CN112639118A - 内毒素测定剂的灵敏度的增强方法 - Google Patents
内毒素测定剂的灵敏度的增强方法 Download PDFInfo
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Abstract
本发明的课题在于提供,在利用现有的重组蛋白质的内毒素测定剂中,增强对源自幽门螺旋杆菌的内毒素的灵敏度的方法。本发明提供一种增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的方法,上述内毒素测定剂包含源自鲎的C因子重组蛋白质,上述方法包含使内毒素测定时的上述C因子重组蛋白质的含量增加至使灵敏度增强的充分的量。
Description
技术领域
本发明涉及一种增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的方法。
背景技术
已知如果存在于鲎的血中的变形细胞(amoebocyte)的提取物(变形细胞溶解物。amoebocyte lysate)与内毒素接触,则产生凝固。利用该性质,变形细胞溶解物作为高灵敏度地检测内毒素的试剂广泛用于医药品的品质管理等。
该试剂被称为“溶解物试剂”。另外,因内毒素而产生凝固的性质最初在美洲鲎(Limulus polyphemus)中被发现,因此,该试剂有时被称为“鲎试剂”或“LAL(Limulusamoebocyte lysate)试剂”。
为了保护鲎,存在利用重组技术人工制造变形细胞溶解物中的蛋白质并制作试剂的构思(专利文献1、2)。而且,实际上,利用重组蛋白质,PyroGene(注册商标)(Lonza公司)、EndoZyme(注册商标)II(生物梅里埃公司)、PyroSmart(注册商标)(生物化学工业株式会社)这样的制品已经上市。
根据棚元等厚生劳动科学研究成果(非专利文献1)、Loverock等(非专利文献2)、Grallert等(非专利文献3)以及Bolden等(非专利文献4)的报告,认为利用重组蛋白质得到的内毒素测定剂即“重组试剂”的性能与溶解物试剂相同。
现有技术文献
专利文献
专利文献1:国际公开第2012/118226号
专利文献2:国际公开第2014/092079号
非专利文献
非专利文献1:厚生劳动科学研究成果“与用于确保医药品的微生物学品质的硬度试验法导入有关的研究”文献编号201427027B
非专利文献2:Loverock,B et al.,"A Recombinant Factor C Procedure forthe Detection of Gram-Negative BacteriaEndotoxina",Pharmacopeial Forum36,321-29,(2010)
非专利文献3:Grallert,H et al.,"EndoLISA:anovel and reliable methodfor endotoxin detection",Nature Methods,October(2011)
非专利文献4:Bolden,J.et al.,"Application of Recombinant Factor CReagent for the Detection of BacteriaEndotoxins in Pharmaceutical Products",PDA J Pharm Sci Technol.,2017,Sep-Oct,71(5),405-412(2017)
发明内容
但是,本发明人等利用现有的重组试剂测定源自幽门螺旋杆菌的内毒素相对于内毒素标准品的相对效价,结果发现:与利用溶解物试剂测定的相对效价相比显著小。因此,本发明的课题在于,提供一种在利用重组蛋白质的内毒素测定剂中,增强对源自幽门螺旋杆菌的内毒素的灵敏度的方法。
本发明人等为了解决上述课题而进行深入研究,结果发现:通过增加利用重组蛋白质的内毒素测定剂中的内毒素测定时的(即,与源自幽门螺旋杆菌的内毒素共存)C因子重组蛋白质的含量,可增强对源自幽门螺旋杆菌的内毒素的灵敏度。本发明人等基于这些发现,完成了本发明。
即,本发明涉及以下内容。
[1]一种增强内毒素测定剂对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度的方法,
上述内毒素测定剂包含源自鲎的C因子重组蛋白质,
上述方法包含增加内毒素测定时的上述C因子重组蛋白质的含量的工序。
[2]根据[1]记载的方法,其中,上述内毒素测定剂包含源自鲎的B因子重组蛋白质。
[3]根据[1]或[2]记载的方法,其中,上述内毒素测定剂包含源自鲎的凝固酶原重组蛋白质。
[4]根据[1]~[3]中任一项记载的方法,其中,上述内毒素测定剂包含检测用化合物。
[5]一种内毒素测定方法,其增强内毒素测定剂对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度,
上述内毒素测定方法包含制备内毒素测定试样的工序,上述内毒素测定试样包含上述内毒素测定剂和检测对象,
上述内毒素测定剂包含源自鲎的C因子重组蛋白质,
上述灵敏度通过增加上述内毒素测定试样中的上述C因子重组蛋白质的浓度而得到增强。
[6]根据[5]记载的方法,其中,上述内毒素测定剂包含源自鲎的B因子重组蛋白质。
[7]根据[5]或[6]记载的方法,其中,上述内毒素测定剂包含源自鲎的凝固酶原重组蛋白质。
[8]根据[5]~[7]中任一项记载的方法,其中,上述内毒素测定剂包含检测用化合物。
[9]一种内毒素测定剂,其增强对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度。
[10]一种内毒素测定剂的制造方法,其中,上述内毒素测定剂增强了对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度,
上述内毒素测定剂包含源自鲎的C因子重组蛋白质,
上述制造方法包含增加上述内毒素测定剂中的上述C因子重组蛋白质的含量的工序。
[11]一种内毒素测定剂,其中,包含源自鲎的C因子,上述源自鲎的C因子为重组蛋白质,源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的相对效价为利用溶解物试剂测定的相对效价的0.1倍以上。
[12]根据[11]记载的内毒素测定剂,其中,上述内毒素测定剂包含源自鲎的B因子重组蛋白质。
[13]根据[11]或[12]记载的内毒素测定剂,其中,上述内毒素测定剂包含源自鲎的凝固酶原重组蛋白质。
[14]根据[11]~[13]中任一项记载的内毒素测定剂,其中,包含检测用化合物。
[15]一种内毒素测定剂,其中,包含源自鲎的C因子,上述源自鲎的C因子为重组蛋白质,源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的相对效价为200(EU/μg)以上。
[16]根据[15]记载的内毒素测定剂,其中,上述内毒素测定剂包含源自鲎的B因子重组蛋白质。
[17]根据[15]或[16]记载的内毒素测定剂,其中,上述内毒素测定剂包含源自鲎的凝固酶原重组蛋白质。
[18]根据[15]~[17]中任一项记载的内毒素测定剂,其中,包含检测用化合物。检测用化合物的一个方式为通式Y-X-Z表示的检测用化合物,上述通式中,Y为氢原子或保护基,X为包含作为上述凝固酶原重组蛋白质的底物的氨基酸序列的肽,Z为从X脱离时可被光学检测到的标记物。检测用化合物的另一方式为通式Y-X-Z表示的检测用化合物,上述通式中,Y为氢原子或保护基,X为包含作为上述B因子重组蛋白质的底物的氨基酸序列的肽,Z为从X脱离时可被光学检测到的标记物。检测用化合物的再一方式为通式Y-X-Z表示的检测用化合物,上述通式中,Y为氢原子或保护基,X为包含作为上述C因子的底物的氨基酸序列的肽,Z为从X脱离时可被光学检测到的标记物。
[19]一种方法,其中,使用[11]~[18]中任一项记载的内毒素测定剂测定检测对象中的内毒素。
附图说明
图1是表示反应液中的重组C因子浓度和源自幽门螺旋杆菌CA2的内毒素的相对效价的关系的图。
图2是表示反应液中的重组B因子浓度和源自幽门螺旋杆菌CA2的内毒素的相对效价的关系的图。
图3是表示反应液中的重组凝固酶原浓度和源自幽门螺旋杆菌CA2的内毒素的相对效价的关系的图。
具体实施方式
对本说明书中使用的缩写及其含义进行说明。
C因子(C因子:FC)
重组C因子(rFC)
B因子(B因子:FB)
重组B因子(rFB)
凝固酶原(凝固酶前体:PCE)
重组凝固酶原(rPCE)
凝结酶(凝固酶)
根据本发明,可提供一种在利用重组蛋白质的内毒素测定剂中,增强对源自幽门螺旋杆菌的内毒素的灵敏度的方法。
本说明书中,有时将C因子、B因子和凝固酶原各自或总称为“鲎因子”。
以下,对本发明进行说明。
<内毒素测定剂的灵敏度的增强方法>
本发明的一个方式涉及一种增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的方法,上述内毒素测定剂包含源自鲎的C因子重组蛋白质,上述方法包含增加内毒素测定时的上述C因子重组蛋白质的含量的工序(以下,有时称为“本发明的增强方法”)。在本发明的一个实施方式中,使内毒素测定时的上述C因子重组蛋白质的含量增加至使灵敏度增强的充分的量。
本发明的一个方式涉及一种提高内毒素测定剂对源自幽门螺旋杆菌的内毒素的反应性的方法,上述内毒素测定剂包含源自鲎的C因子重组蛋白质,上述方法包含增加内毒素测定时的上述C因子重组蛋白质的含量的工序。本发明的另一方式涉及一种赋予源自鲎的C因子重组蛋白质对源自幽门螺旋杆菌的内毒素的反应性的方法,上述方法包含增加与该内毒素共存的上述C因子重组蛋白质的量的工序。在本发明的一实施方式中,上述反应性以200EU/μg以上(例如,250EU/μg以上、300EU/μg以上)的相对效价表述。
如上述所示,本发明人等发现:在利用现有的重组蛋白质的内毒素测定剂中,存在如下课题,即,对源自幽门螺旋杆菌的内毒素的灵敏度与溶解物试剂相比显著低。
在本发明的增强方法中,在使用利用重组蛋白质的内毒素测定剂即重组试剂的内毒素测定中,通过增加内毒素测定时的C因子重组蛋白质的含量,可增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度。即,可提高源自幽门螺旋杆菌的内毒素相对于基准即内毒素标准品的相对效价。更具体而言,通过增加包含内毒素测定剂和检测对象的内毒素测定试样中的C因子重组蛋白质的浓度,可增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度。在此,本发明人等发现:如后述实施例所示,即使增加内毒素测定试样中的C因子重组蛋白质以外的鲎因子的浓度,也不能提高源自幽门螺旋杆菌的内毒素相对于内毒素标准品的相对效价,或者,背景上升,不能增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度。
在本发明的增强方法中,作为内毒素测定时的C因子重组蛋白质的内毒素测定剂的灵敏度的增强充分的含量,可根据目标相对效价、测定体系、C因子重组蛋白质的宿主等变更,没有限定,可增加C因子重组蛋白质的含量,使得利用重组蛋白质的内毒素测定剂测定的源自幽门螺旋杆菌的内毒素相对于内毒素标准品的相对效价成为利用溶解物试剂测定的相对效价的0.1倍以上、0.2倍以上、0.3倍以上、0.4倍以上、0.5倍以上、0.6倍以上、0.7倍以上、0.8倍以上、0.9倍以上或1.0倍以上。
在此,溶解物试剂可举出通过通常的方法(例如,参照J.Biochem.,80,1011-1021(1976))由鲎血淋巴液制备的血球提取物。另外,可以根据需要在这些提取物中添加对C因子的活化有效的二价金属盐、凝结酶的底物(例如,后述的合成底物)、pH调整剂等。此外,作为溶解物试剂,也可使用市售的溶解物试剂。作为溶解物试剂,没有限定,例如可举出Endospecy(注册商标)ES-50M(生物化学工业株式会社)。
另外,使用利用重组蛋白质的内毒素测定剂的源自幽门螺旋杆菌的内毒素的相对效价的测定,以内毒素标准品为基准求出,例如,可通过使用检测用化合物的实施例记载的方法进行。测定方法可以为终点测定或动力学测定(Kinetic Measurements)的任一种。
相对效价的测定,具体而言,例如:(i)测定内毒素测定试样的吸光度,算出每单位时间的吸光度变化率(mAbs/min)。(ii)接着,根据利用内毒素标准品制成的标准曲线,算出内毒素测定试样的内毒素活性(EU/mL),(iii)该值除以内毒素测定试样所包含的内毒素的浓度(μg/mL),算出内毒素的相对效价(EU/μg)。利用吸光度的时间变化的方法,特别适于3因子系中的内毒素的相对效价的测定(包含C因子、B因子和凝固酶原的反应体系)。在一个实施方式中,源自幽门螺旋杆菌的内毒素的相对效价的测定通过利用吸光度的时间变化的方法,在3因子***中进行。
相对效价的测定,例如可以通过基于荧光强度测定的方法来进行。更具体而言,(i)使用内毒素测定剂,测定伴随级联反应的进行的内毒素测定试样的相对荧光强度的变化,(ii)根据利用内毒素标准品制成的标准曲线,算出内毒素测定试样的内毒素活性(EU/mL),(iii)该值除以内毒素测定试样所包含的内毒素的浓度(μg/mL),算出内毒素的相对效价(EU/μg)。利用荧光强度的时间变化的方法,特别适于1因子***中的相对效价的测定(包含C因子,不包含B因子或凝固酶原的反应体***)以及2因子***中的相对效价的测定(包含C因子以及B因子,不包含凝固酶原的反应体系)。在一个实施方式中,源自幽门螺旋杆菌的内毒素的相对效价的测定,通过利用荧光强度的时间变化的方法,在1因子***或2因子***中进行。
在此,相对效价的测定中使用的源自幽门螺旋杆菌的内毒素的量,只要是可根据利用内毒素标准品制成的标准曲线算出内毒素测定试样(即,含有源自幽门螺旋杆菌的内毒素的试样)的内毒素活性(EU/mL)的量,就没有特别限制,可根据相对效价的测定方法的种类等各种条件而适当设定。相对效价的测定中使用的源自幽门螺旋杆菌的内毒素的量,作为测定体系中的浓度,例如可以为0.25~25ng/mL,具体而言,可以为0.25ng/mL、5ng/mL或25ng/mL。相对效价的测定中使用的源自幽门螺旋杆菌的内毒素的量,特别是在1因子***中实施相对效价的测定的情况下,作为测定体***中的浓度,可以为0.25~25ng/mL,具体而言,可以为0.25ng/mL、5ng/mL或25ng/mL。另外,相对效价的测定中使用的源自幽门螺旋杆菌的内毒素的量,特别是在2因子***或3因子***中实施相对效价的测定的情况下,作为测定体系中的浓度,可以为0.25ng/mL。
在此,作为内毒素标准品,例如可举出日本药典内毒素标准品、美国药典内毒素标准品或欧州药典内毒素标准品。
