 990
ccc agt gga tgt ggc aag gct aac cag tat ggg ggc ttc act aaa gtt 3024
Pro Ser Gly Cys Gly Lys Ala Asn Gln Tyr Gly Gly Phe Thr Lys Val
995 1000 1005
aac gtt ttt cta tca tgg att agg cag ttc att tga 3060
Asn Val Phe Leu Ser Trp Ile Arg Gln Phe Ile
1010 1015
<210> 2
<211> 1019
<212> PRT
<213> 东方鲎
<400> 2
Met Val Leu Ala Ser Phe Leu Val Ser Gly Leu Val Leu Gly Ile Leu
1 5 10 15
Ala Gln Gln Met Arg Pro Val Gln Ser Arg Gly Val Asp Leu Gly Leu
20 25 30
Cys Asp Glu Thr Arg Phe Glu Cys Lys Cys Gly Asp Pro Gly Tyr Val
35 40 45
Phe Asn Val Pro Met Lys Gln Cys Thr Tyr Phe Tyr Arg Trp Arg Pro
50 55 60
Tyr Cys Lys Pro Cys Asp Asp Leu Glu Ala Lys Asp Ile Cys Pro Lys
65 70 75 80
Tyr Lys Arg Cys Gln Glu Cys Lys Ala Gly Leu Asp Ser Cys Val Thr
85 90 95
Cys Pro Pro Asn Lys Tyr Gly Thr Trp Cys Ser Gly Glu Cys Gln Cys
100 105 110
Lys Asn Gly Gly Ile Cys Asp Gln Arg Thr Gly Ala Cys Thr Cys Arg
115 120 125
Asp Arg Tyr Glu Gly Ala His Cys Glu Ile Leu Lys Gly Cys Pro Leu
130 135 140
Leu Pro Ser Asp Ser Gln Val Gln Glu Val Arg Asn Pro Pro Asp Asn
145 150 155 160
Pro Gln Thr Ile Asp Tyr Ser Cys Ser Pro Gly Phe Lys Leu Lys Gly
165 170 175
Val Ala Arg Ile Ser Cys Leu Pro Asn Gly Gln Trp Ser Ser Phe Pro
180 185 190
Pro Lys Cys Ile Arg Glu Cys Ala Lys Val Ser Ser Pro Glu His Gly
195 200 205
Lys Val Asn Ala Pro Ser Gly Asn Met Ile Glu Gly Ala Thr Leu Arg
210 215 220
Phe Ser Cys Asp Ser Pro Tyr Tyr Leu Ile Gly Gln Glu Thr Leu Thr
225 230 235 240
Cys Gln Gly Asn Gly Gln Trp Ser Gly Gln Ile Pro Gln Cys Lys Lys
245 250 255
Leu Val Phe Cys Pro Asp Leu Asp Pro Val Asn His Ala Glu His Gln
260 265 270
Val Lys Ile Gly Val Glu Gln Lys Tyr Gly Gln Phe Pro Gln Gly Thr
275 280 285
Glu Val Thr Tyr Thr Cys Ser Gly Asn Tyr Phe Leu Met Gly Phe Asn
290 295 300
Thr Leu Lys Cys Asn Pro Asp Gly Ser Trp Ser Gly Ser Gln Pro Ser
305 310 315 320
Cys Val Lys Val Ala Asp Arg Glu Val Asp Cys Asp Ser Lys Ala Val
325 330 335
Asp Phe Leu Asp Asp Val Gly Glu Pro Val Arg Ile His Cys Pro Ala
340 345 350
Gly Cys Ser Leu Thr Ala Gly Thr Val Trp Gly Thr Ala Ile Tyr His
355 360 365
Glu Leu Ser Ser Val Cys Arg Ala Ala Ile His Ala Gly Lys Leu Pro
370 375 380
Asn Ser Gly Gly Ala Val His Val Val Asn Asn Gly Pro Tyr Ser Asp
385 390 395 400
Phe Leu Gly Ser Asp Leu Asn Gly Ile Lys Ser Glu Glu Leu Lys Ser
405 410 415
Leu Ala Arg Ser Phe Arg Phe Asp Tyr Val Ser Ser Ser Thr Ala Gly
420 425 430
Arg Ser Gly Cys Pro Asp Gly Trp Phe Glu Val Glu Glu Asn Cys Val
435 440 445
Tyr Val Thr Ser Lys Gln Arg Ala Trp Glu Arg Ala Gln Gly Val Cys
450 455 460
Thr Asn Met Ala Ala Arg Leu Ala Val Leu Asp Lys Asp Leu Ile Pro
465 470 475 480
Ser Ser Leu Thr Glu Thr Leu Arg Gly Lys Gly Leu Thr Thr Thr Trp
485 490 495
Ile Gly Leu His Arg Leu Asp Ala Glu Lys Pro Phe Val Trp Glu Leu
500 505 510
Met Asp Arg Ser Asn Val Val Leu Asn Asp Asn Leu Thr Phe Trp Ala
515 520 525
Ser Gly Glu Pro Gly Asn Glu Thr Asn Cys Val Tyr Leu Asp Ile Arg
530 535 540
Asp Gln Leu Gln Pro Val Trp Lys Thr Lys Ser Cys Phe Gln Pro Ser
545 550 555 560
Ser Phe Ala Cys Met Met Asp Leu Ser Asp Arg Asn Lys Ala Lys Cys
565 570 575
Asp Asp Pro Gly Pro Leu Glu Asn Gly His Ala Thr Leu His Gly Gln
580 585 590
Ser Ile Asp Gly Phe Tyr Ala Gly Ser Ser Ile Arg Tyr Ser Cys Glu
595 600 605
