CN110174363A - 6-磷酸葡萄糖脱氢酶突变体及其在制备检测试剂中的用途 - Google Patents
6-磷酸葡萄糖脱氢酶突变体及其在制备检测试剂中的用途 Download PDFInfo
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- CN110174363A CN110174363A CN201910423122.4A CN201910423122A CN110174363A CN 110174363 A CN110174363 A CN 110174363A CN 201910423122 A CN201910423122 A CN 201910423122A CN 110174363 A CN110174363 A CN 110174363A
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Abstract
本申请涉及6‑磷酸葡萄糖脱氢酶突变体及其在制备检测试剂中的用途。具体而言，本申请的6‑磷酸葡萄糖脱氢酶突变体相较于野生型6‑磷酸葡萄糖脱氢酶包含选自以下的一个突变或其组合：D306C、D375C、G426C。使用本申请的6‑磷酸葡萄糖脱氢酶突变体所制备的检测试剂盒，其特异性强、灵敏度高、操作方便、检测时间短、定量准确，适合高通量检测。
Description
技术领域
本申请涉及生物检测领域，特别是涉及一种多位点突变的酶6-磷酸葡萄糖脱氢酶(简称G6PDH)及其在检测试剂盒中的应用。
背景技术
半抗原，某些小分子物质(分子量小于4000Da)，其单独不能诱导免疫应答，即不具备免疫原性，但当其与大分子蛋白质或非抗原性的多聚赖氨酸等载体交联或结合后可获得免疫原性，诱导免疫应答。这些小分子物质可与应答效应产物结合，具备抗原性，它只有免疫反应性，不具免疫原性，又称不完全抗原。
半抗原能与对应抗体结合出现抗原-抗体反应，又不能单独激发人或动物体产生抗体的抗原。它只有免疫反应性，不具免疫原性，又称不完全抗原。大多数多糖、类脂、激素、小分子药物都属于半抗原。如果用化学方法把半抗原与某种蛋白分子(载体)结合，会获得新的免疫原性，并能刺激动物产生相应的抗体。半抗原一旦与蛋白结合，就构成该蛋白质的一个抗原簇。一些比一般半抗原分子量小，但有特异结构的化学活性基团物质(如青霉素、磺胺剂等)，称为简单半抗原。
小分子抗原或半抗原因缺乏可作夹心法的两个以上的位点，因此不能用双抗体夹心法进行测定，多采用竞争模式。原理是标本中的抗原和一定量的酶标抗原竞争与固相抗体结合。标本中抗原量含量愈多，结合在固相上的酶标抗原愈少，显色愈浅。小分子激素、药物等ELISA测定多用此法。
甘胆酸(Cholyglycin，CG)，作为半抗原的具体实例，其是胆酸与甘氨酸结合而形成的结合型胆酸，是胆汁酸的主要成分之一。胆固醇在肝细胞内经过一系列复杂的酶催化反应，形成初级胆汁酸，包含胆酸(CA)和鹅去氧胆酸(CDCA)，胆酸的类固醇核上有三个羟基(C3、C7、C12)，侧链末端的羟基以肽键与甘氨酸结合成为甘胆酸(图1)。
甘胆酸由肝细胞合成，经毛细胆管、胆管排入胆囊，随同胆汁进入十二指肠，帮助食物中脂肪的消化吸收。95％胆汁酸在回肠和结肠被重吸收，经门静脉再回肝脏，由肝细胞摄取再利用，重吸收的甘胆酸又进入肝-肠循环，通过这种机制，机体能充分利用甘胆酸。
正常情况下，外周血液中胆酸的含量及其甚微，正常人无论是在空腹还是在餐后，外周血液中的甘胆酸含量均处于非常低的水平。当人体肝细胞受损或者胆汁淤积时，就会引起甘胆酸代谢和循环紊乱，使肝细胞摄取甘胆酸的能力下降，导致血液中甘胆酸含量升高，且甘胆酸值高低与肝细胞损害及胆汁酸代谢障碍的严重程度相关。