例如,在使用后述实施例中使用的市售重组试剂A的情况下,源自幽门螺旋杆菌的内毒素的相对效价为147.3EU/μg(表1)。另一方面,在使用市售溶解物试剂A、溶解物试剂B的情况下,源自幽门螺旋杆菌的内毒素的相对效价为约2000EU/μg。在使用由哺乳类细胞表达的C因子重组蛋白质在3因子***中测定内毒素的情况下,如果将内毒素测定时的(即,内毒素测定时的测定试样中的)C因子重组蛋白质的含量设为162ng/mL以上,则可实现0.25ng/mL的源自幽门螺旋杆菌的内毒素的相对效价为利用溶解物试剂测定的相对效价的0.1倍以上的200EU/μg以上(表2)。此时,通过使内毒素测定时的测定试样中的C因子重组蛋白质的含量增加至162ng/mL以上,可增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度。应予说明,表1中的市售重组试剂A的内毒素测定时的C因子重组蛋白质的含量小于162ng/mL。
内毒素测定时的测定试样中的C因子重组蛋白质的含量可根据目标相对效价、测定体系、C因子重组蛋白质的宿主等变更。在测定体***为3因子***的情况下,没有限定,可将内毒素测定时的测定试样中的C因子重组蛋白质的含量设为140ng/mL以上、162ng/mL以上、180ng/mL以上、200ng/mL以上、250ng/mL以上、300ng/mL以上、400ng/mL以上、500ng/mL以上、600ng/mL以上或700ng/mL以上。在测定体系为2因子***的情况下,没有限定,可将内毒素测定时的测定试样中的C因子重组蛋白质的含量设定为235ng/mL以上、250ng/mL以上、300ng/mL以上或350ng/mL以上的量。在测定体系为1因子***的情况下,没有限定,可将内毒素测定时的测定试样中的C因子重组蛋白质的含量设为10ng/mL以上、20ng/mL以上、30ng/mL以上、40ng/mL以上、50ng/mL以上、60ng/mL以上、70ng/mL以上、100ng/mL以上、500ng/mL以上或800ng/mL以上。
内毒素测定时的测定试样中的C因子重组蛋白质的含量的上限,没有特别限制,例如为10mg/mL以下,从生产效率的观点考虑,优选小于10μg/mL(例如为5μg/mL以下、2μg/mL以下)。
应予说明,本说明书中,C因子重组蛋白质的含量为通过实施例记载的ELISA法算出的值。
利用鲎试剂的内毒素的测定方法为:变形细胞溶解物所包含的丝氨酸蛋白酶前体(例如,C因子、B因子和凝固酶原)与内毒素接触时,利用逐次活化而进行的级联反应的方法。
应用本发明的增强方法的内毒素测定方法可以为以下方法,即,与内毒素接触的C因子自催化变成活性型(活性型C因子),利用活性型C因子的蛋白酶活性进行测定(1因子***)。另外,本发明中应用的内毒素测定方法可以为以下方法,即,与内毒素接触的C因子自催化变成活性型(活性型C因子),利用通过活性型C因子的蛋白酶活性切断B因子而变成活性型B因子的反应进行测定(2因子***)。另外,本发明中所应用的内毒素测定方法,除上述一系列的反应以外,利用也包含以下反应的一系列的反应进行测定(3因子***),即,通过活性型B因子的蛋白酶活性切断凝固酶原而变成凝结酶的反应。本说明书中的“级联反应”包含上述1因子***、2因子***和3因子***的反应。
应用本发明的增强方法的内毒素测定方法只要是使用利用C因子重组蛋白质的内毒素测定剂即重组试剂的内毒素测定方法,就可没有特别限定地应用。重组试剂可以为市售的重组试剂、或者、由通过公知的方法而制造的鲎因子构成的试剂。
在上述重组试剂中,C因子为利用基因工程方法制备的鲎因子的重组蛋白质。
在上述重组试剂中,B因子和凝固酶原各自独立,可以为由鲎得到的天然的鲎因子,也可以为通过基因工程的方法制备的鲎因子的重组蛋白质,还可以为以任意的比例包含天然的鲎因子和鲎因子的重组蛋白质的混合物。B因子和凝固酶原优选为鲎因子的重组蛋白质。
天然的鲎因子可以为,以鲎的血球为原料,将按照常规方法取得的溶解物适当精制而分取得到的鲎因子。鲎因子的分取,例如可参照文献(Nakamura,T.,Horiuchi,T.,Morita,T.,Iwanaga,S.(1986)J.Biochem.99,847-57)记载的方法而进行。
鲎因子的重组蛋白质可通过在导入有编码鲎因子的多肽的核酸的细胞中生成该鲎因子而取得。编码鲎因子的核酸的碱基序列可由NCBI(www.ncbi.nlm.nih.gov)等公知的数据库取得。应予说明,编码鲎因子的核酸的碱基序列的密码子的组合可以为最适于在宿主细胞中的表达的DNA的变种。
成为各鲎因子的来源的鲎的种类没有特别限定。作为鲎,可例示属于东方鲎属(Tachypleus)、美洲鲎属(Limulus)或蝎鲎属(Carcinoscorpius)的鲎。更具体而言,已知有三刺鲎(Tachypleus tridentatus)、美洲鲎(Limulus polyphemus)、蝎鲎(Carcinoscorpius rotundicauda)、巨鲎(Tachypleus gigas)4种。可例示这些鲎作为成为鲎因子的来源的鲎。另外,这些鲎中,优选为三刺鲎、蝎鲎或美洲鲎,更优选为三刺鲎。
作为鲎因子的多肽,具体而言,可例示后述的<内毒素的测定方法>记载的(1)~(8)的多肽。作为编码鲎因子的核酸,具体而言,可例示后述的<内毒素的测定方法>记载的编码[1]~[7]的多肽的碱基序列。
基于细胞的鲎因子的生成可通过公知的方法而进行,具体而言,可例示使用后述的<实施例2>等记载的哺乳类细胞或非哺乳类细胞(例如,昆虫细胞、酵母、利什曼原虫等寄生性原生动物等)的方法。另外,基于细胞的鲎因子的生成,例如也可参照文献(国际公开第2018/074498号)记载的方法而进行。
在本发明的增强方法中,除使内毒素测定时的C因子重组蛋白质的含量增加至,例如使灵敏度增强的充分的量以外,可在公知的内毒素测定的条件下进行。作为测定的条件,没有限定,例如,作为反应液的pH,可以采用5~10,优选为7~8.5。作为反应温度,可采用10℃~80℃,优选为20℃~50℃,进一步优选为30℃~40℃。作为反应温度,例如可例示37℃。反应时间也没有特别限定,根据各种条件适当设定即可。反应时间例如可以为5分钟~2小时,优选为15分钟~90分钟,更优选为30分钟~40分钟。
<内毒素的测定方法>
本发明的再一方式涉及一种增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的内毒素测定方法,其中,包含制备包含上述内毒素测定剂和检测对象的内毒素测定试样的工序,上述内毒素测定剂包含源自鲎的C因子重组蛋白质,上述灵敏度的增强通过增加上述内毒素测定试样中的上述C因子重组蛋白质的浓度而实现(以下,有时称为“本发明的测定方法”)。本发明的另一实施方式涉及一种测定内毒素的方法,其中,包含制备包含内毒素测定剂和检测对象的内毒素测定试样的工序,上述内毒素测定剂包含源自鲎的C因子重组蛋白质,使上述内毒素测定试样中的上述C因子重组蛋白质的浓度增加至上述内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的增强充分的量。
本发明中,测定作为包含检测、探测以及定量的总称使用。因此,本发明的测定方法,例如可以为内毒素的检测方法、内毒素的探测方法或内毒素的定量方法。
本发明的测定方法为:通过增加内毒素测定试样中的C因子重组蛋白质的浓度,从而增强内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的内毒素的测定方法。本发明的测定方法中,除增加内毒素测定试样中的C因子重组蛋白质的浓度以外,可在公知的内毒素测定的条件下进行。内毒素测定试样中的C因子重组蛋白质的浓度的、内毒素测定剂对源自幽门螺旋杆菌的内毒素的灵敏度的增强充分的量的方式与上述<内毒素测定剂的灵敏度的增强方法>中的C因子重组蛋白质的含量的方式相同。
以下,对测定方法的详细进行说明。
本发明的测定方法,例如为包含下述(A)和(B)的工序的内毒素的测定方法。
(A)将源自鲎的C因子重组蛋白质和检测对象进行混合的工序。
(B)测定鲎因子的蛋白酶活性的工序。
上述(A)的工序为将源自鲎的C因子重组蛋白质和检测对象混合的工序。在检测对象为包含内毒素的试样的情况下,与该内毒素接触的C因子变成活性型C因子。
在上述(A)的工序中,只要包含将C因子重组蛋白质和检测对象混合的操作,则还可以包含混合其它物质的操作。作为此处所谓的“其它物质”,可例示B因子、凝固酶原、检测用化合物(检测用底物)等。上述(A)的工序为将C因子重组蛋白质、B因子、凝固酶原和检测对象混合的工序,且在检测对象为含有内毒素的试样的情况下,进行与该内毒素接触的C因子变成活性型C因子,B因子变成活性型B因子,凝固酶原变成凝结酶的级联反应。
本发明中,“C因子”只要是具有鲎C因子的功能的C因子,就没有特别限定。此处所谓的“鲎”的定义,如上述<内毒素测定剂的灵敏度的增强方法>中的记载所示。“鲎C因子的功能”是指作为鲎的C因子具有的蛋白酶前体的功能。“鲎C因子的功能”具体而言是指在内毒素的共存下变成活性型(活性型C因子)、表达蛋白酶活性的功能。鲎C因子的功能,例如为在内毒素的共存下变成活性型(活性型C因子),切断B因子而变成活性型(活性型B因子)的功能。另外,鲎C因子的功能,例如为在内毒素的共存下变成活性型(活性型C因子),切断成为活性型C因子的底物的检测用化合物而使标记物脱离的功能。作为此处所谓的检测用化合物,例如可优选使用后述的方式。
本发明中,“B因子”只要是具有鲎B因子的功能的B因子,就没有特别限定。此处所谓的“鲎”的定义如上述<内毒素测定剂的灵敏度的增强方法>中的记载所示。“鲎B因子的功能”具体是指:与活性型C因子接触而变成活性型(活性型B因子),表达蛋白酶活性的功能。鲎B因子的功能,例如为与活性型C因子接触而变成活性型(活性型B因子),切断凝固酶原而变成凝结酶的功能。另外,鲎B因子的功能,例如为与活性型C因子接触而变成活性型(活性型B因子),切断成为活性型B因子的底物的检测用化合物而使标记物脱离的功能。作为此处所谓的检测用化合物,例如可优选使用后述的方式。
本发明中“凝固酶原”只要是具有鲎凝固酶原的功能的凝固酶原,就没有特别限定。此处所谓的“鲎”的定义如上述<内毒素测定剂的灵敏度的增强方法>中的记载所示。“鲎凝固酶原的功能”是指作为鲎的凝固酶原具有的蛋白酶前体的功能。“鲎凝固酶原的功能”具体是指:在活性型B因子的共存下变成活性型(凝结酶),表达蛋白酶活性的功能。鲎凝固酶原的功能,例如为在活性型B因子的共存下变成活性型(凝结酶),切断凝固蛋白原而形成凝固蛋白凝胶的功能。另外,鲎凝固酶原的功能,例如为在活性型B因子的共存下变成活性型(凝结酶),切断成为凝结酶的底物的检测用化合物而使标记物脱离的功能。作为此处所谓的检测用化合物,例如可优选使用后述的方式。
作为本发明中的C因子,具体而言,可例示下述(1)~(4)中任一项所示的多肽。
(1)具有序列号2所示的氨基酸序列的多肽。
(2)具有序列号4所示的氨基酸序列的多肽。
(3)具有序列号12所示的氨基酸序列的多肽。
(4)在上述(1)~(3)中任一项所示的氨基酸序列中,具有置换、缺失、***和/或附加1个或多个氨基酸残基而得到的氨基酸序列,且具有鲎C因子的功能的多肽。
作为本发明中的B因子,具体可例示下述(5)或(6)中任一项所示的多肽。
(5)具有序列号6所示的氨基酸序列的多肽。
(6)在上述(5)所示的氨基酸序列中,具有置换、缺失、***和/或附加1个或多个氨基酸残基而得到的氨基酸序列,且具有鲎B因子的功能的多肽。
作为本发明中的凝固酶原,具体可例示下述(7)或(8)中任一项所示的多肽。
(7)具有序列号8所示的氨基酸序列的多肽。
(8)在上述(7)所示的氨基酸序列中,具有置换、缺失、***和/或附加1个或多个氨基酸残基而得到的氨基酸序列,且具有鲎凝固酶原的功能的多肽。
上述(4)、(6)和(8)中所谓的“多个”是指:即使进行置换、缺失、***和/或附加,多肽也不丧失鲎因子的功能的程度的氨基酸残基的数量(总数)。“多个”例如相对构成于多肽的氨基酸残基的总数,可以优选为10%以下,更优选为5%以下,进一步优选为2%以下,特别优选为1%以下,最优选为0.5%以下的数。
因此,例如在上述(4)所示的多肽的氨基酸序列的情况下,氨基酸残基的总数为1019个,因此,“多个”可以优选为2~100个,更优选为2~50个,进一步优选为2~20个,特别优选为2~10个,最优选为2~5个。在上述(4)、(6)和(8)中,“多个”作为具体的各个数量,可以为2个、3个、4个、5个等整数。
上述(4)、(6)和(8)中所谓的“置换、缺失、***和/或附加”,例如为保守的突变。保守的突变的代表性突变是保守的置换。保守的置换为以下突变,即,在置换部位为芳香族氨基酸的情况下,在Phe、Trp、Tyr间相互置换;在置换部位为疏水性氨基酸的情况下,在Leu、Ile、Val间相互置换;在其为极性氨基酸的情况下,在Gln、Asn间相互置换;在其为碱基性氨基酸的情况下,在Lys、Arg、His间相互置换;在其为酸性氨基酸的情况下,在Asp、Glu间相互置换;在其为具有羟基的氨基酸的情况下,在Ser、Thr间相互置换。作为被看作保守的置换的置换,具体可例示:从Ala向Ser或Thr的置换、从Arg向Gln、His或Lys的置换、从Asn向Glu、Gln、Lys、His或Asp的置换、从Asp向Asn、Glu或Gln的置换、从Cys向Ser或Ala的置换、从Gln向Asn、Glu、Lys、His、Asp或Arg的置换、从Glu向Gly、Asn、Gln、Lys或Asp的置换、从Gly向Pro的置换、从His向Asn、Lys、Gln、Arg或Tyr的置换、从Ile向Leu、Met、Val或Phe的置换、从Leu向Ile、Met、Val或Phe的置换、从Lys向Asn、Glu、Gln、His或Arg的置换、从Met向Ile、Leu、Val或Phe的置换、从Phe向Trp、Tyr、Met、Ile或Leu的置换、从Ser向Thr或Ala的置换、从Thr向Ser或Ala的置换、从Trp向Phe或Tyr的置换、从Tyr向His、Phe或Trp的置换以及从Val向Met、Ile或Leu的置换。
上述(4)、(6)和(8)所示的多肽,例如可以为分别与上述(1)、(2)、(3)、(5)和(7)所示的多肽的氨基酸序列,具有优选85%以上,更优选90%以上,进一步优选95%以上,特别优选99%以上的相似性,且具有鲎因子的功能的多肽。应予说明,此处所谓的“相似性”(similarity)为包含“同源性”(identity)的概念,因此,可以将相似性替换为同源性而应用于该多肽的优选方式。
上述多肽可基于本说明书的记载,通过公知的方法制备。例如,上述多肽可通过基因工程的方法制备。具体而言,可通过将编码上述多肽的DNA人工导入于宿主细胞并使其表达而得到。
作为编码上述多肽的DNA,例如可举出以下DNA。
[1]具有序列号1所示的碱基序列的DNA。
[2]具有序列号3所示的碱基序列的DNA。
[3]具有序列号5所示的碱基序列的DNA。
[4]具有序列号7所示的碱基序列的DNA。