Val Leu His Tyr Leu Ser Gly Thr Glu Thr Val Thr Cys Thr Thr Asn
610 615 620
Gly Thr Trp Ser Ala Pro Lys Pro Arg Cys Ile Lys Val Ile Thr Cys
625 630 635 640
Gln Asn Pro Pro Val Pro Ser Tyr Gly Ser Val Glu Ile Lys Pro Pro
645 650 655
Ser Arg Thr Asn Ser Ile Ser Arg Val Gly Ser Pro Phe Leu Arg Leu
660 665 670
Pro Arg Leu Pro Leu Pro Leu Ala Arg Ala Ala Lys Pro Pro Pro Lys
675 680 685
Pro Arg Ser Ser Gln Pro Ser Thr Val Asp Leu Ala Ser Lys Val Lys
690 695 700
Leu Pro Glu Gly His Tyr Arg Val Gly Ser Arg Ala Ile Tyr Thr Cys
705 710 715 720
Glu Ser Arg Tyr Tyr Glu Leu Leu Gly Ser Gln Gly Arg Arg Cys Asp
725 730 735
Ser Asn Gly Asn Trp Ser Gly Arg Pro Ala Ser Cys Ile Pro Val Cys
740 745 750
Gly Arg Ser Asp Ser Pro Arg Ser Pro Phe Ile Trp Asn Gly Asn Ser
755 760 765
Thr Glu Ile Gly Gln Trp Pro Trp Gln Ala Gly Ile Ser Arg Trp Leu
770 775 780
Ala Asp His Asn Met Trp Phe Leu Gln Cys Gly Gly Ser Leu Leu Asn
785 790 795 800
Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Thr Tyr Ser Ala Thr
805 810 815
Ala Glu Ile Ile Asp Pro Ser Gln Phe Lys Ile Tyr Leu Gly Lys Tyr
820 825 830
Tyr Arg Asp Asp Ser Arg Asp Asp Asp Tyr Val Gln Val Arg Glu Ala
835 840 845
Leu Glu Ile His Val Asn Pro Asn Tyr Asp Pro Gly Asn Leu Asn Phe
850 855 860
Asp Ile Ala Leu Ile Gln Leu Lys Thr Pro Val Thr Leu Thr Thr Arg
865 870 875 880
Val Gln Pro Ile Cys Leu Pro Thr Asp Ile Thr Thr Arg Glu His Leu
885 890 895
Lys Glu Gly Thr Leu Ala Val Val Thr Gly Trp Gly Leu Asn Glu Asn
900 905 910
Asn Thr Tyr Ser Glu Met Ile Gln Gln Ala Val Leu Pro Val Val Ala
915 920 925
Ala Ser Thr Cys Glu Glu Gly Tyr Lys Glu Ala Asp Leu Pro Leu Thr
930 935 940
Val Thr Glu Asn Met Phe Cys Ala Gly Tyr Lys Lys Gly Arg Tyr Asp
945 950 955 960
Ala Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Phe Ala Asp Asp Ser
965 970 975
Arg Thr Glu Arg Arg Trp Val Leu Glu Gly Ile Val Ser Trp Gly Ser
980 985 990
Pro Ser Gly Cys Gly Lys Ala Asn Gln Tyr Gly Gly Phe Thr Lys Val
995 1000 1005
Asn Val Phe Leu Ser Trp Ile Arg Gln Phe Ile
1010 1015
<210> 3
<211> 1203
<212> DNA
<213> 东方鲎
<220>
<221> CDS
<222> (1)..(1203)
<223>
<400> 3
atg acg tgg ata tgt gtg ata acg ttg ttt gct ctg gct tct gct acg 48
Met Thr Trp Ile Cys Val Ile Thr Leu Phe Ala Leu Ala Ser Ala Thr
1 5 10 15
ttg ggt aac aaa gtt agt aga gtg ggg gtc ctc ttc ccc aag aca cgg 96
Leu Gly Asn Lys Val Ser Arg Val Gly Val Leu Phe Pro Lys Thr Arg
20 25 30
aac gac aat gag tgt aca gca aga ggg gga ttg aaa gga tcc tgc aaa 144
Asn Asp Asn Glu Cys Thr Ala Arg Gly Gly Leu Lys Gly Ser Cys Lys
35 40 45
tcc ctc ata gac tgt cct agt gtc ttg gct acg ttg aag gac agt ttt 192
Ser Leu Ile Asp Cys Pro Ser Val Leu Ala Thr Leu Lys Asp Ser Phe
50 55 60
cct gtc gtt tgc tct tgg aat ggt cga ttt cag cct att gtc tgc tgt 240
Pro Val Val Cys Ser Trp Asn Gly Arg Phe Gln Pro Ile Val Cys Cys
65 70 75 80
cct gat gca ata gca cca cca cct gta acc aca aca gct gta act gta 288
Pro Asp Ala Ile Ala Pro Pro Pro Val Thr Thr Thr Ala Val Thr Val
85 90 95
ata tct aca aaa gaa cca aag ctt cca aga tta cat ata tca ggt tgt 336
Ile Ser Thr Lys Glu Pro Lys Leu Pro Arg Leu His Ile Ser Gly Cys
100 105 110
gga aaa aga aaa gtc aaa ata gat att aca act gtt gga cgc tct gga 384
Gly Lys Arg Lys Val Lys Ile Asp Ile Thr Thr Val Gly Arg Ser Gly