测定血清中甘胆酸的含量是评价肝细胞功能及肝胆系物质循环功能的敏感指标之一。与ALT、AST、总胆红素(TBIL)、碱性磷酸酶(ALP)、谷酰转肽酶(GGT)、血清白蛋白(ALB)等常规肝功能检测相比，甘胆酸的测定更加敏感。因此，在慢性肝炎、急性肝炎、肝硬化、肝癌、梗阻性肝病、肝肠循环障碍、胆管、胆囊排泄功能障碍等肝功检测中，甘胆酸可以作为更好的检测指标。
目前已知的甘胆酸检测方法主要有：放射免疫分析法、酶联免疫法、化学发光免疫分析法、高效液相色谱法、气液色谱法、气相色谱法和质谱联用等。但这些检测方法均存在较多的缺陷，如放射免疫分析法同位素具有放射性污染、有效期较短、操作不方便等诸多弊端，酶联免疫吸附法操作较为繁琐、耗时较长，不适宜在临床上使用。化学发光尽管灵敏度较好，但需要配套的专用设备，投入使用成本较高不利于推广。在临床检测诊断过程中，以均相酶免疫法(EMIT)和胶乳增强免疫比浊法检测为主。
均相酶免疫测定的原理：在液体均相反应体系中，酶标记抗原(如G6PDH-CG)与非标记抗原(CG)，竞争与定量的抗体(CG抗体)进行结合，当抗体与非标记抗原结合越多，酶标记抗原释放的活性就越多，酶催化底物NAD+生成NADH就越多，在340nm波长下检测NADH的吸光度变化，即可推算出液体中CG的含量。
发明内容
本申请要求201910017764.4的优先权(优先权日2019年1月9日)。
鉴于本领域的需求，本申请提供了一种新型的6-磷酸葡萄糖脱氢酶突变体、及其在制备甘胆酸检测试剂盒中的用途。
根据一些实施方案，提供了一种6-磷酸葡萄糖脱氢酶突变体。区别于已有发表的专利United States Patent 20000507 6033890(Homogeneous immunoassays usingmutant glucose-6-phosphate dehydrogenases Edward Benjamin Jakobovits等)的6磷酸葡萄糖脱氢酶的突变体，本申请的6-磷酸葡萄糖脱氢酶突变体，其包含选自以下的突变：D306C、G426C、D375C。
根据一些实施方案，提供了一种6-磷酸葡萄糖脱氢酶突变体，所述6-磷酸葡萄糖脱氢酶突变体是选自以下的序列所示：SEQ ID No.2、SEQ ID No.3、SEQ ID No.4。
根据一些实施方案，提供了一种多核苷酸，其编码本申请的6-磷酸葡萄糖脱氢酶突变体。
根据一些实施方案，提供了一种表达载体，其包含本申请的多核苷酸。
根据一些实施方案，提供了一种宿主细胞，其包含本申请的表达载体。宿主细胞可以是原核(如细菌)或真核(如酵母)。
根据一些实施方案，提供了一种偶联物，其是本申请的6-磷酸葡萄糖脱氢酶突变体与半抗原按照摩尔比1：n偶联而成。
在一些实施方案中，n是1至50，例如，1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50。
在一些具体的实施方案中，本申请的6-磷酸葡萄糖脱氢酶突变体与半抗原按照摩尔比优选为1：30。
在一些具体的实施方案中，半抗原的分子量为200Da至4000Da，例如：200、250、300、350、400、410、420、430、440、450、460、470、480、490、500、520、550、570、600、620、650、700、750、800、850、900、950、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2100、2200、2300、2400、2500、2600、2700、2800、2900、3000、3100、3200、3300、3400、3500、3600、3700、3800、3900、4000。