[5]具有序列号9所示的碱基序列的DNA。
[6]具有序列号10所示的碱基序列的DNA。
[7]具有序列号11所示的碱基序列的DNA。
上述多肽,例如可以为作为培养细胞得到的培养液本身而制备的多肽,也可以为作为将培养液精制成期望的程度的组分而制备的多肽。
本发明中,“检测用化合物”为用于测定活化的鲎因子的有无或其量、级联反应的进行的底物。检测用化合物可以为用于测定活性型C因子的底物,也可以为用于测定活性型B因子的底物,还可以为用于测定凝结酶的底物。检测用化合物只要成为活化的鲎因子的底物,就没有特别限定。检测用化合物,例如可以为蛋白质、肽或它们的衍生物。
上述蛋白质可以为天然的蛋白质,也可以为重组的蛋白质。作为上述蛋白质,可例示凝结酶的底物即凝固蛋白原。例如,天然的凝固蛋白原可从溶解物中分取而制备。另外,例如重组的凝固蛋白原可参照文献(宫田等,蛋白质核酸酶增刊No.29;P30-43;1986)记载的方法而制备。
上述肽,例如可以为化学合成的合成底物。合成底物只要是适于测定活化的鲎因子的有无或其量、级联反应的进行的底物,就没有特别限制。合成底物优选为肽的衍生物。
作为合成底物,可例示通式Y-X-Z(式中,Y可以存在也可以不存在,在Y存在的情况下,Y为保护基(即,Y为氢原子或保护基),X为肽,Z为标记物。)表示的底物。上述合成底物被活化的鲎因子切断X-Z间的共价键,且具有标记物Z脱离的性质即可。上述通式中,Y优选为对肽的N末端的氨基的保护基。上述通式中,Y-X间的键合优选为在保护基的羧基和肽的N末端的α氨基之间形成的酰胺键。另外,上述通式中,X-Z间的键合优选为在肽的C末端的羧基和标记物Z的氨基之间形成的酰胺键。
作为Y使用的保护基没有特别限制,可使用能够应用于肽的保护的公知的保护基。作为保护基,可例示叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)、苄基(Bzl)、苯甲酰基(Bz)、乙酰基(Ac)。
肽(X)只要是成为活化的鲎因子的底物的具有氨基酸序列的肽,就没有特别限定。肽优选为适于丝氨酸蛋白酶的测定的底物,优选为C末端具有Arg(R)残基的肽。
在活化的鲎因子为C因子的情况下,肽优选为具有通式X-Pro-Arg(式中,X为任意的氨基酸。)表示的氨基酸序列的肽。具体而言,在活化的鲎因子为C因子的情况下,肽优选为具有Val-Pro-Arg(VPR)或Asp-Pro-Arg(DPR)表示的氨基酸序列的肽。
在活化的鲎因子为B因子的情况下,肽优选为具有通式X-Thr-Arg(式中,X为任意的氨基酸。)表示的氨基酸序列的肽。具体而言,在活化的鲎因子为B因子的情况下,肽优选为具有Leu-Thr-Arg(LTR)或Met-Thr-Arg(MTR)表示的氨基酸序列的肽。
在活化的鲎因子为凝固酶原的情况下,肽优选为具有通式X-Gly-Arg(式中,X为任意的氨基酸。)表示的氨基酸序列的肽。具体而言,在活化的鲎因子为凝固酶原的情况下,肽优选为具有Leu-Gly-Arg(LGR)或Glu-Gly-Arg(EGR)表示的氨基酸序列的肽。
标记物(Z)没有特别限制,可使用能够应用于蛋白酶活性的测定的公知的标记物。作为标记物,例如可使用从肽中脱离时可被光学检测到(作为显色、荧光、发光等)的化合物。作为上述标记物,可例示对硝基苯胺(pNA)、7-甲氧基香豆素-4-乙酸、2,4-二硝基苯胺(DNP)、7-氨基-4-甲基香豆素(AMC)和7-氨基-4-三氟甲基香豆素。另外,作为标记物,例如可使用从肽中脱离时可利用电化学测定法(伏安法、安培法等)检测的化合物。作为上述标记物,可例示对氨基苯酚(pAP)、对甲氧基苯胺(pMA)、N-甲基-对苯二胺(MPDD)、N,N‘-二甲基-对苯二胺(DMPD)。
在上述本发明的测定方法的(A)的工序中,鲎因子、检测对象、检测用化合物以及其它物质(缓冲剂等),可以以任意的顺序添加并混合。例如,在上述(A)的工序中,检测对象可以在鲎因子、检测用化合物、其它物质的混合物中添加并混合。另外,例如在上述(A)的工序中,检测对象可以添加鲎因子、检测用化合物、其它物质的混合物并混合。在上述(A)的工序中,混合例如可以在一端具有开口的容器(试管、管型瓶(vial)等)的内部(容器内)内进行。上述检测对象只要是内毒素的检测需要的试样,就没有特别限定,除注射用水、医药品、输液、血液制剂、医疗器械(医疗用具)、医药部外品、化妆品等以外,可举出食品、水、空气、河川、土壤等环境试样;天然的蛋白质、基因重组蛋白质、核酸、酶、糖质、电解质、以及血液、体液、组织等生物成分等。
上述(B)的工序为测定本发明中使用的多肽的蛋白酶活性的工序。该工序,例如为测定从检测用化合物脱离的标记物的工序。在该工序中,与活性型鲎因子的蛋白酶活性(总活性)对应的量(摩尔数)的标记物从检测用化合物脱离,因此,可通过测定从检测用化合物脱离的标记物而测定本发明中使用的多肽的蛋白酶活性。从检测用化合物脱离的标记物,例如可通过分光光度计、荧光光度计等光学器械来测定。另外,从检测用化合物脱离的标记物,例如可通过伏安计、安培计等电化学测定器械来测定。例如,通过将该工序中所示的测定值与空白值(以无内毒素的检测对象为测定对象时的测定值)进行比较,可判定检测对象中的内毒素的有无。另外,本发明的测定方法,例如可以为通过判定混合液的凝胶化的有无而判定检测对象中的内毒素的有无的工序。
本发明的测定方法,除上述(A)及(B)的工序以外,还可以包含其它工序。本发明的测定方法,例如可以包含通过将上述(B)的工序中得到的测定值与空白值进行比较而判定检测对象中的内毒素的有无的工序。此外,本发明的测定方法,例如可以包含将上述(B)的工序中得到的测定值变换为其它值的工序。作为将测定值变换为其它值的工序,例如可例示基于测定值算出内毒素的量的工序。上述工序,具体而言,例如为基于在将检测对象替换为浓度已知的标准物质而测定时得到的测定值和标准物质的浓度的关系(标准曲线),将测定检测对象时得到的测定值变换为内毒素的量的工序。
在本发明的测定方法中,鲎反应优选在水性溶剂中进行。
<内毒素测定剂>
在本发明的其它方面,提供一种包含源自鲎的C因子的内毒素测定剂。也包含以下内毒素测定剂的方式,即,本发明涉及的内毒素测定剂所包含的源自鲎的C因子为下述(a),还可以包含(b)和/或(c),源自幽门螺旋杆菌的内毒素的相对效价为利用溶解物试剂测定的相对效价的0.1倍以上。
(a)源自鲎的C因子重组蛋白质
(b)源自鲎的B因子重组蛋白质
(c)源自鲎的凝固酶原重组蛋白质
在此,(a)、(b)和(c)的鲎因子的重组蛋白质的方式与上述<内毒素的测定方法>中的方式相同。
作为溶解物试剂,例如可以为上述<内毒素测定剂的灵敏度的增强方法>中已描述的溶解物试剂。
上述内毒素测定剂可优选用于进行本发明的测定方法。
如上述所示,在使用内毒素测定剂测定的源自幽门螺旋杆菌的内毒素的相对效价不是期望的效价的情况下,通过增加内毒素测定时的C因子重组蛋白质的含量,可提高源自幽门螺旋杆菌的内毒素的相对效价。
作为其它方式,可以制成以下内毒素测定剂,即,本发明至少包含上述(a),还可以包含(b)和/或(c),源自幽门螺旋杆菌的内毒素的(通过比色法、荧光法等测定)相对效价为200(EU/μg)以上,优选为250(EU/μg)以上,更优选为300(EU/μg)以上。
在此,(a)、(b)和(c)的鲎因子的重组蛋白质的方式与上述<内毒素的测定方法>中的方式相同。
源自幽门螺旋杆菌的内毒素的相对效价,例如可以为200(EU/μg)以上且3000(EU/μg)以下、250(EU/μg)以上且2500(EU/μg)以下、或300(EU/μg)以上且2000(EU/μg)以下。在一个实施方式中,内毒素测定剂包含成为上述相对活性的量的C因子重组蛋白质。源自幽门螺旋杆菌的内毒素的相对效价,为使用包含定量下限以上的浓度的源自幽门螺旋杆菌的内毒素的测定试样而测定得到的值。
应予说明,本方式可以为,上述源自幽门螺旋杆菌的内毒素的相对效价为利用溶解物试剂测定的相对效价的0.1倍以上的方式的具体例。
上述内毒素测定剂只要包含上述成分作为构成成分,则还可以包含其它构成。作为此处所谓的其它构成,例如可例示记载有检测用化合物、制品信息的添加文件等。在内毒素测定剂的源自幽门螺旋杆菌的内毒素的相对效价不是期望的效价的情况下,添加文件可为表示使内毒素测定时的C因子重组蛋白质的含量增加至使灵敏度增强的充分的量的添加文件。
在一个实施方式中,内毒素测定剂为3因子***,包含上述通式Y-X-Z(式中,Y为氢原子或保护基,X为包含作为凝固酶原的底物的氨基酸序列的肽,Z为从X脱离时可被光学检测到的标记物。)表示的检测用化合物。Z可例示:对硝基苯胺、7-甲氧基香豆素-4-乙酸、7-氨基-4-甲基香豆素和7-氨基-4-三氟甲基香豆素等。在具体的一个实施方式中,Z为从X脱离时作为显色可检测的标记物,优选为对硝基苯胺。
在一个实施方式中,内毒素测定剂为2因子***,包含上述通式Y-X-Z(式中,Y为氢原子或保护基,X为包含作为B因子的底物的氨基酸序列的肽,Z为从X脱离时可被光学检测到的标记物。)表示的检测用化合物。Z可例示:对硝基苯胺、7-甲氧基香豆素-4-乙酸、7-氨基-4-甲基香豆素和7-氨基-4-三氟甲基香豆素等。在具体的一个实施方式中,Z为从X脱离时作为荧光可检测的标记物,优选为7-甲氧基香豆素-4-乙酸、7-氨基-4-甲基香豆素或7-氨基-4-三氟甲基香豆素。
在一个实施方式中,内毒素测定剂为1因子***,包含上述通式Y-X-Z(式中,Y为氢原子或保护基,X为包含作为C因子的底物的氨基酸序列的肽,Z为从X脱离时可被光学检测到的标记物。)表示的检测用化合物。Z可例示:对硝基苯胺、7-甲氧基香豆素-4-乙酸、7-氨基-4-甲基香豆素和7-氨基-4-三氟甲基香豆素等。在具体的一个实施方式中,Z为从X脱离时作为荧光可检测的标记物,优选为7-甲氧基香豆素-4-乙酸、7-氨基-4-甲基香豆素或7-氨基-4-三氟甲基香豆素。应予说明,1因子***的情况下,与2因子***或3因子***相比,即使为少量的C因子重组蛋白质,也可实现源自幽门螺旋杆菌的内毒素的相对效价200EU/μg以上。
上述内毒素测定剂的鲎因子优选作为冻结干燥品提供。
本发明的一个方式涉及一种增强对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度的内毒素测定剂。
本发明的另一方式涉及一种增强对源自幽门螺旋杆菌的内毒素的灵敏度的内毒素测定剂的制造方法,其中,上述内毒素测定剂包含源自鲎的C因子重组蛋白质,上述内毒素测定剂的制造方法包含使上述内毒素测定剂中的上述C因子重组蛋白质的含量增加的工序(以下,有时称为“本发明的制造方法”)。在本发明的一个实施方式中,使内毒素测定剂中的上述C因子重组蛋白质的含量增加至使灵敏度增强的充分的量。
作为内毒素测定剂中的上述C因子重组蛋白质的含量的使灵敏度增强的充分的量的方式,例如可设定成为上述<内毒素测定剂的灵敏度的增强方法>中记载的内毒素测定时的测定试样中的C因子重组蛋白质的含量的方式。具体而言,可根据目标相对效价、测定体系、C因子重组蛋白质的宿主等变更。在测定体系为3因子***的情况下,没有限定,将内毒素测定剂(1次使用量)中的C因子重组蛋白质的含量作为内毒素测定时的测定试样中的浓度,可设定为成为140ng/mL以上、162ng/mL以上、180ng/mL以上、200ng/mL以上、250ng/mL以上、300ng/mL以上、400ng/mL以上、500ng/mL以上、600ng/mL以上或700ng/mL以上的量。在测定体系为2因子***的情况下,没有限定,将内毒素测定剂(1次使用量)中的C因子重组蛋白质的含量作为内毒素测定时的测定试样中的浓度,可设定为成为235ng/mL以上、250ng/mL以上、300ng/mL以上或350ng/mL以上的量。在测定体系为1因子***的情况下,没有限定,将内毒素测定剂(1次使用量)中的C因子重组蛋白质的含量作为内毒素测定时的测定试样中的浓度,可设定为成为10ng/mL以上、20ng/mL以上、30ng/mL以上、40ng/mL以上、50ng/mL以上、60ng/mL以上、70ng/mL以上、100ng/mL以上、500ng/mL以上或800ng/mL以上的量。
内毒素测定时的测定试样中的C因子重组蛋白质的含量的上限没有特别限制,例如为10mg/mL以下,从生产效率的观点出发,优选小于10μg/mL(例如5μg/mL以下、2μg/mL以下)。
本发明的测定剂和通过本发明的制造方法制造的内毒素测定剂可优选用于进行本发明的测定方法。
本发明的测定剂和通过本发明的制造方法制造的内毒素测定剂通,过增加C因子重组蛋白质的含量而增强使用内毒素测定剂测定的源自幽门螺旋杆菌的内毒素的相对效价。
本发明的测定剂和通过本发明的制造方法制造的内毒素测定剂只要包含C因子重组蛋白质作为构成成分,则还可以包含其它构成。作为此处所谓的其它构成,例如可例示记载有B因子、凝固酶原、检测用化合物、制品信息的添加文件等。C因子重组蛋白质和上述其它构成成分的方式,与上述<内毒素测定剂的灵敏度的增强方法>和<内毒素的测定方法>中的C因子重组蛋白质以及其它构成的方式相同。在一个实施方式中,内毒素测定剂实质上不包含表面活性剂。
本发明的制造方法,除增加内毒素测定剂中的C因子重组蛋白质的含量以外,可通过公知的重组试剂的制造方法来制造。即,可将C因子重组蛋白质和上述其它构成成分组合而制造内毒素测定剂。
<内毒素测定用试剂盒>
此外,本发明也可包含内毒素测定用试剂盒的方式,其特征在于,上述内毒素测定用试剂盒包含上述内毒素测定剂作为构成品。
上述试剂盒可优选用于进行本发明的测定方法。
上述试剂盒只要包含上述内毒素测定剂作为构成品,则还可以包含其它构成品。作为此处所谓的其它构成品,例如可例示检测用化合物、缓冲剂、蒸馏水、内毒素标准品、微量培养板、记载有制品信息的添加文件等。
上述试剂盒可以各自个别包含各构成品,也可以包含将各构成品任意组合而成的混合物。上述试剂盒,例如可以个别包含各鲎因子,也可以作为预先混合的方式包含,此外检测用化合物也可以作为预先混合的方式包含。
实施例
以下,通过实施例具体说明本发明,但这些实施例为本发明的例示,本发明的范围并不限定于这些实施例。
<实施例1:对内毒素的灵敏度的试剂间比较>
使用重组试剂和溶解物试剂,比较对来源不同的内毒素的灵敏度的差异。
准备以下内毒素测定剂。应予说明,“重组试剂”为包含通过基因重组技术生产的C因子的制剂,“溶解物试剂”为包含由鲎的血球提取成分制备的天然的C因子的制剂。
(1)包含重组C因子(rFC)、重组B因子(rFB)和重组凝固酶原(rPCE)、检测用化合物(合成底物Boc-LGR-pNA;肽研究所)以及PyroSmart(注册商标)的添加剂的制剂:市售重组试剂A
(2)PyroGene(Lonza公司):市售重组试剂B
(3)EndoZyme(注册商标)II(生物梅里埃公司):市售重组试剂C
(4)Endospecy(注册商标)ES-50M(生物化学工业株式会社):市售溶解物试剂A