115 120 125
tca cca ata ctt cct ccg ata tct act cct caa aat tca aca ggt ggg 432
Ser Pro Ile Leu Pro Pro Ile Ser Thr Pro Gln Asn Ser Thr Gly Gly
130 135 140
aga gga att att gct gga ggc gta gaa gcc aaa att ggc gcg tgg cct 480
Arg Gly Ile Ile Ala Gly Gly Val Glu Ala Lys Ile Gly Ala Trp Pro
145 150 155 160
tgg atg gca gct gtt ttt gtg aaa aac ttt ggc att ggc aga ttc cac 528
Trp Met Ala Ala Val Phe Val Lys Asn Phe Gly Ile Gly Arg Phe His
165 170 175
tgt gct ggt agc ata atc agt aac aag tac att ttg tca gct gcc cac 576
Cys Ala Gly Ser Ile Ile Ser Asn Lys Tyr Ile Leu Ser Ala Ala His
180 185 190
gcc ttc ctt atc gga ggt cga aag ttg acc cca act cgc tta gct gtc 624
Ala Phe Leu Ile Gly Gly Arg Lys Leu Thr Pro Thr Arg Leu Ala Val
195 200 205
cgt gtg gga ggc cac tac ata aag agg ggt caa gag tat cca gtg aaa 672
Arg Val Gly Gly His Tyr Ile Lys Arg Gly Gln Glu Tyr Pro Val Lys
210 215 220
gac gtg att atc cat cct cat tat gta gaa aag gag aac tac aat gat 720
Asp Val Ile Ile His Pro His Tyr Val Glu Lys Glu Asn Tyr Asn Asp
225 230 235 240
ata gcc ata atc gag tta aaa gag gaa ctg aac ttt acg gac ttg gtc 768
Ile Ala Ile Ile Glu Leu Lys Glu Glu Leu Asn Phe Thr Asp Leu Val
245 250 255
aat cct ata tgt ctc cct gat cca gag aca gta acg gat cca tta aaa 816
Asn Pro Ile Cys Leu Pro Asp Pro Glu Thr Val Thr Asp Pro Leu Lys
260 265 270
gac aga att gtg act gca gcg gga tgg ggc gat ctg gat ttc tcc ggt 864
Asp Arg Ile Val Thr Ala Ala Gly Trp Gly Asp Leu Asp Phe Ser Gly
275 280 285
cca cgg agc caa gtt cta cgt gag gta agc atc cca gtt gtt cca gtt 912
Pro Arg Ser Gln Val Leu Arg Glu Val Ser Ile Pro Val Val Pro Val
290 295 300
gat aaa tgt gat caa gcc tat gag aaa ctc aac acc cct tca cta aaa 960
Asp Lys Cys Asp Gln Ala Tyr Glu Lys Leu Asn Thr Pro Ser Leu Lys
305 310 315 320
aat ggg ata acg aat aac ttc ctt tgc gct gga ttg gaa gaa gga ggg 1008
Asn Gly Ile Thr Asn Asn Phe Leu Cys Ala Gly Leu Glu Glu Gly Gly
325 330 335
aaa gac gct tgc caa ggc gat tct ggt gga ccg ttg atg cta gtg aac 1056
Lys Asp Ala Cys Gln Gly Asp Ser Gly Gly Pro Leu Met Leu Val Asn
340 345 350
aac act agg tgg ata gta gta gga gtt gtg tcg ttc ggg cac aag tgt 1104
Asn Thr Arg Trp Ile Val Val Gly Val Val Ser Phe Gly His Lys Cys
355 360 365
gcc gag gaa gga tat cct ggt gtg tac tcg cgc gta gcg agt tac cta 1152
Ala Glu Glu Gly Tyr Pro Gly Val Tyr Ser Arg Val Ala Ser Tyr Leu
370 375 380
gac tgg atc gcg aaa gtt acg aac tcg tta gat cat gcc gtc act aac 1200
Asp Trp Ile Ala Lys Val Thr Asn Ser Leu Asp His Ala Val Thr Asn
385 390 395 400
taa 1203
<210> 4
<211> 400
<212> PRT
<213> 东方鲎
<400> 4
Met Thr Trp Ile Cys Val Ile Thr Leu Phe Ala Leu Ala Ser Ala Thr
1 5 10 15
Leu Gly Asn Lys Val Ser Arg Val Gly Val Leu Phe Pro Lys Thr Arg
20 25 30
Asn Asp Asn Glu Cys Thr Ala Arg Gly Gly Leu Lys Gly Ser Cys Lys
35 40 45
Ser Leu Ile Asp Cys Pro Ser Val Leu Ala Thr Leu Lys Asp Ser Phe
50 55 60
Pro Val Val Cys Ser Trp Asn Gly Arg Phe Gln Pro Ile Val Cys Cys
65 70 75 80
Pro Asp Ala Ile Ala Pro Pro Pro Val Thr Thr Thr Ala Val Thr Val
85 90 95
Ile Ser Thr Lys Glu Pro Lys Leu Pro Arg Leu His Ile Ser Gly Cys
100 105 110
Gly Lys Arg Lys Val Lys Ile Asp Ile Thr Thr Val Gly Arg Ser Gly
115 120 125
Ser Pro Ile Leu Pro Pro Ile Ser Thr Pro Gln Asn Ser Thr Gly Gly
130 135 140