根据本申请，技术人员将理解，“半抗原”还包含其衍生物的形式。为了便于和6-磷酸葡萄糖脱氢酶进行偶联，对于那些自身不带有偶联基团(例如，与巯基反应的基团)的半抗原(例如CG)，可以经改造而带有接头，以便和巯基共价结合。因此，在本申请中，半抗原衍生物是指，经改造而带有巯基反应基团的半抗原。
半抗原选自：小分子药物(如抗生素、精神药物)、激素、代谢物、糖、脂质、氨基酸。
半抗原例如但不限于：维生素D、25羟维生素D、1，25双羟维生素D、叶酸、强心甙、酶酚酸、雷帕明、环胞菌素A、乙胺碘复酮、甲胺喋呤、他克莫司、血清氨基酸、胆汁酸、甘胆酸、苯丙氨酸、乙醇、尿尼柯丁代谢产物柯替宁、尿吗啡、尿单羟酚衍生物、神经肽酪氨酸、血浆甘丙素、多胺、组织胺、促甲状腺激素、泌乳素、胎盘泌乳素、生长激素、促卵泡刺激素、促黄体生成素、促肾上腺皮质激素、抗利尿激素、降钙素、降钙素原、甲状旁腺激素、甲状腺素、三碘甲状原氨酸、反三碘甲状原氨酸、游离甲状腺素、游离三碘甲状原氨酸、皮质醇、尿17-羟皮质类固醇、尿17-酮类固醇、脱氢表雄酮及硫酸酯、醛固酮、尿香草苦杏仁酸、血浆肾素、血管紧张素、促红细胞生成素、睾酮、双氢睾酮、雄烯二酮、17α羟孕酮、雌酮、雌三醇、雌二醇、孕酮、人绒毛膜促性腺激素、胰岛素、胰岛素原、C肽、胃泌素、血浆前列腺素、血浆6-酮前列腺素F1α、前列环素、肾上腺素、儿茶酚胺、去甲肾上腺素、胆囊收缩素、纳素、环磷酸腺苷、环磷酸鸟苷、血管活性肽、生长抑素、促胰液素、P-物质、神经降压素、血栓素A2、血栓素B2、5羟色胺、神经肽Y、骨钙素。
在具体的实施方案中，半抗原是甘胆酸或其衍生物。虽然以甘胆酸作为一个具体的实例，但是技术人员可以理解，本申请的技术效果不依赖于半抗原的特定类型，其适用于任何可以借助竞争法进行免疫学检测的半抗原。
在具体的实施方案中，半抗原是甘胆酸衍生物，其带有巯基反应基团，例如来酰亚胺、溴乙酰基、乙烯基砜或氮丙啶。在具体的实施方案中，半抗原是甘胆酸衍生物，如式I所示：
根据一些实施方案，提供了一种试剂，其包含本申请的偶联物。
根据一些实施方案，提供了本申请的6-磷酸葡萄糖脱氢酶突变体在制备检测试剂中的用途。
根据一些实施方案，提供了本申请的偶联物在制备检测试剂中的用途。
在具体的实施方案中，所述的检测试剂选自：酶联免疫法检测试剂、化学发光免疫法检测试剂、均相酶免疫法检测试剂、胶乳增强免疫比浊法检测试剂。
在具体的实施方案中，所述的检测试剂优选是基于竞争法检测的试剂。
根据一些实施方案，提供了一种甘胆酸检测试剂盒，其包含：
-第一试剂，所述第一试剂包含底物和甘胆酸抗体；所述底物是6-磷酸葡萄糖脱氢酶的底物；
-第二试剂，所述第二试剂包含本申请的偶联物；
-任选地，校准品，所述校准品包含10mM至500mM缓冲液、0mg/L至40mg/L甘胆酸；以及
-任选地，质控品，所述质控品包含10mM至500mM缓冲液、0mg/L至40mg/L甘胆酸。
根据一个的实施方案，提供了一种甘胆酸检测试剂盒，其包含：
第一试剂，其包含：
10mM至500mM缓冲液、
0.5g/L至5g/L底物、
0.1mg/L至1mg/L的甘胆酸抗体、
10mM至300mM NaCl、
0.1g/L至5g/L稳定剂、
0.1g/L至5g/L表面活性剂、
0.1g/L至5g/L防腐剂；
第二试剂，其包含：
10mM至500mM缓冲液、
权利要求5中所述的偶联物、
0.1g/L至5g/L稳定剂、
0.1g/L至5g/L表面活性剂、
0.1g/L至5g/L防腐剂。