(5)Kinetic QCL(Lonza社):市售溶解物试剂B
作为测定的内毒素,使用源自幽门螺旋杆菌(Helicobacter pylori)CA2(LPS研究所)和明尼苏达沙门氏菌(Salmonella minnesota)R595Re(List BiologicalLaboratories公司)这2种的内毒素。另外,作为源自大肠杆菌(Escherichia coli)O113:H10的内毒素标准品(Reference StandardEndotoxin、RSE),使用日本药典(医药品医疗器械监管科学财团)或美国药典内毒素标准品(生物化学工业株式会社)。
源自幽门螺旋杆菌CA2的内毒素利用注射用水(大塚制药工厂)溶解,使其成为1mg/mL。源自明尼苏达沙门氏菌R595Re的内毒素利用0.1(v/v)%三乙基胺(富士胶片和光纯药株式会社)溶解,使其成为1mg/mL,然后利用Tris缓冲液(富士胶片和光纯药株式会社)进行中和。利用注射用水将这些内毒素的原液稀释,使内毒素浓度落入各试剂的添加文件中记载的定量范围,得到内毒素稀释液。
使用市售重组试剂A的测定中,在微量培养板内将注射用水(空白)或内毒素稀释液与制剂混合,制备测定试样。在该分析系中,通过内毒素使C因子(FC)活化而生成活性型FC,通过活性型FC使B因子(FB)活化而生成活性型FB,通过活性型FB使凝固酶原(PCE)活化而生成凝结酶,凝结酶切断合成底物Boc-LGR-pNA,使硝基苯胺脱离。使用吸光酶标仪对测定试样的吸光度(以主波长405nm、副波长492nm,每隔15秒,37℃、30分钟)进行测定,算出每单位时间(1分钟)的吸光度变化率(mAbs/min)。接着,根据利用RSE制成的标准曲线算出各浓度的内毒素稀释液的内毒素活性(EU/mL),这些内毒素稀释液的内毒素活性除以内毒素稀释液的各浓度,算出内毒素的各浓度中的相对效价(EU/μg)。这些相对效价中,将RSE的检量范围所包含的值进行平均,确定内毒素的相对效价(表1)。
关于其它的重组试剂(市售重组试剂B、市售重组试剂C)和溶解物试剂(市售溶解物试剂A、市售溶解物试剂B),基于按照添加文件测定的结果,利用与市售重组试剂A相同的方法确定相对效价(表1)。
其结果,利用市售重组试剂A、B和C得到的源自幽门螺旋杆菌CA2的内毒素的相对效价分别为147.3、3.21和0.07EU/μg。其与利用溶解物试剂得到的相对效价(约2000EU/μg)相比显著小,其差为14倍以上(表1)。即,在市售的重组试剂和溶解物试剂之间,对源自幽门螺旋杆菌CA2的内毒素的灵敏度可观察到大的偏离。另一方面,源自明尼苏达沙门氏菌R595Re的内毒素的相对效价,在市售的重组试剂和溶解物试剂之间没有观察到大的差异(表1)。
应予说明,使用源自大肠杆菌(Escherichia coli)O55:B5和鼠伤寒沙门氏菌(Salmonella typhimulium)的内毒素进行同样的试验,这些内毒素的相对效价,在市售的重组试剂和溶解物试剂之间没有观察到大的差异。
[表1]
表1
<实施例2:rFC含量产生的对源自幽门螺旋杆菌CA2的内毒素的灵敏度的影响>
A.重组蛋白质的制备
按照Mizumura H,Ogura N,Aketagawa J,Aizawa M,Kobayashi Y,Kawabata SI,Oda T.Innate Im mun.2017Feb;23(2):136-146.或“源自鲎属的重组蛋白质及编码其的DNA”(WO2018/074498A1),使源自三刺鲎(Tachypleus tridentatus、T.t.)的rFC、rFB和rPCE如下所示进行表达,得到各种酶液。应予说明,使用序列号1作为编码源自T.t.的FC的DNA,使用序列号5或9作为编码源自T.t.的FB的DNA,使用序列号7作为编码源自T.t.的PCE的DNA。
(1)基于哺乳类细胞(CHO DG44细胞)的rFC的稳定表达
使用源自中国仓鼠卵巢的细胞株(CHO DG44细胞)作为宿主,通过以下的步骤制备rFC酶液。
将编码源自T.t.的FC的DNA(序列号1)***于表达载体(pCI-neo;Promega制造)的EcoRI和XbaI识别部位之间,制作FC表达质粒。使用脂质体转染试剂(Lipofectamine LTX;Life Technologies Corporation),将FC表达质粒和二氢叶酸还原酶(dhfr)表达质粒导入于CHO DG44细胞。将细胞在37℃、5(v/v)%CO2供给下静置培养,利用遗传霉素(Invitrogen)选择在基因组上导入有表达质粒的细胞,在多克隆中取得rFC高表达细胞株。由在包含5μM甲氨蝶呤(MTX)的培养基中驯化得到的多克隆细胞组将rFC高表达细胞株单克隆化。经过在无血清完全合成培养基中的驯化而使细胞株(单克隆)浮游化。在37℃、5(v/v)%CO2供给下从生长至对数增殖后期的浮游培养液,通过离心分离(3000xg、30分钟、4℃)得到培养上清液,制备rFC酶液。
(2)基于昆虫细胞(Sf9细胞)的rFC的稳定表达
将昆虫细胞(Sf9细胞)用作宿主细胞,通过以下步骤制备rFC酶液。
将编码源自T.t.的FC的DNA(序列号1)***于表达载体(pIZ-V5;LifeTechnologies Corporation)的EcoRV和MluI识别部位之间,制作FC表达质粒。使用Cellfectin试剂(Life Technologies Corporation)将FC表达质粒导入于Sf9细胞。将细胞在28℃下静置培养,利用博来霉素(Invitrogen)选择在基因组上导入有表达质粒的细胞。其后,利用克隆柱法(Cloning cylinder)分离稳定表达C因子基因的候选,选拔C因子高表达Sf9细胞株。在包含1×青霉素/链霉素(Life Technologies Corporation)和50μg/mL博来霉素的Sf900III培养基中,浮游培养(28℃)rFC高表达Sf9细胞株至对数增殖期后半(6-8×106cells/mL)。将培养液进行离心分离(3000xg、30分钟、4℃)而得到培养上清液,制备rFC酶液。
(3)基于昆虫细胞(Sf9细胞)的rFB和rPCE的稳定表达
将昆虫细胞(Sf9细胞)用作宿主,通过以下步骤制备rFB和rPCE酶液。
将编码源自T.t.的FB和PCE的DNA(序列号7、9)***于表达载体(pIZ-V5;LifeTechnologies Corporation)的EcoRV和MluI识别部位之间,分别制作FB表达质粒和PCE表达质粒。应予说明,序列号9所示的碱基序列为:序列号5所示的碱基序列最适于昆虫细胞中的表达的碱基序列。通过与FC的情况相同的方法,制备rFB和rPCE酶液。rFB和rPCE酶液中的蛋白浓度通过蛋白质分析试剂盒(Bio-Rad Laboratories)来测定。
(4)基于Expi CHO表达***的rFC的一过性表达
使用Expi CHO表达***(Thermo Fisher Scientific),按照添加的说明书制备rFC酶液。
将编码源自T.t.的FC的DNA(序列号1)***于表达用载体(pCI-neo;Promega)的EcoRI和XbaI识别部位之间,制作FC表达质粒。将与ExpiFectamin CHO混合的FC表达质粒,在Expi CHO表达培养基共存下,导入于Expi CHO-S细胞。使细胞在无血清完全合成培养基中37℃、8(v/v)%CO2供给下进行生长。将浮游培养液进行离心分离(3000xg、30分钟、4℃)而得到培养上清液,制备rFC酶液。
B.rFC浓度的测定
试样中的rFC浓度以Kobayashi Y,Shiga T,Shibata T,Sako M,Maenaka K,Koshiba T,Mizumura H,Oda T,Kawabata S.J Biol Chem.2014Sep12;289(37):25987-95.为参考,通过使用抗FC抗体的ELISA法算出。具体而言,使用抗FC抗体即2C12单克隆抗体(小鼠)作为捕获抗体,使用抗FC多克隆抗体(兔)作为检测抗体,使用辣根过氧化酶(HRP)标识抗兔IgG多克隆抗体(山羊)(Bio-Rad Laboratories)作为二次抗体。使用TMB OneComponent HRP Microwell Substrate(SURMODICS)测定450nm(对照630nm)的吸光度。试样中的rFC浓度,通过利用精制FC预先制成的标准曲线算出。应予说明,在使用市售重组试剂A的试验中,内毒素测定时的rFC浓度小于162ng/mL。
C.源自幽门螺旋杆菌CA2的内毒素的相对效价的测定
使用有溶解物试剂的情况下,源自幽门螺旋杆菌CA2的内毒素的相对效价约为2000EU/μg(表1)。由此,使用重组试剂时的源自幽门螺旋杆菌CA2的内毒素相对效价优选为200EU/μg以上(菊池裕等,医药品医疗器械监管科学Vol.48(2017),No.4,P252-260)。
(1)包含利用CHO DG44细胞制作的rFC的内毒素测定剂(3因子***)
求出包含利用CHO DG44细胞制作的rFC、rFB以及rPCE的3因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
在Tris缓冲液中添加rFC、rFB、rPCE和检测用化合物(合成底物Boc-LGR-pNA;肽研究所),制备内毒素测定剂。各内毒素测定剂的rFC浓度,通过改变rFC酶液的添加量而进行调整。在微量培养板内混合注射用水(空白)或内毒素稀释液以及测定剂,制备测定试样。应予说明,以RSE和源自幽门螺旋杆菌CA2的内毒素的测定试样中的浓度分别成为0.025EU/mL和0.25ng/mL的方式制备。相对效价的测定,根据实施例1(市售重组试剂A)进行。应予说明,rFB和rPCE在测定试样间以成为相同浓度的方式制备。
在空白和RSE的2点间制成标准曲线,由源自幽门螺旋杆菌CA2的内毒素的吸光度变化率求出内毒素活性。使用各内毒素测定剂时的源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg),通过上述得到的内毒素活性(EU/mL)的值除以源自幽门螺旋杆菌CA2的内毒素的浓度而求出。绘制rFC浓度和相对效价而进行分析,其结果,测定试样中的rFC浓度为162ng/mL以上时,源自幽门螺旋杆菌CA2的内毒素的相对效价为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得到增强(表2、图1)。应予说明,即使提高测定试样中的rFC浓度,空白的吸光度变化率也不上升。
[表2]
表2利用CHO DG44细胞制作的rFC(3因子***)
(2)包含利用CHO DG44细胞制作的rFC的内毒素测定剂(2因子***)
求出包含利用CHO DG44细胞制作的rFC和rFB的(不包含rPCE)2因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
在Tris缓冲液中添加rFC、rFB和检测用化合物(合成底物Boc-LTR-MCA(即,Boc肽化AMC);肽研究所),制备内毒素测定剂。各内毒素测定剂的rFC浓度,通过改变rFC酶液的添加量而进行调整。在微量培养板内混合注射用水(空白)或内毒素稀释液以及测定剂,制备测定试样。应予说明,以RSE和源自幽门螺旋杆菌CA2的内毒素的测定试样中的浓度分别成为0.025EU/mL和0.25ng/mL的方式制备。应予说明,rFB在测定试样间以成为相同浓度的方式制备。荧光酶标仪将测定试样的相对荧光强度(RFU0)进行测定(激发波长380nm、荧光波长445nm)。其后,将测定试样在37℃下加热90分钟,再次测定相对荧光强度(RFU90)。从RFU90减去RFU0(背景),算出ΔRFU。从RSE和空白的ΔRFU分别减去空白的ΔRFU,求出修正ΔRFURSE(Blanked ΔRFURSE)和修正ΔRFUblank(BlankedΔRFUblank)。在空白的修正ΔRFUblank(即0)和修正ΔRFURSE的2点间制成标准曲线。接着,从源自幽门螺旋杆菌CA2的内毒素的ΔRFU减去空白的ΔRFU而求出修正ΔRFUHpy,从上述标准曲线求出内毒素活性(EU/mL)。对使用各内毒素测定剂的情况,根据实施例2C.(1)求出源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg)。
其结果,测定试样中的rFC浓度为235ng/mL以上时,源自幽门螺旋杆菌CA2的内毒素的相对效价为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得到增强(表3)。应予说明,即使提高测定试样中的rFC浓度,空白的ΔRFU也几乎不上升。
[表3]
表3利用CHO DG44细胞制作的rFC(2因子***)
(3)包含利用CHO DG44细胞制作的rFC的内毒素测定剂(1因子***)
求出包含利用CHO DG44细胞制作的rFC的(不包含rFB或rPCE)1因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
在Tris缓冲液中添加rFC和检测用化合物(合成底物Boc-VPR-MCA(即,Boc肽化AMC);肽研究所),制备内毒素测定剂。各内毒素测定剂的rFC浓度通过改变rFC酶液的添加量而进行调整。在微量培养板内混合注射用水(空白)或内毒素稀释液以及测定剂,制备测定试样。应予说明,以RSE和源自幽门螺旋杆菌CA2的内毒素的测定试样中的浓度分别成为5EU/mL和25ng/mL的方式制备。根据实施例2C.(2)求出使用各内毒素测定剂时的源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg)。
其结果,测定试样中的rFC浓度为13ng/mL以上时,源自幽门螺旋杆菌CA2的内毒素的相对效价成为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得以增强(表4)。应予说明,即使提高测定试样中的rFC浓度,空白的ΔRFU也几乎不上升。
[表4]
表4利用CHO DG44细胞制作的rFC(1因子***)
(4)包含利用Expi CHO表达***制作的rFC的内毒素测定剂(3因子***)
求出包含利用Expi CHO表达***(一过性表达***)制作的rFC、rFB以及rPCE的3因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
根据实施例2C.(1)求出源自幽门螺旋杆菌CA2的内毒素的相对效价。其结果,测定试样中的rFC浓度为743ng/mL以上时,相对效价为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得到增强(表5)。应予说明,即使提高测定试样中的rFC浓度,空白的吸光度变化率也不上升。
[表5]
表5利用Expi CHO表达***制作的rFC(3因子***)