Arg Gly Ile Ile Ala Gly Gly Val Glu Ala Lys Ile Gly Ala Trp Pro
145 150 155 160
Trp Met Ala Ala Val Phe Val Lys Asn Phe Gly Ile Gly Arg Phe His
165 170 175
Cys Ala Gly Ser Ile Ile Ser Asn Lys Tyr Ile Leu Ser Ala Ala His
180 185 190
Ala Phe Leu Ile Gly Gly Arg Lys Leu Thr Pro Thr Arg Leu Ala Val
195 200 205
Arg Val Gly Gly His Tyr Ile Lys Arg Gly Gln Glu Tyr Pro Val Lys
210 215 220
Asp Val Ile Ile His Pro His Tyr Val Glu Lys Glu Asn Tyr Asn Asp
225 230 235 240
Ile Ala Ile Ile Glu Leu Lys Glu Glu Leu Asn Phe Thr Asp Leu Val
245 250 255
Asn Pro Ile Cys Leu Pro Asp Pro Glu Thr Val Thr Asp Pro Leu Lys
260 265 270
Asp Arg Ile Val Thr Ala Ala Gly Trp Gly Asp Leu Asp Phe Ser Gly
275 280 285
Pro Arg Ser Gln Val Leu Arg Glu Val Ser Ile Pro Val Val Pro Val
290 295 300
Asp Lys Cys Asp Gln Ala Tyr Glu Lys Leu Asn Thr Pro Ser Leu Lys
305 310 315 320
Asn Gly Ile Thr Asn Asn Phe Leu Cys Ala Gly Leu Glu Glu Gly Gly
325 330 335
Lys Asp Ala Cys Gln Gly Asp Ser Gly Gly Pro Leu Met Leu Val Asn
340 345 350
Asn Thr Arg Trp Ile Val Val Gly Val Val Ser Phe Gly His Lys Cys
355 360 365
Ala Glu Glu Gly Tyr Pro Gly Val Tyr Ser Arg Val Ala Ser Tyr Leu
370 375 380
Asp Trp Ile Ala Lys Val Thr Asn Ser Leu Asp His Ala Val Thr Asn
385 390 395 400
<210> 5
<211> 1128
<212> DNA
<213> 东方鲎
<220>
<221> CDS
<222> (1)..(1128)
<223>
<400> 5
atg ttg gtg aat aac gtg ttt tca cta ctg tgt ttc cca ctc ttg atg 48
Met Leu Val Asn Asn Val Phe Ser Leu Leu Cys Phe Pro Leu Leu Met
1 5 10 15
tct gtg gtt aga tgc agt act ctc agc aga cag cgt aga cag ttt gtt 96
Ser Val Val Arg Cys Ser Thr Leu Ser Arg Gln Arg Arg Gln Phe Val
20 25 30
ttc cct gac gag gaa gaa ctt tgc tca aac cga ttt act gaa gaa gga 144
Phe Pro Asp Glu Glu Glu Leu Cys Ser Asn Arg Phe Thr Glu Glu Gly
35 40 45
aca tgc aaa aat gtc ttg gat tgt aga ata ctt tta caa aaa aat gat 192
Thr Cys Lys Asn Val Leu Asp Cys Arg Ile Leu Leu Gln Lys Asn Asp
50 55 60
tat aat tta ctc aaa gaa tca ata tgc ggc ttt gaa ggc ata aca ccc 240
Tyr Asn Leu Leu Lys Glu Ser Ile Cys Gly Phe Glu Gly Ile Thr Pro
65 70 75 80
aaa gtt tgt tgt ccg aaa tca agc cat gta att tca agt aca cag gca 288
Lys Val Cys Cys Pro Lys Ser Ser His Val Ile Ser Ser Thr Gln Ala
85 90 95
cct cca gaa acc act acg act gaa cgc cca cca aaa cag ata cca ccc 336
Pro Pro Glu Thr Thr Thr Thr Glu Arg Pro Pro Lys Gln Ile Pro Pro
100 105 110
aat ctt cat gaa gtg tgt gga att cac aat act aca act acc agg att 384
Asn Leu His Glu Val Cys Gly Ile His Asn Thr Thr Thr Thr Arg Ile
115 120 125
att gga ggt cgg gaa gca cct att gga gcc tgg ccg tgg atg act gct 432
Ile Gly Gly Arg Glu Ala Pro Ile Gly Ala Trp Pro Trp Met Thr Ala
130 135 140
gtc tac ata aaa caa gga gga atc aga agt gtt cag tgt ggt ggc gca 480
Val Tyr Ile Lys Gln Gly Gly Ile Arg Ser Val Gln Cys Gly Gly Ala
145 150 155 160
ctt gtc act aac agg cac gtg att aca gct tcg cac tgt gtt gta aac 528
Leu Val Thr Asn Arg His Val Ile Thr Ala Ser His Cys Val Val Asn
165 170 175
agt gca gga aca gat gtg atg cca gct gat gta ttc tcg gtt cgt ctg 576
Ser Ala Gly Thr Asp Val Met Pro Ala Asp Val Phe Ser Val Arg Leu
180 185 190
ggt gaa cac aat tta tac agt acc gat gac gat tcg aat cca ata gat 624
Gly Glu His Asn Leu Tyr Ser Thr Asp Asp Asp Ser Asn Pro Ile Asp
195 200 205
