Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.
Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.
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DOI：
10.3390/ijms221910206
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发表时间：
2021-09-22
影响因子：
5.6
通讯作者：
Shah MB
中科院分区：
文献类型：
--
作者：
Parikh SJ;Kamat S;Phillips M;Boyson SP;Yarbrough T;Davie D;Zhang Q;Glass KC;Shah MB
细胞色素P450（Cytochromes P450，CYP 450）是一种重要的外源性物质代谢酶，在药物遗传学研究中具有重要意义。CYP 2C 9酶负责多种临床药物的代谢。在CYP 2C 9中已经鉴定了60多种遗传变异，其中许多变异与野生型（WT）酶相比活性降低。CYP 2C 9 *8等位基因主要存在于非洲血统的人群中，并导致CYP 2C 9的几种药物底物的清除率改变。CYP 2C 9 *8的X-射线晶体结构，代表了在150位（R150 H）从精氨酸到组氨酸的氨基酸变异，在与氯沙坦的复合物中得到了解析。CYP 2C 9 *8-氯沙坦复合物的总体构象与先前解析的野生型（WT）蛋白复合物相似，但其在氯沙坦占据方面不同。一个分子的氯沙坦结合在活性部位，另一个分子结合在表面上，与WT复合物中观察到的方向相同。然而，与WT结构不同，在 *8复合体中未观察到通路通道中的氯沙坦。此外，等温滴定量热法研究表明，与WT相比，氯沙坦与 *8的结合较弱。有趣的是，CYP 2C 9 *8与氯沙坦的相互作用不像CYP 2C 9 *3变体那么弱，与WT相比，CYP 2C 9 *3变体的平均解离常数最多弱3倍。两者合计，结构和溶液表征产生深入了解氯沙坦结合CYP 2C 9变体的相似性和差异，并提供了一个有用的框架，用于探测氨基酸取代和底物依赖性活性的作用。
Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
2.6
作者：
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DOI：
10.1073/pnas.1221442110
发表时间：
2013-03-26
影响因子：
11.1
作者：
Lee, Sung Chang;Bennett, Brad C.;Zhang, Qinghai
通讯作者：
Zhang, Qinghai
影响因子：
15
作者：
Wilderman, P. Ross;Shah, Manish B.;Jang, Hyun-Hee;Stout, C. David;Halpert, James R.
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DOI：
10.1107/s090744499900846x
发表时间：
1999-10-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Leslie, AGW
通讯作者：
Leslie, AGW