在一些实施方案中，所述缓冲液选自以下的一种或组合：氨基丁三醇缓冲液、磷酸盐缓冲液、Tris-HCl缓冲液、柠檬酸-柠檬酸钠缓冲液、巴比妥缓冲液、甘氨酸缓冲液、硼酸盐缓冲液、三羟甲基甲烷缓冲液；优选，磷酸盐缓冲液；所述缓冲液的浓度为10mmol/L至500mmol/L，优选100mM；所述缓冲液的pH为6.5至7.5，优选7.2或者7.0。
在一些实施方案中，所述稳定剂选自以下的一种或组合：牛血清白蛋白、海藻糖、甘油、蔗糖、甘露醇、甘氨酸、精氨酸、聚乙二醇6000、聚乙二醇8000；优选牛血清白蛋白。
在一些实施方案中，所述表面活性剂选自以下的一种或组合：Brij35、Tritiom X-100、Tritiom X-405、Tween20、Tween30、Tween80、椰子油脂肪酸二乙醇酰胺、AEO7，优选Tween20。
在一些实施方案中，所述的防腐剂选自以下的一种或组合：叠氮化物、MIT、PC-300、硫柳汞；所述叠氮化物选自：叠氮钠、叠氮锂。
在一些实施方案中，所述底物包含：6-磷酸葡糖糖、β-烟酰胺腺嘌呤二核苷酸。
在一些实施方案中，缓冲液的浓度是100mM。
在一些实施方案中，G6PDH酶催化反应的底物浓度为5g/L。
在一些实施方案中，甘胆酸抗体的浓度为0.1mg/L。
在一些实施方案中，NaCl的浓度为300mM。
在一些实施方案中，稳定剂的浓度为0.5g/L。
在一些实施方案中，表面活性剂的浓度为0.1g/L。
在一些实施方案中，防腐剂的浓度为1g/L。
附图说明
图1.甘胆酸结构图。
图2.甘胆酸衍生物结构图。
图3A.G6PDH(野生型)氨基酸序列(SEQ ID No.1)；源自明串珠菌属假肠膜明串珠菌Leuconostoc pseudomesenteroides。
图3B.G6PDH(D306C)氨基酸序列(SEQ ID No.2)。
图3C.G6PDH(D375C)氨基酸序列(SEQ ID No.3)。
图3D.G6PDH(G426C)氨基酸序列(SEQ ID No.4)。
具体实施方式
实施例
实施例1.甘胆酸衍生物的合成
向干燥洁净的25mL两口瓶中加入甘胆酸(1.0eq)、马来酰亚胺基乙胺(1.0g，1.0eq)、三乙胺(3.0eq)；
再加入二甲基甲酰胺(5mL)搅至全溶，加入二氯乙烷(1.25eq)，在25℃搅拌2h；
HPLC监测，直至反应完毕；
把上述反应混合物加入水(25mL)中，加入乙酸乙酯20mL×3进行萃取；
合并有机相，无水Na2SO4干燥，减压浓缩，所得油状物用柱层析法纯化得到1.04g乳白色粉末状固体，收率45％，M+：602.72。
本实施例的作用在于使得CG带有一个可以和酶结合的基团，本申请的技术效果不依赖于特定的半抗原衍生物。
实施例2.甘胆酸衍生物与G6PDH分子的偶联
根据本申请的G6PDH-甘胆酸偶联物，按照以下方式进行偶联：甘胆酸衍生物分子上的巯基反应性基团(如马来酰亚胺基团)与G6PDH分子上的巯基共价结合。
1.溶液配制：
甘胆酸衍生物溶液：实施例1制备的甘胆酸衍生物10mg/ml溶于DMF；
G6PDH溶液：6.7mg/mL G6PDH(本申请的突变体或野生型)、PB 100mmol、NaCl100mmol、pH＝8.0；
偶联溶液：100mM PB/K、100mM EDTA、150mM NaCl，pH＝7.2；
脱盐溶液：100mM PB/K、100mM EDTA、150mM NaCl，pH＝7.2。
2.偶联操作：1.6ml G6PDH溶液、6ml偶联溶液和0.40ml甘胆酸衍生物溶液，在室温(20至25℃)反应4h。
3.将上述反应体系室温振荡反应4h后，用上述脱盐溶液使用脱盐柱进行洗脱，收集蛋白峰，所得产物即G6PDH-甘胆酸偶联物。
