Maekawa Keiko, Adachi Motoyasu, Matsuzawa Yumiko, Zhang Qinghai, Kuroki Ryota, Saito Yoshiro, Shah Manish B
Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kodo, Kyotanabe, Kyoto 610-0395, Japan.
Division of Medicinal Safety Science, National Institute of Health Sciences , Kamiyoga 1-18-1, Setagaya, Tokyo 158-8501, Japan.
Biochemistry. 2017 Oct 17;56(41):5476-5480. doi: 10.1021/acs.biochem.7b00795. Epub 2017 Oct 3.
Single-nucleotide polymorphisms in drug-metabolizing cytochrome P450 (CYP) enzymes are important contributors to interindividual differences in drug metabolism leading to adverse drug reactions. Despite their extensive characterization and importance in pharmacogenetics of clinical drugs, the structural basis of CYP polymorphisms has remained scant. Here we report the crystal structures of human CYP2C9 and its polymorphic variants, *3 (I359L) and *30 (A477T), with an antihypertensive drug losartan. The structures show distinct interaction and occupation of losartan in the active site, the access channel, and the peripheral binding site. The I359L substitution located far from the active site remarkably altered the residue side chains near the active site and the access channel, whereas the T477 substitution illustrated hydrogen-bonding interaction with the reoriented side chain of Q214. The results yield structural insights into the reduced catalytic activity of the CYP2C9 variants and have important implications for understanding genetic polymorphisms in CYP-mediated drug metabolism.
药物代谢细胞色素P450（CYP）酶中的单核苷酸多态性是导致个体间药物代谢差异进而引发药物不良反应的重要因素。尽管它们在临床药物的药物遗传学中已得到广泛表征且具有重要意义，但CYP多态性的结构基础仍知之甚少。在此，我们报告了人CYP2C9及其多态性变体3（I359L）和30（A477T）与抗高血压药物氯沙坦的晶体结构。这些结构显示氯沙坦在活性位点、进入通道和外周结合位点存在不同的相互作用和占据情况。位于远离活性位点的I359L取代显著改变了活性位点和进入通道附近的残基侧链，而T477取代则显示与重新定向的Q214侧链存在氢键相互作用。这些结果为了解CYP2C9变体催化活性降低提供了结构见解，对理解CYP介导的药物代谢中的基因多态性具有重要意义。