ttt gca gtt acg tcg gtg aaa cat cac gaa cac ttt gta ctc gcg acg 672
Phe Ala Val Thr Ser Val Lys His His Glu His Phe Val Leu Ala Thr
210 215 220
tat ttg aat gac atc gca att cta acg tta aat gac aca gtt acg ttt 720
Tyr Leu Asn Asp Ile Ala Ile Leu Thr Leu Asn Asp Thr Val Thr Phe
225 230 235 240
aca gac aga att cga ccc att tgt cta cct tat cgt aag ttg aga tac 768
Thr Asp Arg Ile Arg Pro Ile Cys Leu Pro Tyr Arg Lys Leu Arg Tyr
245 250 255
gat gat cta gca atg aga aaa ccg ttt atc act gga tgg gga aca aca 816
Asp Asp Leu Ala Met Arg Lys Pro Phe Ile Thr Gly Trp Gly Thr Thr
260 265 270
gca ttt aac ggc cca tct agt gca gtg ttg aga gaa gta cag tta cca 864
Ala Phe Asn Gly Pro Ser Ser Ala Val Leu Arg Glu Val Gln Leu Pro
275 280 285
ata tgg gaa cac gag gcc tgt aga cag gcc tac gag aag gat tta aat 912
Ile Trp Glu His Glu Ala Cys Arg Gln Ala Tyr Glu Lys Asp Leu Asn
290 295 300
att aca aac gtg tat atg tgt gct ggc ttt gca gat ggc ggg aag gat 960
Ile Thr Asn Val Tyr Met Cys Ala Gly Phe Ala Asp Gly Gly Lys Asp
305 310 315 320
gct tgc cag ggt gat tct gga ggt cca atg atg ttg cct gtt aaa acc 1008
Ala Cys Gln Gly Asp Ser Gly Gly Pro Met Met Leu Pro Val Lys Thr
325 330 335
gga gag ttt tat ctc att gga att gtg tct ttc gga aag aaa tgc gca 1056
Gly Glu Phe Tyr Leu Ile Gly Ile Val Ser Phe Gly Lys Lys Cys Ala
340 345 350
ttg cct gga ttt cct ggg gtt tac aca aaa gtg aca gag ttt tta gat 1104
Leu Pro Gly Phe Pro Gly Val Tyr Thr Lys Val Thr Glu Phe Leu Asp
355 360 365
tgg att gca gaa cat atg gtg tag 1128
Trp Ile Ala Glu His Met Val
370 375
<210> 6
<211> 375
<212> PRT
<213> 东方鲎
<400> 6
Met Leu Val Asn Asn Val Phe Ser Leu Leu Cys Phe Pro Leu Leu Met
1 5 10 15
Ser Val Val Arg Cys Ser Thr Leu Ser Arg Gln Arg Arg Gln Phe Val
20 25 30
Phe Pro Asp Glu Glu Glu Leu Cys Ser Asn Arg Phe Thr Glu Glu Gly
35 40 45
Thr Cys Lys Asn Val Leu Asp Cys Arg Ile Leu Leu Gln Lys Asn Asp
50 55 60
Tyr Asn Leu Leu Lys Glu Ser Ile Cys Gly Phe Glu Gly Ile Thr Pro
65 70 75 80
Lys Val Cys Cys Pro Lys Ser Ser His Val Ile Ser Ser Thr Gln Ala
85 90 95
Pro Pro Glu Thr Thr Thr Thr Glu Arg Pro Pro Lys Gln Ile Pro Pro
100 105 110
Asn Leu His Glu Val Cys Gly Ile His Asn Thr Thr Thr Thr Arg Ile
115 120 125
Ile Gly Gly Arg Glu Ala Pro Ile Gly Ala Trp Pro Trp Met Thr Ala
130 135 140
Val Tyr Ile Lys Gln Gly Gly Ile Arg Ser Val Gln Cys Gly Gly Ala
145 150 155 160
Leu Val Thr Asn Arg His Val Ile Thr Ala Ser His Cys Val Val Asn
165 170 175
Ser Ala Gly Thr Asp Val Met Pro Ala Asp Val Phe Ser Val Arg Leu
180 185 190
Gly Glu His Asn Leu Tyr Ser Thr Asp Asp Asp Ser Asn Pro Ile Asp
195 200 205
Phe Ala Val Thr Ser Val Lys His His Glu His Phe Val Leu Ala Thr
210 215 220
Tyr Leu Asn Asp Ile Ala Ile Leu Thr Leu Asn Asp Thr Val Thr Phe
225 230 235 240
Thr Asp Arg Ile Arg Pro Ile Cys Leu Pro Tyr Arg Lys Leu Arg Tyr
245 250 255
Asp Asp Leu Ala Met Arg Lys Pro Phe Ile Thr Gly Trp Gly Thr Thr
260 265 270
Ala Phe Asn Gly Pro Ser Ser Ala Val Leu Arg Glu Val Gln Leu Pro
275 280 285
Ile Trp Glu His Glu Ala Cys Arg Gln Ala Tyr Glu Lys Asp Leu Asn
290 295 300
Ile Thr Asn Val Tyr Met Cys Ala Gly Phe Ala Asp Gly Gly Lys Asp
305 310 315 320
Ala Cys Gln Gly Asp Ser Gly Gly Pro Met Met Leu Pro Val Lys Thr
325 330 335
Gly Glu Phe Tyr Leu Ile Gly Ile Val Ser Phe Gly Lys Lys Cys Ala