实施例3.试剂盒的制备
制备以下检测甘胆酸的试剂盒，其包含：
试剂R1，包含：
100mM PB缓冲液，pH 7.2
15mM 6-磷酸葡萄糖
15mMβ-烟酰胺腺嘌呤二核苷酸
0.1mg/L甘胆酸抗体
200mM NaCl
0.5g/L牛血清白蛋白
0.1g/L Tween20
1g/L叠氮钠；
试剂R2，包括：
100mM PB缓冲液,pH 7.2
0.1mg/L G6PDH-CG偶联物
0.5g/L牛血清白蛋白
0.1g/L Tween 20
1g/L叠氮钠；
校准品：100mM PB缓冲液，pH 7.2，以及0、2.5、5.0、10、20、40mg/L甘胆酸(或按需加入)；
质控品：100mM PB缓冲液，pH 7.2，以及1.5、8.0、25、35mg/L甘胆酸(或按需加入)。
检测例
反应时间：10min，其中孵育时间为4.7min，加入试剂R2后孵育1min后，测定读取吸光度A1，在孵育1min后，测定读取吸光度A2，计算ΔA＝(A2-A1)/min。通过校准曲线计算样本中甘胆酸的含量：CG＝样品管吸光度*校准品浓度/校准品吸光度。
对实施例3中制备的甘胆酸检测试剂盒进行性能检测，主要的检测性能为总不精密度、重复性、回收、线性、特异性等。
表1.全自动生化仪参数
| 检测机型 | 日立7180 |
| 分析/时间/点 | 2点速率/10min/20-24个点 |
| R1/R2/S | 120:40:9 |
| 波长(副/主) | 405/340 |
| 反应类型 | 递增 |
| 校准类型 | Spine型 |
| 校准点 | 6 |
| 校准品浓度 | 0/2.50/5.00/10.00/20.00/40.00 |
测试例1.甘胆酸检测试剂盒定标吸光度
表2.甘胆酸检测试剂盒定标吸光度
检测例2.甘胆酸检测试剂盒总不精密度
表3.总不精密度
检测例3.甘胆酸检测试剂盒重复性
表4.重复性
检测例4.甘胆酸检测试剂盒回收
表5.回收
检测例5.甘胆酸检测试剂盒线性
表6.线性
检测例6.甘胆酸检测试剂盒抗特异性
表7.特异性
| 干扰物(40μg/ml) | 本申请试剂(D306C) | 对照试剂(A45C突变体) |
| 甘氨脱氧胆酸 | 18.61％ | 30.20％ |
| 甘氨鹅脱氧胆酸 | 1.63％ | 37.91％ |
| 鹅去氧胆酸 | 0.61％ | 16.28％ |
| 熊去氧胆酸 | -0.42％ | 6.55％ |
| 胆酸钠 | 61.21％ | 61.90％ |
| 脱氧胆酸钠 | 4.22％ | 11.74％ |
本申请试剂与甘胆酸的结构类似物交叉反应很小甚至没有。
检测例7.抗体抑制率
1.抗体抑制率的检测原理
当抗体与G6PDH-CG偶联物结合时，由于空间位阻导致G6PDH酶活性受到影响，从而使得其催化NAD转化为NADH的效率降低，通过检测NADH量的变化，从而比较加入抗体与未加入抗体的实验组的差异，这种差异即体现为抗体对G6PDH的抑制能力。
2.反应体系：
表8.抗体抑制率的检测试剂制备
表9.抗体抑制率检测上机参数
| 检测机型 | 日立7180 |
| 分析/时间/点 | 2点速率/10min/10-15个点 |
| R1/S | 120:20 |
| 波长(副/主) | 405/340 |
| 反应类型 | 递增 |
3.结果：
比较加入抗体与未加入抗体时，分别检测G6PDH-CG偶联物吸光度测值，即可得到抗体对G6PDH的抑制情况。
抗体抑制率＝含抗体时G6PDH-CG的吸光度变化值/不含抗体时G6PDH-CG的吸光度变化值。