(5)包含利用Expi CHO表达***制作的rFC的内毒素测定剂(1因子***)
求出包含利用Expi CHO表达***(一过性表达***)制作的rFC的(不包含rFB或rPCE)1因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
根据实施例2C.(3)求出源自幽门螺旋杆菌CA2的内毒素的相对效价。其结果,测定试样中的rFC浓度为77ng/mL以上时,相对效价为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得到增强(表6)。应予说明,即使提高测定试样中的rFC浓度,空白的ΔRFU也几乎不上升。
[表6]
表6利用Expi CHO表达***制作的rFC(1因子***)
(6)包含利用Sf9细胞制作的rFC的内毒素测定剂(3因子***)
求出包含利用Sf9细胞制作的rFC、rFB及rPCE的3因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
根据实施例2C.(1)求出源自幽门螺旋杆菌CA2的内毒素的相对效价。其结果,测定试样中的rFC浓度为394ng/mL以上时,相对效价为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得到增强(表7)。应予说明,即使提高测定试样中的rFC浓度,空白的吸光度变化率也不上升。
[表7]
表7利用Sf9制作的rFC(3因子***)
(7)包含利用Sf9细胞制作的rFC的内毒素测定剂(1因子***)
求出包含利用Sf9细胞制作的rFC的(不包含rFB或rPCE)1因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。
根据实施例2C.(3)求出源自幽门螺旋杆菌CA2的内毒素的相对效价。其中,以RSE和源自幽门螺旋杆菌CA2的内毒素的测定试样中的浓度分别成为0.25EU/mL和0.25ng/mL的方式制备。其结果,测定试样中的rFC浓度为93ng/mL以上时,相对效价为200EU/μg以上。即,判明:通过增加测定试样中的rFC浓度,灵敏度得到增强(表8)。应予说明,即使提高测定试样中的rFC浓度,空白的ΔRFU也几乎不上升。
[表8]
表8利用Sf9制作的rFC(1因子***)
<实施例3:rFC含量产生的对源自幽门螺旋杆菌CA2的内毒素的灵敏度的影响>
A.重组蛋白质的制备
根据实施例2A.(1),将源自中国仓鼠卵巢的细胞株(CHO DG44细胞)作为宿主,使美洲鲎(Limulus Polyphemus、L.p.)源自rFC表达,得到L.p.rFC酶液。应予说明,作为编码源自L.p.的FC的DNA,使用序列号11的DNA。
B.L.p.rFC浓度的测定
根据实施例2B.测定试样中的L.p.rFC浓度。试样中的L.p.rFC浓度通过利用精制的L.p.rFC预先制成的标准曲线算出。
C.源自幽门螺旋杆菌CA2的内毒素的相对效价的测定
(1)包含利用CHO DG44细胞制作的L.p.rFC的内毒素测定剂(1因子***)
求出包含利用CHO DG44细胞制作的L.p.rFC的(不包含rFB或rPCE)1因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。应予说明,RSE和源自幽门螺旋杆菌CA2的内毒素的测定试样中的浓度以分别成为5EU/mL和25ng/mL的方式制备。
源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg),根据实施例2C.(3)求出。将反应液中的L.p.rFC浓度从45.8ng/mL阶段性增加至457.9ng/mL时,源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg)从33EU/μg增加至917EU/μg。绘制rFC浓度和相对效价并进行分析,其结果,测定试样中的L.p.rFC浓度为133ng/mL以上时,源自幽门螺旋杆菌CA2的内毒素的相对效价为200EU/μg以上。即,判明:使用L.p.rFC的一因子***的测定中,通过增加测定试样中的L.p.rFC浓度,灵敏度也得到增强。
<实施例4:rFC含量产生的对源自幽门螺旋杆菌CA2的内毒素的灵敏度的影响>
作为rFC,使用市售重组试剂B(PyroGene、Lonza公司)所包含的rFC酶溶液。
A.rFC酶溶液中的rFC浓度的测定
根据实施例2B.测定试样中的rFC浓度。试样中的rFC浓度通过利用精制的蝎鲎(Carcinoscorpius rotundicauda、C.r.)rFC预先制成的标准曲线算出。
B.源自幽门螺旋杆菌CA2的内毒素的相对效价的测定
(1)包含rFC的内毒素测定剂(1因子***)
使用rFC酶溶液(不包含rFB或rPCE)求出1因子***中的源自幽门螺旋杆菌CA2的内毒素的相对效价。应予说明,以RSE和源自幽门螺旋杆菌CA2的内毒素的测定试样中的浓度分别成为0.025EU/mL和5ng/mL的方式制备。
源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg)根据实施例2C.(3)求出。将反应液中的rFC浓度从203.7ng/mL阶段性增加至1426ng/mL时,源自幽门螺旋杆菌CA2的内毒素的相对效价(EU/μg)从9.09EU/μg增加至440EU/μg。绘制rFC浓度和相对效价并进行分析,其结果,测定试样中的rFC浓度为858ng/mL以上时,源自幽门螺旋杆菌CA2的内毒素的相对效价为200EU/μg以上。即,判明:使用有市售重组试剂时,通过增加测定试样中的rFC浓度,灵敏度也得到增强。
<参考例1:rFB含量产生的对源自幽门螺旋杆菌CA2的内毒素的灵敏度的影响>
制备rFB含量不同的测定试样,根据实施例2C.(1)求出源自幽门螺旋杆菌CA2的内毒素的相对效价。应予说明,测定试样间的rFC和rPCE以成为相同浓度的方式制备。
其结果,如果增加测定试样中的rFB的浓度,则空白和RSE的吸光度变化率上升,但源自幽门螺旋杆菌CA2的内毒素的吸光度变化率几乎没有变化。即,即使增加测定试样中的rFB,对源自幽门螺旋杆菌CA2的内毒素的灵敏度也不增强(图2)。
<参考例2:rPCE含量产生的对源自幽门螺旋杆菌的CA2内毒素的灵敏度的影响>
制备rPCE含量不同的测定试样,根据实施例2C.(1)求出源自幽门螺旋杆菌CA2的内毒素的相对效价。应予说明,测定试样间的rFC和rFB以成为相同浓度的方式制备。
其结果,如果增加测定试样中的rPCE的浓度,则空白、RSE和源自幽门螺旋杆菌CA2的内毒素的吸光度变化率同时上升。即,即使增加测定试样中的rPCE,对源自幽门螺旋杆菌CA2的内毒素的灵敏度也不增强(图3)。
工业上的可利用性
根据本发明,可提供一种在利用重组蛋白质的内毒素测定剂中,使对源自幽门螺旋杆菌的内毒素的灵敏度增强的方法。因此,本发明提供一种降低源自内毒素的差异导致的影响,且使用利用重组蛋白质的内毒素测定剂的内毒素测定方法。
<序列表的说明>
序列号1:三刺鲎的C因子的cDNA的碱基序列
序列号2:三刺鲎的C因子的氨基酸序列
序列号3:蝎鲎的C因子的cDNA的碱基序列
序列号4:蝎鲎的C因子的氨基酸序列
序列号5:三刺鲎的B因子的cDNA的碱基序列
序列号6:三刺鲎的B因子的氨基酸序列
序列号7:三刺鲎的凝固酶原的cDNA的碱基序列
序列号8:三刺鲎的凝固酶原的氨基酸序列
序列号9:使密码子最适于昆虫细胞中的表达的三刺鲎的B因子的cDNA的碱基序列
序列号10:美洲鲎的C因子的cDNA的碱基序列
序列号11:使密码子最适于CHO细胞中的表达的美洲鲎的C因子的cDNA的碱基序列
序列号12:美洲鲎的C因子的氨基酸序列
本申请主张基于2018年10月3在日本国专利厅提出申请的日本特愿2018-188587号的优先权,其内容通过参照作为整体援引入本申请。
SEQUENCE LISTING
<110> 生化学工业株式会社
<120> 内毒素测定剂的灵敏度的增强方法
<130> F201905-9296
<150> JP2018-188587
<151> 2018-10-03
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 3060
<212> DNA
<213> 三刺鲎
<220>
<223> 三刺鲎的C因子
<400> 1
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 gttcatttga 3060
<210> 2
<211> 1019
<212> PRT
<213> 三刺鲎
<220>
<223> 三刺鲎的C因子
<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> 3060
<212> DNA
<213> 蝎鲎
<220>
<223> 蝎鲎的C因子
<400> 3
atggtcttag cgtcgttttt ggtgtctggt ttagttctag ggctactagc ccaaaaaatg 60
cgcccagttc agtccaaagg agtagatcta ggcttgtgtg atgaaacgag gttcgagtgt 120
aagtgtggcg atccaggcta tgtgttcaac attccagtga aacaatgtac atacttttat 180
cgatggaggc cgtattgtaa accatgtgat gacctggagg ctaaggatat ttgtccaaag 240
tacaaacgat gtcaagagtg taaggctggt cttgatagtt gtgttacttg tccacctaac 300
aaatatggta cttggtgtag cggtgaatgt cagtgtaaga atggaggtat ctgtgaccag 360
aggacaggag cttgtgcatg tcgtgacaga tatgaagggg tgcactgtga aattctcaaa 420
ggttgtcctc ttcttccatc ggattctcag gttcaggaag tcagaaatcc accagataat 480
ccccaaacta ttgactacag ctgttcacca gggttcaagc ttaagggtat ggcacgaatt 540
agctgtctcc caaatggaca gtggagtaac tttccaccca aatgtattcg agaatgtgcc 600
atggtttcat ctccagaaca tgggaaagtg aatgctctta gtggtgatat gatagaaggg 660
gctactttac ggttctcatg tgatagtccc tactacttga ttggtcaaga aacattaacc 720
tgtcagggta atggtcagtg gaatggacag ataccacaat gtaagaactt ggtcttctgt 780
cctgacctgg atcctgtaaa ccatgctgaa cacaaggtta aaattggtgt ggaacaaaaa 840
tatggtcagt ttcctcaagg cactgaagtg acctatacgt gttcgggtaa ctacttcttg 900
atgggttttg acaccttaaa atgtaaccct gatgggtctt ggtcaggatc acagccatcc 960
tgtgttaaag tggcagacag agaggtcgac tgtgacagta aagctgtaga cttcttggat 1020
gatgttggtg aacctgtcag gatccactgt cctgctggct gttctttgac agctggtact 1080
gtgtggggta cagccatata ccatgaactt tcctcagtgt gtcgtgcagc catccatgct 1140
ggcaagcttc caaactctgg aggagcggtg catgttgtga acaatggccc ctactcggac 1200
tttctgggta gtgacctgaa tgggataaaa tcggaagagt tgaagtctct tgcccggagt 1260
ttccgattcg attatgtccg ttcctccaca gcaggtaaat caggatgtcc tgatggatgg 1320
tttgaggtag acgagaactg tgtgtacgtt acatcaaaac agagagcctg ggaaagagct 1380
caaggtgtgt gtaccaatat ggctgctcgt cttgctgtgc tggacaaaga tgtaattcca 1440
aattcgttga ctgagactct acgagggaaa gggttaacaa ccacgtggat aggattgcac 1500
agactagatg ctgagaagcc ctttatttgg gagttaatgg atcgtagtaa tgtggttctg 1560
aatgataacc taacattctg ggcctctggc gaacctggaa atgaaactaa ctgtgtatat 1620
atggacatcc aagatcagtt gcagtctgtg tggaaaacca agtcatgttt tcagccctca 1680
agttttgctt gcatgatgga tctgtcagac agaaataaag ccaaatgcga tgatcctgga 1740
tcactggaaa atggacacgc cacacttcat ggacaaagta ttgatgggtt ctatgctggt 1800
tcttctataa ggtacagctg tgaggttctc cactacctca gtggaactga aaccgtaact 1860
tgtacaacaa atggcacatg gagtgctcct aaacctcgat gtatcaaagt catcacctgc 1920
caaaaccccc ctgtaccatc atatggttct gtggaaatca aacccccaag tcggacaaac 1980
tcgataagtc gtgttgggtc acctttcttg aggttgccac ggttacccct cccattagct 2040
agagcagcca aacctcctcc aaaacctaga tcctcacaac cctctactgt ggacttggct 2100
tctaaagtta aactacctga aggtcattac cgggtagggt ctcgagccat ctacacgtgc 2160