340 345 350
Leu Pro Gly Phe Pro Gly Val Tyr Thr Lys Val Thr Glu Phe Leu Asp
355 360 365
Trp Ile Ala Glu His Met Val
370 375
<210> 7
<211> 3078
<212> DNA
<213> 东方鲎
<400> 7
atggtcttag cgtcgttttt ggtgtctggt ttagttctag ggatactagc ccaacaaatg 60
cgtccagttc agtccagagg agtagatctg ggcttgtgtg atgaaacgag gttcgagtgt 120
aagtgtggag atccaggcta tgtgttcaac gtccctatga aacaatgcac gtacttctat 180
cgatggaggc cttattgtaa accatgtgat gacctggagg ctaaggacat ttgtccaaag 240
tacaaacgat gtcaagagtg taaggctggt cttgatagtt gtgttacttg tccacctaac 300
aaatatggta cttggtgtag cggtgaatgt caatgtaaga atggaggtat ctgtgaccag 360
aggacaggag cttgtacctg tcgtgacaga tatgaaggag cgcactgtga aattctcaaa 420
ggttgtcctc ttcttccatc ggattctcaa gttcaggaag tcagaaaccc accagataat 480
ccccaaacta ttgactacag ctgttcacca gggttcaagc ttaaaggcgt ggcacgaatt 540
agctgtctcc caaatggaca gtggagtagc tttccaccca aatgtattcg agaatgtgcc 600
aaggtttcat ctccagaaca cgggaaagtg aatgctccta gtggcaatat gatagaaggg 660
gctactttac ggttctcatg tgatagtccc tactacttga ttggtcaaga aacattaacc 720
tgccagggta atggtcagtg gagtggacaa ataccacaat gtaagaagtt ggtcttctgt 780
cctgaccttg atcctgtaaa ccatgctgaa caccaggtta aaattggtgt ggaacaaaaa 840
tatggtcagt ttcctcaagg cactgaagtg acctatacgt gttcgggtaa ctacttcttg 900
atgggtttta acaccttaaa atgtaaccct gatgggtcct ggtcaggatc acagccatcc 960
tgtgttaaag tggcagacag agaggtcgac tgtgacagta aagctgtaga cttcttggat 1020
gatgttggtg aacctgtcag gatccactgt cctgctggct gttctttgac agctggtact 1080
gtgtggggta cagccatata ccacgaactt tcctcagtgt gtcgtgcagc catccatgct 1140
ggcaagcttc caaactctgg aggggcggtg catgtagtga acaatggccc ctactcggac 1200
tttctgggta gtgacctgaa tgggataaaa tcggaagagt tgaagtctct tgcccgcagt 1260
tttcgatttg attatgtcag ttcatccaca gcaggtagat caggatgtcc tgatggatgg 1320
tttgaggtag aagagaactg tgtgtacgtt acatcaaaac agagagcctg ggaaagagct 1380
caaggtgtgt gtaccaatat ggctgctcgt cttgctgtgc tagacaaaga tctaattccg 1440
agttccttga ctgagactct acgagggaaa gggttaacaa ccacatggat aggattgcac 1500
agactagatg ctgagaagcc ctttgtttgg gagctaatgg atcgtagtaa tgtggttctg 1560
aatgataacc taacattctg ggcctctggc gaacctggaa atgaaactaa ctgtgtatat 1620
ctggacatcc gagatcagct gcagcctgtg tggaaaacca agtcatgttt tcagccctca 1680
agctttgctt gcatgatgga tttgtcagac agaaataaag ccaaatgcga tgaccctgga 1740
ccactggaaa atggacacgc cacacttcat ggacaaagta ttgatgggtt ctatgctggt 1800
tcttctataa ggtacagctg tgaggttctc cactacctca gtggaactga gaccgtaact 1860
tgtacaacaa atggcacatg gagtgctcct aaacctcgat gtatcaaagt catcacctgc 1920
caaaaccctc ctgtaccatc atatggttct gtggaaatca aacccccaag tcggacaaac 1980
tcgatcagtc gtgttgggtc acctttcttg aggttgccac ggttacccct cccattagcc 2040
agagcagcca aacctcctcc aaaacctaga tcctcacaac cctctactgt ggacttggct 2100
tctaaagtta aactacctga aggtcattac cgggtagggt ctcgagccat ttacacgtgc 2160
gagtcgagat actacgaact acttggatct caaggcagaa gatgtgactc taatggaaac 2220
tggagtggtc ggcccgctag ctgtattcca gtttgtggac ggtcagactc tcctcgttct 2280
cctttcatct ggaatgggaa ttctacagaa ataggtcagt ggccgtggca ggcaggaatc 2340
tctcgatggc ttgcagacca caatatgtgg tttctccagt gtggaggatc cctattgaat 2400
gagaaatgga tcgtcactgc tgcccactgt gtcacctact ctgctactgc tgagataatt 2460
gatcccagtc agtttaaaat ctatctgggc aagtactacc gtgatgacag tagagacgat 2520
gactacgtac aagtaagaga ggctctcgag atccacgtaa atcctaacta cgaccccggc 2580