相对于已发表的突变位点，本申请的突变体在抗体抑制率上有明显提高，能达到30％以上，最高达50％。而之前常用的突变位点(例如A45C、K55C)的抑制率只有20％左右甚至更低。
表10.不同G6PDH突变体的抗体抑制率
虽然不限于具体理论，但是可以部分地解释为：和现有技术中的G6PDH突变体相比，本申请酶突变体(D306C、D375C、G426C)中突变位点(即引入游离巯基的位点)是和半抗原(比如激素、小分子药物等)发生偶联的位置所在。半抗原在这个位置上与半抗原特异性抗体结合时，所构成的空间位阻对G6PDH酶的活性影响最小，同时在引入突变后，还不能实质上影响分子的空间折叠。因此，这个突变位点的位置非常重要，需要同时兼顾G6PDH酶的活性、偶联分子的空间折叠、以及半抗原表位的充分暴露。
由于酶的突变体在抗体抑制率上有明显的提高，在定标吸光度上能够有明显的优势。将酶的突变体与半抗原偶联后的偶联物配制成试剂盒后，由于定标曲线的改善变，试剂在重复性、总不精密度、线性、特异性等性能方面有明显的性能提升。
序列表
<110> 北京九强生物技术股份有限公司
<120> 6-磷酸葡萄糖脱氢酶突变体及其在制备检测试剂中的用途
<130> 390017CG-390010
<150> 201910017764.4
<151> 2019-01-09
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<223> G6PDH突变体,相较于野生型，426位的G替换为C
<400> 5
Met Val Ser Glu Ile Lys Thr Leu Val Thr Phe Phe Gly Gly Thr Gly
1 5 10 15
Asp Leu Ala Lys Arg Lys Leu Tyr Pro Ser Val Phe Asn Leu Tyr Lys
20 25 30
Lys Gly Tyr Leu Gln Lys His Phe Ala Ile Val Gly Thr Ala Arg Gln
35 40 45
Ala Leu Asn Asp Asp Glu Phe Lys Gln Leu Val Arg Asp Ser Ile Lys
50 55 60
Asp Phe Thr Asp Asp Gln Ala Gln Ala Glu Ala Phe Ile Glu His Phe
65 70 75 80
Ser Tyr Arg Ala His Asp Val Thr Asp Ala Ala Ser Tyr Ala Val Leu
85 90 95
Lys Glu Ala Ile Glu Glu Ala Ala Asp Lys Phe Asp Ile Asp Gly Asn
100 105 110
Arg Ile Phe Tyr Met Ser Val Ala Pro Arg Phe Phe Gly Thr Ile Ala
115 120 125
Lys Tyr Leu Lys Ser Glu Gly Leu Leu Ala Asp Thr Gly Tyr Asn Arg
130 135 140
Leu Met Ile Glu Lys Pro Phe Gly Thr Ser Tyr Asp Thr Ala Ala Glu
145 150 155 160
Leu Gln Asn Asp Leu Glu Asn Ala Phe Asp Asp Asn Gln Leu Phe Arg
165 170 175
Ile Asp His Tyr Leu Gly Lys Glu Met Val Gln Asn Ile Ala Ala Leu
180 185 190
Arg Phe Gly Asn Pro Ile Phe Asp Ala Ala Trp Asn Lys Asp Tyr Ile