gagtcgagat actacgaact acttggatct caaggcagaa gatgtgactc taatggaaac 2220
tggagtggtc ggccagcgag ctgtattcca gtttgtggac ggtcagactc tcctcgttct 2280
ccttttatct ggaatgggaa ttctacagaa ataggtcagt ggccgtggca ggcaggaatc 2340
tctagatggc ttgcagacca caatatgtgg tttctccagt gtggaggatc tctattgaat 2400
gagaaatgga tcgtcactgc tgcccactgt gtcacctact ctgctactgc tgagattatt 2460
gaccccaatc agtttaaaat gtatctgggc aagtactacc gtgatgacag tagagacgat 2520
gactatgtac aagtaagaga ggctcttgag atccacgtga atcctaacta cgaccccggc 2580
aatctcaact ttgacatagc cctaattcaa ctgaaaactc ctgttacttt gacaacacga 2640
gtccaaccaa tctgtctgcc tactgacatc acaacaagag aacacttgaa ggagggaaca 2700
ttagcagtgg tgacaggttg gggtttgaat gaaaacaaca cctattcaga gacgattcaa 2760
caagctgtgc tacctgttgt tgcagccagc acctgtgaag aggggtacaa ggaagcagac 2820
ttaccactga cagtaacaga gaacatgttc tgtgcaggtt acaagaaggg acgttatgat 2880
gcctgcagtg gggacagtgg aggaccttta gtgtttgctg atgattcccg taccgaaagg 2940
cggtgggtct tggaagggat tgtcagctgg ggcagtccca gtggatgtgg caaggcgaac 3000
cagtacgggg gcttcactaa agttaacgtt ttcctgtcat ggattaggca gttcatttga 3060
<210> 4
<211> 1019
<212> PRT
<213> 蝎鲎
<220>
<223> 蝎鲎的C因子
<400> 4
Met Val Leu Ala Ser Phe Leu Val Ser Gly Leu Val Leu Gly Leu Leu
1 5 10 15
Ala Gln Lys Met Arg Pro Val Gln Ser Lys 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 Ile Pro Val 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 Ala Cys Arg
115 120 125
Asp Arg Tyr Glu Gly Val 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
Met Ala Arg Ile Ser Cys Leu Pro Asn Gly Gln Trp Ser Asn Phe Pro
180 185 190
Pro Lys Cys Ile Arg Glu Cys Ala Met Val Ser Ser Pro Glu His Gly
195 200 205
Lys Val Asn Ala Leu Ser Gly Asp 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 Asn Gly Gln Ile Pro Gln Cys Lys Asn
245 250 255
Leu Val Phe Cys Pro Asp Leu Asp Pro Val Asn His Ala Glu His Lys
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 Asp
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 Arg Ser Ser Thr Ala Gly
420 425 430
Lys Ser Gly Cys Pro Asp Gly Trp Phe Glu Val Asp 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 Val Ile Pro
465 470 475 480
Asn 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 Ile 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 Met Asp Ile Gln
530 535 540
Asp Gln Leu Gln Ser 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 Ser 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 Asn Gln Phe Lys Met 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 Thr 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> 5
<211> 1203
<212> DNA
<213> 三刺鲎
<220>
<223> 三刺鲎的B因子
<400> 5
atgacgtgga tatgtgtgat aacgttgttt gctctggctt ctgctacgtt gggtaacaaa 60
gttagtagag tgggggtcct cttccccaag acacggaacg acaatgagtg tacagcaaga 120
gggggattga aaggatcctg caaatccctc atagactgtc ctagtgtctt ggctacgttg 180
aaggacagtt ttcctgtcgt ttgctcttgg aatggtcgat ttcagcctat tgtctgctgt 240
cctgatgcaa tagcaccacc acctgtaacc acaacagctg taactgtaat atctacaaaa 300
gaaccaaagc ttccaagatt acatatatca ggttgtggaa aaagaaaagt caaaatagat 360
attacaactg ttggacgctc tggatcacca atacttcctc cgatatctac tcctcaaaat 420
tcaacaggtg ggagaggaat tattgctgga ggcgtagaag ccaaaattgg cgcgtggcct 480
tggatggcag ctgtttttgt gaaaaacttt ggcattggca gattccactg tgctggtagc 540
ataatcagta acaagtacat tttgtcagct gcccacgcct tccttatcgg aggtcgaaag 600
ttgaccccaa ctcgcttagc tgtccgtgtg ggaggccact acataaagag gggtcaagag 660
tatccagtga aagacgtgat tatccatcct cattatgtag aaaaggagaa ctacaatgat 720
atagccataa tcgagttaaa agaggaactg aactttacgg acttggtcaa tcctatatgt 780
ctccctgatc cagagacagt aacggatcca ttaaaagaca gaattgtgac tgcagcggga 840
tggggcgatc tggatttctc cggtccacgg agccaagttc tacgtgaggt aagcatccca 900
gttgttccag ttgataaatg tgatcaagcc tatgagaaac tcaacacccc ttcactaaaa 960
aatgggataa cgaataactt cctttgcgct ggattggaag aaggagggaa agacgcttgc 1020
caaggcgatt ctggtggacc gttgatgcta gtgaacaaca ctaggtggat agtagtagga 1080
gttgtgtcgt tcgggcacaa gtgtgccgag gaaggatatc ctggtgtgta ctcgcgcgta 1140
gcgagttacc tagactggat cgcgaaagtt acgaactcgt tagatcatgc cgtcactaac 1200
taa 1203
<210> 6
<211> 400
<212> PRT
<213> 三刺鲎
<220>
<223> 三刺鲎的B因子
<400> 6
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> 7
<211> 1128
<212> DNA
<213> 三刺鲎
<220>
<223> 三刺鲎的凝固酶原
<400> 7
atgttggtga ataacgtgtt ttcactactg tgtttcccac tcttgatgtc tgtggttaga 60
tgcagtactc tcagcagaca gcgtagacag tttgttttcc ctgacgagga agaactttgc 120
tcaaaccgat ttactgaaga aggaacatgc aaaaatgtct tggattgtag aatactttta 180
caaaaaaatg attataattt actcaaagaa tcaatatgcg gctttgaagg cataacaccc 240
aaagtttgtt gtccgaaatc aagccatgta atttcaagta cacaggcacc tccagaaacc 300
actacgactg aacgcccacc aaaacagata ccacccaatc ttcctgaagt gtgtggaatt 360
cacaatacta caactaccag gattattgga ggtcgggaag cacctattgg agcctggccg 420
tggatgactg ctgtctacat aaaacaagga ggaatcagaa gtgttcagtg tggtggcgca 480
cttgtcacta acaggcacgt gattacagct tcgcactgtg ttgtaaacag tgcaggaaca 540
gatgtgatgc cagctgatgt attctcggtt cgtctgggtg aacacaattt atacagtacc 600
gatgacgatt cgaatccaat agattttgca gttacgtcgg tgaaacatca cgaacacttt 660
gtactcgcga cgtatttgaa tgacatcgca attctaacgt taaatgacac agttacgttt 720
acagacagaa ttcgacccat ttgtctacct tatcgtaagt tgagatacga tgatctagca 780
atgagaaaac cgtttatcac tggatgggga acaacagcat ttaacggccc atctagtgca 840
gtgttgagag aagtacagtt accaatatgg gaacacgagg cctgtagaca ggcctacgag 900
aaggatttaa atattacaaa cgtgtatatg tgtgctggct ttgcagatgg cgggaaggat 960
gcttgccagg gtgattctgg aggtccaatg atgttgcctg ttaaaaccgg agagttttat 1020
ctcattggaa ttgtgtcttt cggaaagaaa tgcgcattgc ctggatttcc tggggtttac 1080
acaaaagtga cagagttttt agattggatt gcagaacata tggtgtag 1128
<210> 8
<211> 375
<212> PRT
<213> 三刺鲎
<220>
<223> 三刺鲎的凝固酶原
<400> 8
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 Pro 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> 9
<211> 1203
<212> DNA
<213> 三刺鲎
<220>
<223> 三刺鲎的B因子, 密码子最适序列
<400> 9
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> 10
<211> 3063
<212> DNA
<213> 美洲鲎
<220>
<223> 美洲鲎的C因子
<400> 10
atggtactag cgtcgttctt ggtgtctggt ttagttctag ggctattagc ccaacaaatg 60
cacccagttc agtccagagg agtagatctg ggcttgtgtg atgacacgag gtttgagtgt 120
aagtgtggag atccaggata cgtgttcaac gtccccgcga agcaatgtac gtacttctat 180
cgatggaggc cttattgtaa accatgtgac aaactggagg ctaaagatgt gtgtcccaag 240
tacaaacgat gtcaagagtg tagggctggt ctcgacagtt gtgtgagttg tccacctaac 300
aaatatggaa cttggtgtag cggtgagtgt cagtgtaaga atgggggtat ttgtgatcag 360
aggacaggag cttgtacatg tcgtgacaga tatgaaggtg tgcattgtga aatccttcaa 420
ggttgtcctc ttcttcaatc ggatccccag gttcaggaag taaaaaatcc accaaatgat 480