aatctcaact ttgacatagc cctaattcaa ctgaaaactc ctgttacttt gacaacacga 2640
gtccaaccaa tctgtctgcc tactgacatc acaacaagag aacacttgaa ggagggaaca 2700
ttagcagtgg tgacaggttg gggtttgaat gaaaacaaca catattcaga gatgattcaa 2760
caagctgtgc tacctgttgt tgcagcaagc acctgtgaag aggggtacaa ggaagcagac 2820
ttaccactga cagtaacaga gaacatgttc tgtgcaggtt acaagaaggg acgttatgat 2880
gcctgcagtg gggacagtgg aggaccatta gtgtttgctg atgattcccg taccgaaagg 2940
cggtgggtct tggaagggat tgtcagctgg ggcagtccca gtggatgtgg caaggctaac 3000
cagtatgggg gcttcactaa agttaacgtt tttctatcat ggattaggca gttcattcat 3060
catcaccatc accattga 3078
<210> 8
<211> 1203
<212> DNA
<213> 东方鲎
<400> 8
atgacctgga tctgcgtgat caccctgttc gctctggctt ccgctaccct gggcaacaag 60
gtgtcccgtg tgggtgtcct gttccccaag acccgtaacg acaacgagtg caccgctcgt 120
ggtggtctga agggctcctg caagtccctg atcgactgcc cctccgtgct ggctaccctg 180
aaggactcct tccccgtcgt gtgctcctgg aacggtcgtt tccagcccat cgtgtgctgc 240
cccgacgcta tcgctccccc ccctgtgacc accaccgctg tgaccgtgat ctccaccaag 300
gagcccaagc tgccccgtct gcacatctcc ggttgcggca agcgcaaggt caagatcgac 360
atcaccaccg tgggccgttc cggttccccc atcctgcccc ccatctccac cccccagaac 420
tccactggtg gtcgtggtat catcgctggc ggtgtcgagg ctaagatcgg tgcttggccc 480
tggatggctg ctgtgttcgt gaagaacttc ggtatcggtc gcttccactg cgctggttcc 540
atcatctcca acaagtacat cctgtccgct gctcacgctt tcctcatcgg tggtcgcaag 600
ctgaccccca cccgtctggc tgtgcgtgtg ggtggtcact acatcaagcg tggccaggag 660
taccccgtca aggacgtgat catccacccc cactacgtgg agaaggagaa ctacaacgac 720
atcgccatca tcgagctgaa ggaggagctg aacttcaccg acctggtcaa ccccatctgc 780
ctgcccgacc ccgagactgt gaccgaccct ctgaaggacc gtatcgtgac cgctgctggc 840
tggggcgacc tggacttctc cggtccccgt tcccaggtgc tgcgtgaggt gtccatcccc 900
gtggtgcccg tggacaagtg cgaccaggct tacgagaagc tgaacacccc ctccctgaag 960
aacggtatta ccaacaactt cctctgcgcc ggactcgagg agggtggcaa ggacgcttgc 1020
cagggcgact ccggtggtcc cctgatgctg gtcaacaaca cccgttggat cgtcgtgggt 1080
gtcgtgtcct tcggtcacaa gtgcgctgag gagggttacc ccggcgtcta ctcccgtgtg 1140
gcttcctacc tggactggat cgctaaggtc accaactccc tggaccacgc tgtcaccaac 1200
taa 1203
<210> 9
<211> 1128
<212> DNA
<213> 东方鲎
<400> 9
atgctggtca acaacgtgtt ctccctgctg tgcttccccc tgctgatgtc cgtcgtgcgt 60
tgctccaccc tgtcccgtca gcgtcgtcag ttcgtgttcc ccgacgaaga ggagctgtgc 120
tccaaccgtt tcaccgagga gggcacttgc aagaacgtgc tggactgccg tatcctgctg 180
cagaagaacg actacaacct cctgaaggag tccatctgcg gtttcgaggg tatcactccc 240
aaggtctgct gccccaagtc ctcccacgtg atctccagca cccaggctcc ccccgagact 300
accaccaccg agcgtccccc caagcagatc ccccccaacc tccacgaggt ctgcggtatc 360
cacaacacca ccaccacccg tatcatcggt ggtcgcgagg ctcccatcgg tgcttggccc 420
tggatgaccg ctgtgtacat caagcagggt ggtatccgtt ccgtgcagtg cggaggtgct 480
ctggtcacca accgtcacgt gatcaccgct tcccactgcg tggtcaactc cgctggcacc 540
gacgtgatgc ccgctgacgt gttctctgtg cgtctgggcg agcacaacct gtactccacc 600
gacgacgact ccaaccccat cgacttcgct gtgacctccg tgaagcacca cgagcacttc 660
gtgctggcta cctacctgaa cgacatcgct atcctgactc tgaacgacac cgtgaccttc 720
accgaccgta tccgtcccat ctgcctgccc taccgcaagc tgcgttacga cgacctggct 780
atgcgcaagc ccttcatcac cggctggggc accaccgctt tcaacggtcc ctcctccgct 840
gtgctgcgtg aggtgcagct gcccatctgg gagcacgagg cttgccgtca ggcttacgag 900
aaggacctga acatcaccaa cgtgtacatg tgcgctggtt tcgctgacgg tggcaaggac 960