195 200 205
Lys Asn Val Gln Val Thr Leu Ser Glu Val Leu Gly Val Glu Glu Arg
210 215 220
Ala Gly Tyr Tyr Asp Thr Ala Gly Ala Leu Leu Asp Met Ile Gln Asn
225 230 235 240
His Thr Met Gln Ile Val Gly Trp Leu Ala Met Glu Lys Pro Glu Ser
245 250 255
Phe Thr Asp Lys Asp Ile Arg Ala Ala Lys Asn Ala Ala Phe Asn Ala
260 265 270
Leu Lys Ile Tyr Asp Glu Ala Glu Val Asn Lys Tyr Phe Gly Arg Ala
275 280 285
Gln Tyr Gly Ala Gly Asp Ser Ala Asp Phe Lys Pro Tyr Leu Glu Glu
290 295 300
Leu Asp Val Pro Ala Asp Ser Lys Asn Asn Thr Phe Ile Ala Gly Glu
305 310 315 320
Leu Gln Phe Asp Leu Pro Arg Trp Glu Gly Val Pro Phe Tyr Val Arg
325 330 335
Ser Gly Lys Arg Leu Ala Ala Lys Gln Thr Arg Val Asp Ile Val Phe
340 345 350
Lys Ala Gly Thr Phe Asn Phe Gly Ser Glu Gln Glu Ala Gln Glu Ala
355 360 365
Val Leu Ser Ile Ile Ile Asp Pro Lys Gly Ala Ile Glu Leu Lys Leu
370 375 380
Asn Ala Lys Ser Val Glu Asp Ala Phe Asn Thr Arg Thr Ile Asp Leu
385 390 395 400
Gly Trp Thr Val Ser Asp Glu Asp Lys Lys Asn Thr Pro Glu Pro Tyr
405 410 415
Glu Arg Met Ile His Asp Thr Met Asn Cys Asp Gly Ser Asn Phe Ala
420 425 430
Asp Trp Asn Gly Val Ser Ile Ala Trp Lys Phe Val Asp Ala Ile Ser
435 440 445
Ala Val Tyr Thr Ala Asp Lys Ala Pro Leu Glu Thr Tyr Lys Ser Gly
450 455 460
Ser Met Gly Pro Glu Ala Ser Asp Lys Leu Leu Ala Ala Asn Gly Asp
465 470 475 480
Ala Trp Val Phe Lys Gly
485
Claims (10)
1.一种6-磷酸葡萄糖脱氢酶突变体，相较于野生型6-磷酸葡萄糖脱氢酶，其包含选自以下的一个突变或其组合：D306C、D375C、G426C；
优选地，所述6-磷酸葡萄糖脱氢酶突变体是选自以下的序列所示：SEQ ID No.2、SEQID No.3、SEQ ID No.4。
2.一种多核苷酸，其编码权利要求1所述的6-磷酸葡萄糖脱氢酶突变体。