ccacaaacta ttgactacag ctgttcacca ggcttcaagc ttaaaggcgt ggcacgtatc 540
acctgtcttc caaatgggca gtggagtagc tttccaccca aatgtattcg agaatgttcc 600
atggtttcat ctctagaaca tggcaaagta aactctccta gtgccgatct gatagaagga 660
gctactttaa ggttctcatg tgatagtccc tactacttga ttggtcaaga aacattaacc 720
tgccagggca acggtcagtg gagtgggcag ataccacagt gtcagaaatt ggtcttctgc 780
cctgaccttg accctgtaag ccatgctgaa caccaggtta aaattggcct agaacaaaaa 840
tatggtcaat ttcctcaagg cactgaagta acctatacgt gtactggtaa ttacttcttg 900
atgggtttgg acaccttaaa atgtaaccct gatgggtcct ggtcgggaac acagccgtcc 960
tgtgttaaag tggcagacag agaggtcaac tgtgacagta aagctgtgga cttcttggat 1020
gatgttggcg aacctgtcag gatccactgt cctgctggct gttccttaac tgctggtact 1080
gtatggggta cagccatata tcacgaactt tcctcagtat gtcgtgcagc tattcatgct 1140
ggcaaggttc caaactctgg aggtgcagtg catgtagtga acaacggtcc gtactcagac 1200
tttctggcta gtgatctgaa tgggataaaa tcagacgagt tgaagtctct tgctcagagt 1260
ttccgattcg attatgtcag ttcatcaaca gcagggagaa agtcaggatg tcctgatgga 1320
tggttcgaga ttgaggagaa ctgtgtgtac gttacatcga aacagagagc ctgggaaaga 1380
gctcaaggtg tatgtaccaa tatggccgct cgtcttgctg tgttagacaa agatgtaatt 1440
ccaagttcct tgactgagac tctacgaggg aaagggttag caacgacgtg gattggacta 1500
cacagattag atgctgataa tcactttatt tgggagctaa tggatcgcag tagtgttgct 1560
ttgaatgaca gcctaacatt ctgggctcct ggagaacctg ggaatgaaac taactgtgta 1620
tatctggata tccaagatca gctacagcca gtgtggaaaa ccaagtcttg ttttcaaccc 1680
tcaagttttg tttgtatgat ggatttgtca gacaagaaca aagccaaatg caaagaccct 1740
ggacctttgg aaaacggaca cgccaagctt catggtcaaa gtattgatgg attttatgct 1800
gggtcttctg taagatacag ctgcgaggtc ctccactacc tcagtggaac tgagacagta 1860
tcttgtacat caaatggcac gtggagtgcc cctaaacctc gatgtattaa agtcatcacc 1920
tgccaaaccc ctcctgtacc atcctatggt tctgtggaca tcaaaccccc aagtagaaca 1980
aactcaatca gtcgtgttgg gtcgccattc ttgaggttgc cacggttacc cctcccttta 2040
gccagagcag ccggacctcc tccaaaacct agatccgcac caccctctac tgtggacctg 2100
tcttccaagg tcaaactgcc tgaaggtcat taccgggtgg ggtctcaagc catttacacg 2160
tgcgagtcaa gatactacga actgcttgga tctcaaggta gaagatgcga ctctaatgga 2220
aagtggagtg gtcgaccagc aagctgtata ccagtttgtg gacggtcaga ctctccccgt 2280
tctcctttca tcgtcaatgg aaattccacc gaaataggtc agtggccgtg gcaggcagga 2340
atctccagat ggcttgcaga tcataatatg tggtttcttc agtgtggagg agctctactg 2400
aatgagaaat ggatcattac tgcagcccac tgtgtcacct actctgctac tgccgagatc 2460
attgacccaa gtcagtttaa attctacctg ggcaaatact atcgagatga cagtaaggat 2520
gatgactacg tacaagtaag agaggctatc gagatccatg tgaatcctaa ctacgatcct 2580
ggaaatctca actttgacat agccctgatt caactgaaga cttctgttgc tctgaccaca 2640
cgagtgcaac caatatgtct gcctactgat ctcactacaa gagaaaacct gaaagaggga 2700
gcgttagcgg tggtgacagg atggggtttg aatgaaaaca acacatattc agagatgatt 2760
cagcaagccg ttctgcctgt tgttgcagca agcacctgtg aacaaggata tcaggactcg 2820
ggcttgccac tgacagtgac agagaacatg ttctgtgcag gttacaagca ggggcgctat 2880
gatgcctgca gtggagacag tggaggacca ttagtgtttg ctgatgattc ccgcaccgat 2940
aggcggtggg tcctggaagg gatcgtcagc tggggcagcc ccaatggatg tggcaagtct 3000
aaccagtatg ggggcttcac taaagttaac gtttttctat cgtggattcg gcagttcatt 3060
tga 3063
<210> 11
<211> 3063
<212> DNA
<213> 美洲鲎
<220>
<223> 美洲鲎的C因子, 密码子最适序列
<400> 11
atggtgctgg ccagcttcct ggtgtctggg ctggtgctgg ggcttctggc ccagcagatg 60
caccctgttc aatccagagg ggttgacctt ggcctgtgcg atgatacccg ctttgaatgt 120
aagtgcgggg atcccgggta cgtctttaac gtgcccgcta agcaatgcac atacttctac 180
cggtggcggc catattgcaa accttgcgac aagcttgagg caaaagacgt atgtcccaag 240
tataaacgat gtcaggagtg tcgggctggc ctggatagct gtgtgtcctg cccacctaac 300
aagtacggaa cctggtgttc aggcgagtgc cagtgcaaga acggtggaat ttgtgatcag 360
cgtacaggtg cctgtacatg tcgtgacaga tacgaaggag tgcactgcga gattctgcag 420
ggctgcccct tgctccagtc tgacccacag gtgcaggaag tcaagaatcc tcccaacgat 480
cctcagacga ttgactattc ctgctcaccc ggttttaagc tcaagggcgt ggcccgaatt 540
acttgtctcc ccaatggtca gtggtccagc tttcctccca agtgcattag agaatgtagc 600
atggtgtcca gtttggagca tggtaaggtc aacagtcctt cagctgacct cattgagggc 660
gcaacactcc ggttttcctg tgactctccc tattacttga ttggacagga aaccttgact 720
tgtcagggta atggccaatg gagtggtcag atcccacagt gccagaaact ggtcttttgc 780
cccgacctgg atcccgtcag ccatgccgaa caccaagtga aaatcgggct cgagcaaaag 840
tatgggcagt ttccacaggg caccgaggtg acctacacgt gtactggcaa ttactttctg 900
atgggactgg ataccctcaa atgcaatccc gacggaagtt ggagtggtac acagccatct 960
tgtgttaaag tcgcagatag ggaagtaaat tgcgattcca aggcagtaga ctttctggat 1020
gacgttgggg aacctgttcg catccattgt ccagctggtt gttccttgac tgctggtacc 1080
gtgtggggca cagctatcta tcacgagttg tcctcagtct gtagagctgc catacacgct 1140
ggcaaggtcc ctaactctgg aggcgccgtc catgtcgtga ataacggtcc atactctgac 1200
tttctggcct ccgaccttaa cggaatcaag tcagacgagc ttaaatcctt ggcacagtct 1260
ttccgcttcg actatgtgag ctcttctacc gcaggacgta agagcggctg tcccgacggc 1320
tggttcgaga tcgaagagaa ctgcgtgtac gtgacttcta agcagagggc ttgggagcga 1380
gcacagggag tatgcacaaa catggccgcc aggctcgctg tgctggataa ggacgtcatc 1440
cccagtagcc tgacagaaac actgagaggc aaagggctcg ccacaacttg gattggactg 1500
catcgcttgg acgcagataa ccactttatc tgggagctta tggatcgcag ctccgtggct 1560
ttgaacgatt ctttgacctt ttgggcaccc ggggagccag gcaatgagac taattgcgtc 1620
tacctggaca tacaggatca gctgcaaccc gtgtggaaaa cgaaatcttg cttccaaccc 1680
tcctcctttg tgtgcatgat ggatctgagc gacaagaaca aagccaagtg caaagatccc 1740
ggacctctgg agaatgggca tgcaaagctc catggacagt caattgatgg gttctatgcc 1800
ggcagttccg tccgttactc ctgcgaagtg ctccactacc tgagtgggac cgaaactgtg 1860
tcatgcacat ccaatggcac ctggagtgct cccaaaccta gatgtattaa ggtcatcact 1920
tgccaaactc cacccgtgcc cagctacgga tctgttgaca tcaagcctcc tagtaggaca 1980
aacagcataa gccgagtggg atcacccttc ctcagactgc ccagacttcc tctgcctctg 2040
gcccgcgctg ccggacctcc accaaagcca cgtagtgcac ctccctctac cgttgacctg 2100
tcctcaaaag tgaagctgcc agaaggccat taccgcgtcg ggtcacaagc catctatacg 2160
tgtgaaagtc gctactatga gctgctgggc agccaaggca ggcggtgtga ctccaatgga 2220
aagtggagcg gacgaccagc ctcatgcatt ccagtctgtg gcaggagcga ttccccacgg 2280
agtccattca tcgtcaatgg caattctaca gagattggtc agtggccttg gcaggctggt 2340
atctctcggt ggttggccga ccacaacatg tggtttctcc agtgtggcgg cgctctcctg 2400
aacgagaaat ggattatcac agcagctcac tgcgtaacct atagcgcaac cgccgagata 2460
atcgatccat cacagttcaa gttttacctg ggaaagtact acagggacga tagtaaagat 2520
gacgactacg tgcaagtgag agaggccatc gagatccacg ttaaccccaa ctatgatcct 2580
gggaatctga atttcgatat tgccctgatc cagcttaaaa ccagcgttgc tctgactaca 2640
cgagtgcagc ccatatgtct cccaactgac ctgaccacca gggagaacct gaaggaaggg 2700
gcccttgctg ttgttaccgg ttggggtctg aatgagaata acacttactc tgaaatgatc 2760
