人类细胞色素 P450 酶 CYP4A22 的功能特征分析和机制建模。
Functional characterization and mechanistic modeling of the human cytochrome P450 enzyme CYP4A22.
机构信息
School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin University, China.
Pharmaceutical and Medicinal Chemistry, Computer-Aided Drug Design, Institute of Pharmacy, Freie University Berlin, Germany.
出版信息
FEBS Lett. 2019 Aug;593(16):2214-2225. doi: 10.1002/1873-3468.13489. Epub 2019 Jul 7.
The human cytochrome P450 (CYP) enzyme CYP4A22 is an orphan CYP with unknown function. Here, through functional expression in fission yeast, we show that CYP4A22 catalyzes fatty acid hydroxylation as well as aliphatic or aromatic hydroxylations of luciferin-based probe substrates. Mechanistic molecular modeling of CYP4A22 suggests that its ω-hydroxylation activity is hampered by a more spacious active site compared to CYP4B1. Substrate recognition via side-chains R96 and R233 is indicated by dynamic three-dimensional pharmacophores (dynophores) derived from molecular dynamics simulations. CYP4A22 activity is inhibited by three unspecific CYP inhibitors. A comparison of CYP4A22*1 (the reference standard sequence) with CYP4A22-WT (the most common allele) revealed that for the four substrates tested the WT-enzyme always had lower activity.
人细胞色素 P450（CYP）酶 CYP4A22 是一种未知功能的孤儿 CYP。在这里，我们通过裂殖酵母中的功能表达表明，CYP4A22 催化脂肪酸羟化以及荧光素探针底物的脂肪族或芳族羟化。CYP4A22 的机制分子建模表明，与 CYP4B1 相比，其 ω-羟化活性受到更宽敞的活性部位的阻碍。通过源自分子动力学模拟的动态三维药效团（dynophores）表明，通过侧链 R96 和 R233 进行底物识别。三种非特异性 CYP 抑制剂抑制 CYP4A22 的活性。将 CYP4A22*1（参考标准序列）与 CYP4A22-WT（最常见的等位基因）进行比较表明，在所测试的四种底物中，WT 酶的活性总是较低。
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