3.一种表达载体，其包含权利要求2所述的多核苷酸。
4.一种宿主细胞，其包含权利要求3所述的表达载体。
5.一种偶联物，其是权利要求1所述的6-磷酸葡萄糖脱氢酶突变体与半抗原按照摩尔比1：n偶联而成；
n是1至50，优选为10、15、20、25、30、35、40、45或50；
更优选n为30；
优选，所述半抗原选自：抗生素、激素、代谢物、糖、脂质、氨基酸；
所述半抗原的分子量为200Da至4000Da，优选200Da至1500Da；
更优选，所述半抗原是甘胆酸或其衍生物。
6.一种试剂，其包含权利要求5所述的偶联物。
7.选自以下的任一项在制备检测试剂中的用途：
权利要求1所述的6-磷酸葡萄糖脱氢酶突变体、权利要求5所述的偶联物；
优选地，所述检测试剂是半抗原的检测试剂；
优选地，所述检测试剂选自：酶联免疫法检测试剂、化学发光免疫法检测试剂、均相酶免疫法检测试剂、胶乳增强免疫比浊法检测试剂；
优选地，所述半抗原选自：抗生素、激素、代谢物、糖、脂质、氨基酸；
所述半抗原的分子量为200Da至4000Da，优选200Da至1500Da。
8.一种甘胆酸检测试剂盒，其包含：
第一试剂，所述第一试剂包含底物、甘胆酸抗体；
第二试剂，所述第二试剂包含权利要求5所述的偶联物；
任选地，校准品，所述校准品包含10mM至500mM缓冲液、0mg/L至40mg/L甘胆酸；以及
任选地，质控品，所述质控品包含10mM至500mM缓冲液、0mg/L至40mg/L甘胆酸。
9.根据权利要求8所述的甘胆酸检测试剂盒，其包含：
第一试剂，其包含：
10mM至500mM缓冲液、
0.5g/L至5g/L底物、
0.1mg/L至1mg/L的甘胆酸抗体、
10mM至300mM NaCl、
0.1g/L至5g/L稳定剂、
0.1g/L至5g/L表面活性剂、
0.1g/L至5g/L防腐剂；
第二试剂，其包含：
10mM至500mM缓冲液、
权利要求5中所述的偶联物、
0.1g/L至5g/L稳定剂、
0.1g/L至5g/L表面活性剂、
0.1g/L至5g/L防腐剂；
所述缓冲液选自以下的一种或组合：氨基丁三醇缓冲液、磷酸盐缓冲液、Tris-HCl缓冲液、柠檬酸-柠檬酸钠缓冲液、巴比妥缓冲液、甘氨酸缓冲液、硼酸盐缓冲液、三羟甲基甲烷缓冲液；优选，磷酸盐缓冲液；
所述缓冲液的浓度为10mmol/L至500mmol/L；
所述缓冲液的pH为6.5至7.5；
所述稳定剂选自以下的一种或组合：牛血清白蛋白、海藻糖、甘油、蔗糖、甘露醇、甘氨酸、精氨酸、聚乙二醇6000、聚乙二醇8000；优选牛血清白蛋白；
所述表面活性剂选自以下的一种或组合：Brij35、Tritiom X-100、Tritiom X-405、Tween20、Tween30、Tween80、椰子油脂肪酸二乙醇酰胺、AEO7，优选Tween20；
所述的防腐剂选自以下的一种或组合：叠氮化物、MIT、PC-300、硫柳汞；
所述叠氮化物选自：叠氮钠、叠氮锂；
所述底物包含：6-磷酸葡糖糖、β-烟酰胺腺嘌呤二核苷酸。
10.一种偶联物的制备方法，其包括步骤：
提供权利要求1所述的6-磷酸葡萄糖脱氢酶突变体；
提供半抗原，所述半抗原选自：抗生素、激素、代谢物、糖、脂质、氨基酸；
所述半抗原的分子量为200Da至4000Da，优选200Da至1500Da；
所述的6-磷酸葡萄糖脱氢酶突变体与所述半抗原按照摩尔比1：n偶联；
n是1至50，优选为10、15、20、25、30、35、40、45或50；
更优选，n是30；
更优选，所述半抗原是甘胆酸或其衍生物。
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