caacaggcag tgctgcctgt ggtagctgcc tctacgtgcg aacagggata tcaggactca 2820
ggacttcctc tgacagtaac cgaaaacatg ttctgcgccg ggtataaaca gggccgctat 2880
gacgcctgtt ccggggattc cggcgggcct ctggttttcg ccgatgacag ccggactgat 2940
cggcgatggg tgcttgaggg tatcgtatcc tggggctctc ccaacggatg cggtaagagc 3000
aatcagtatg gtggcttcac caaagtgaac gttttcctgt cctggataag gcagttcatc 3060
tga 3063
<210> 12
<211> 1020
<212> PRT
<213> 美洲鲎
<220>
<223> 美洲鲎的C因子
<400> 12
Met Val Leu Ala Ser Phe Leu Val Ser Gly Leu Val Leu Gly Leu Leu
1 5 10 15
Ala Gln Gln Met His Pro Val Gln Ser Arg Gly Val Asp Leu Gly Leu
20 25 30
Cys Asp Asp Thr Arg Phe Glu Cys Lys Cys Gly Asp Pro Gly Tyr Val
35 40 45
Phe Asn Val Pro Ala Lys Gln Cys Thr Tyr Phe Tyr Arg Trp Arg Pro
50 55 60
Tyr Cys Lys Pro Cys Asp Lys Leu Glu Ala Lys Asp Val Cys Pro Lys
65 70 75 80
Tyr Lys Arg Cys Gln Glu Cys Arg Ala Gly Leu Asp Ser Cys Val Ser
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 Val His Cys Glu Ile Leu Gln Gly Cys Pro Leu
130 135 140
Leu Gln Ser Asp Pro Gln Val Gln Glu Val Lys Asn Pro Pro Asn Asp
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 Thr Cys Leu Pro Asn Gly Gln Trp Ser Ser Phe Pro
180 185 190
Pro Lys Cys Ile Arg Glu Cys Ser Met Val Ser Ser Leu Glu His Gly
195 200 205
Lys Val Asn Ser Pro Ser Ala Asp Leu 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 Gln Lys
245 250 255
Leu Val Phe Cys Pro Asp Leu Asp Pro Val Ser His Ala Glu His Gln
260 265 270
Val Lys Ile Gly Leu Glu Gln Lys Tyr Gly Gln Phe Pro Gln Gly Thr
275 280 285
Glu Val Thr Tyr Thr Cys Thr Gly Asn Tyr Phe Leu Met Gly Leu Asp
290 295 300
Thr Leu Lys Cys Asn Pro Asp Gly Ser Trp Ser Gly Thr Gln Pro Ser
305 310 315 320
Cys Val Lys Val Ala Asp Arg Glu Val Asn 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 Val 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 Ala Ser Asp Leu Asn Gly Ile Lys Ser Asp Glu Leu Lys Ser
405 410 415
Leu Ala Gln Ser Phe Arg Phe Asp Tyr Val Ser Ser Ser Thr Ala Gly
420 425 430
Arg Lys Ser Gly Cys Pro Asp Gly Trp Phe Glu Ile Glu Glu Asn Cys
435 440 445
Val Tyr Val Thr Ser Lys Gln Arg Ala Trp Glu Arg Ala Gln Gly Val
450 455 460
Cys Thr Asn Met Ala Ala Arg Leu Ala Val Leu Asp Lys Asp Val Ile
465 470 475 480
Pro Ser Ser Leu Thr Glu Thr Leu Arg Gly Lys Gly Leu Ala Thr Thr
485 490 495
Trp Ile Gly Leu His Arg Leu Asp Ala Asp Asn His Phe Ile Trp Glu
500 505 510
Leu Met Asp Arg Ser Ser Val Ala Leu Asn Asp Ser Leu Thr Phe Trp
515 520 525
Ala Pro Gly Glu Pro Gly Asn Glu Thr Asn Cys Val Tyr Leu Asp Ile
530 535 540
Gln Asp Gln Leu Gln Pro Val Trp Lys Thr Lys Ser Cys Phe Gln Pro
545 550 555 560
Ser Ser Phe Val Cys Met Met Asp Leu Ser Asp Lys Asn Lys Ala Lys
565 570 575
Cys Lys Asp Pro Gly Pro Leu Glu Asn Gly His Ala Lys Leu His Gly
580 585 590
Gln Ser Ile Asp Gly Phe Tyr Ala Gly Ser Ser Val Arg Tyr Ser Cys
595 600 605
Glu Val Leu His Tyr Leu Ser Gly Thr Glu Thr Val Ser Cys Thr Ser
610 615 620
Asn Gly Thr Trp Ser Ala Pro Lys Pro Arg Cys Ile Lys Val Ile Thr
625 630 635 640
Cys Gln Thr Pro Pro Val Pro Ser Tyr Gly Ser Val Asp Ile Lys Pro
645 650 655
Pro Ser Arg Thr Asn Ser Ile Ser Arg Val Gly Ser Pro Phe Leu Arg
660 665 670
Leu Pro Arg Leu Pro Leu Pro Leu Ala Arg Ala Ala Gly Pro Pro Pro
675 680 685
Lys Pro Arg Ser Ala Pro Pro Ser Thr Val Asp Leu Ser Ser Lys Val
690 695 700
Lys Leu Pro Glu Gly His Tyr Arg Val Gly Ser Gln Ala Ile Tyr Thr
705 710 715 720
Cys Glu Ser Arg Tyr Tyr Glu Leu Leu Gly Ser Gln Gly Arg Arg Cys
725 730 735
Asp Ser Asn Gly Lys Trp Ser Gly Arg Pro Ala Ser Cys Ile Pro Val
740 745 750
Cys Gly Arg Ser Asp Ser Pro Arg Ser Pro Phe Ile Val Asn Gly Asn
755 760 765
Ser Thr Glu Ile Gly Gln Trp Pro Trp Gln Ala Gly Ile Ser Arg Trp
770 775 780
Leu Ala Asp His Asn Met Trp Phe Leu Gln Cys Gly Gly Ala Leu Leu
785 790 795 800
Asn Glu Lys Trp Ile Ile Thr Ala Ala His Cys Val Thr Tyr Ser Ala
805 810 815
Thr Ala Glu Ile Ile Asp Pro Ser Gln Phe Lys Phe Tyr Leu Gly Lys
820 825 830
Tyr Tyr Arg Asp Asp Ser Lys Asp Asp Asp Tyr Val Gln Val Arg Glu
835 840 845
Ala Ile Glu Ile His Val Asn Pro Asn Tyr Asp Pro Gly Asn Leu Asn
850 855 860
Phe Asp Ile Ala Leu Ile Gln Leu Lys Thr Ser Val Ala Leu Thr Thr
865 870 875 880
Arg Val Gln Pro Ile Cys Leu Pro Thr Asp Leu Thr Thr Arg Glu Asn
885 890 895
Leu Lys Glu Gly Ala Leu Ala Val Val Thr Gly Trp Gly Leu Asn Glu
900 905 910
Asn Asn Thr Tyr Ser Glu Met Ile Gln Gln Ala Val Leu Pro Val Val
915 920 925
Ala Ala Ser Thr Cys Glu Gln Gly Tyr Gln Asp Ser Gly Leu Pro Leu
930 935 940
Thr Val Thr Glu Asn Met Phe Cys Ala Gly Tyr Lys Gln Gly Arg Tyr
945 950 955 960
Asp Ala Cys Ser Gly Asp Ser Gly Gly Pro Leu Val Phe Ala Asp Asp
965 970 975
Ser Arg Thr Asp Arg Arg Trp Val Leu Glu Gly Ile Val Ser Trp Gly
980 985 990
Ser Pro Asn Gly Cys Gly Lys Ser Asn Gln Tyr Gly Gly Phe Thr Lys
995 1000 1005
Val Asn Val Phe Leu Ser Trp Ile Arg Gln Phe Ile
1010 1015 1020
Claims (13)
1.一种增强内毒素测定剂对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度的方法,其特征在于,
所述内毒素测定剂包含源自鲎的C因子重组蛋白质,
所述方法包含增加内毒素测定时的所述C因子重组蛋白质的含量的工序。
2.根据权利要求1所述的方法,其中,
所述内毒素测定剂包含源自鲎的B因子重组蛋白质。
3.根据权利要求1或2所述的方法,其中,
所述内毒素测定剂包含源自鲎的凝固酶原重组蛋白质。
4.根据权利要求1~3中任一项所述的方法,其中,
所述内毒素测定剂包含检测用化合物。
5.一种内毒素测定方法,其特征在于,增强内毒素测定剂对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度,
所述内毒素测定方法包含:制备内毒素测定试样的工序,其中,所述内毒素测定试样包含所述内毒素测定剂和检测对象,
所述内毒素测定剂包含源自鲎的C因子重组蛋白质,
所述灵敏度通过增加所述内毒素测定试样中的所述C因子重组蛋白质的浓度而得到增强。
6.根据权利要求5所述的方法,其中,
所述内毒素测定剂包含源自鲎的B因子重组蛋白质。
7.根据权利要求5或6所述的方法,其中,
所述内毒素测定剂包含源自鲎的凝固酶原重组蛋白质。
8.根据权利要求5~7中任一项所述的方法,其中,
所述内毒素测定剂包含检测用化合物。
9.一种内毒素测定剂的制造方法,其特征在于,所述内毒素测定剂增强了对源自幽门螺旋杆菌(Helicobacter pylori)的内毒素的灵敏度,
所述内毒素测定剂包含源自鲎的C因子重组蛋白质,
所述制造方法包含:增加所述内毒素测定剂中的所述C因子重组蛋白质的含量的工序。
10.一种内毒素测定剂,其特征在于,包含源自鲎的C因子,
所述源自鲎的C因子为重组蛋白质,
源自幽门螺旋杆菌的内毒素的相对效价为200EU/μg以上。
11.根据权利要求10所述的内毒素测定剂,其中,
所述内毒素测定剂包含源自鲎的B因子重组蛋白质、源自鲎的凝固酶原重组蛋白质以及通式Y-X-Z表示的检测用化合物,
其中,上述通式中,Y为氢原子或保护基,X为包含作为所述凝固酶原重组蛋白质的底物的氨基酸序列的肽,Z为从X脱离时能够被光学检测到的标记物。
12.根据权利要求10所述的内毒素测定剂,其中,
所述内毒素测定剂包含源自鲎的B因子重组蛋白质以及通式Y-X-Z表示的检测用化合物,
其中,上述通式中,Y为氢原子或保护基,X为包含作为所述B因子重组蛋白质的底物的氨基酸序列的肽,Z为从X脱离时能够被光学检测到的标记物。
13.根据权利要求10所述的内毒素测定剂,其中,
所述内毒素测定剂包含通式Y-X-Z表示的检测用化合物,
其中,上述通式中,Y为氢原子或保护基,X为包含作为所述C因子的底物的氨基酸序列的肽,Z为从X脱离时能够被光学检测到的标记物。
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CN105866080A (zh) * | 2016-04-05 | 2016-08-17 | 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 |
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KR101616599B1 (ko) * | 2009-07-31 | 2016-04-28 | 내셔날 리서치 카운실 오브 캐나다 | 헬리코박터 파일로리균의 지질 폴리사카라이드 외측 코어 에피토프 |
JP2014510898A (ja) | 2011-02-28 | 2014-05-01 | 生化学工業株式会社 | エンドトキシン測定剤 |
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