gcttgccagg gcgactccgg tggtcccatg atgctgcccg tcaagaccgg cgagttctac 1020
ctgatcggta tcgtgtcctt cggcaagaag tgcgctctgc ccggtttccc cggtgtctac 1080
accaaggtca ccgagttcct cgactggatc gccgagcaca tggtgtaa 1128
<210> 10
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 引物FC-N-Pst
<400> 10
caactgcaga tggtcttagc gtcgtttttg 30
<210> 11
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FC-无标签-R-Bam
<400> 11
caggatcctc aaatgaactg cctaatccat gat 33
<210> 12
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 12
Ile Glu Gly Arg
1
Claims (4)
1.一种内毒素测量剂,其包含下面的重组蛋白(1)至(3):
(1) 因子C;
(2) 因子B;和
(3) 前凝固酶;
其中该蛋白中的每一种是通过使用昆虫细胞作为宿主进行表达可得到的重组蛋白,其中所述因子C是下面的蛋白(A);所述因子B是下面的蛋白(B);以及所述前凝固酶是下面的蛋白(C);
(A)由SEQ ID NO:2中所示的氨基酸序列组成的蛋白;
(B)由SEQ ID NO:4中所示的氨基酸序列组成的蛋白;和
(C)由SEQ ID NO:6中所示的氨基酸序列组成的蛋白。
2.一种在试验样品中测量内毒素的方法,该方法包括:使根据权利要求1所述的测量剂与试验样品混合的步骤,和测量级联反应的进展的步骤。
3.根据权利要求2所述的方法,该方法包括:将用于检测级联反应的进展的底物加入反应系统中的步骤。
4.根据权利要求3所述的方法,该方法另外包括:基于所述底物的反应计算试验样品中的内毒素水平的步骤。
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EP2740791A1 (en) * | 2012-12-05 | 2014-06-11 | MicroCoat Biotechnologie GmbH | Method for recombinant production of horseshoe crab Factor C protein in protozoa |
CN108642030A (zh) * | 2012-12-10 | 2018-10-12 | 生化学工业株式会社 | 新重组因子c、其制造方法、及内毒素的测定法 |
JP6432083B2 (ja) | 2012-12-28 | 2018-12-05 | 生化学工業株式会社 | リムルス試験に付されるアンチトロンビンiii用の前処理剤及び前処理方法 |
JP6562765B2 (ja) * | 2015-08-13 | 2019-08-21 | 大日本印刷株式会社 | 電気化学式エンドトキシン濃度検出用容器、電極チップおよびエンドトキシンの検出方法 |
JP6557090B2 (ja) * | 2015-08-13 | 2019-08-07 | 大日本印刷株式会社 | 電極チップおよび電極チップの製造方法 |
JP6895139B2 (ja) | 2016-02-16 | 2021-06-30 | 生化学工業株式会社 | フェニレンジアミン誘導体を用いた電気化学測定 |
CN105866080B (zh) * | 2016-04-05 | 2019-11-12 | 中国科学院苏州生物医学工程技术研究所 | 重组鲎三因子试剂及其检测内毒素的方法 |
CN109689681B (zh) * | 2016-10-18 | 2022-04-26 | 生化学工业株式会社 | 源自鲎属的重组蛋白及编码该重组蛋白的dna |
CA3054780A1 (en) * | 2017-03-01 | 2018-09-07 | Seikagaku Corporation | Horseshoe crab factor b variant |
CN108913707B (zh) * | 2018-07-23 | 2021-06-15 | 广东医科大学 | 一种特异性检测内毒素的试剂及其制备方法 |
EP3862437A4 (en) | 2018-10-03 | 2022-07-06 | Seikagaku Corporation | METHOD OF INCREASING THE SENSITIVITY OF AN ENDOTOXIN DETECTION DEVICE |
EP4137817A1 (en) | 2020-04-16 | 2023-02-22 | Kikkoman Corporation | Trace material measurement method using hydrolase |
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JP2024010024A (ja) | 2024-01-23 |
US20180259527A1 (en) | 2018-09-13 |
SG10202110031YA (en) | 2021-10-28 |
JP2020100622A (ja) | 2020-07-02 |
US20140024062A1 (en) | 2014-01-23 |
CN103562724A (zh) | 2014-02-05 |
SG192578A1 (en) | 2013-09-30 |
US11162949B2 (en) | 2021-11-02 |
EP3517962A1 (en) | 2019-07-31 |
CN106432457A (zh) | 2017-02-22 |
WO2012118226A1 (en) | 2012-09-07 |
JP2018141797A (ja) | 2018-09-13 |
EP3273244A1 (en) | 2018-01-24 |
JP7372392B2 (ja) | 2023-10-31 |
JP2022119887A (ja) | 2022-08-17 |
US20220018841A1 (en) | 2022-01-20 |
EP2681564A1 (en) | 2014-01-08 |
EP3273244B1 (en) | 2019-09-25 |
JP6640267B2 (ja) | 2020-02-05 |
EP2681564B1 (en) | 2017-10-25 |
SG10201601351WA (en) | 2016-03-30 |
ES2650170T3 (es) | 2018-01-17 |
ES2763089T3 (es) | 2020-05-27 |
JP2014510898A (ja) | 2014-05-01 |
US20150252405A1 (en) | 2015-09-10 |
US20170138945A1 (en) | 2017-05-18 |
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