Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism
Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism
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DOI：
10.1074/jbc.m113.452953
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发表时间：
2013-05-03
影响因子：
4.8
通讯作者：
Scott, Emily E.
中科院分区：
文献类型：
--
作者：
Walsh, Agnes A.;Szklarz, Grazyna D.;Scott, Emily E.
细胞色素P450 (CYP) 1A1是一种肝外单加氧酶，参与内源性底物和药物的代谢，以及某些毒素和环境污染物的活化。CYP1A1尤其以其将多环芳烃（如烟草烟雾中的苯并[a]芘）生物转化为致癌物的能力而闻名。CYP1A1与人类CYP1A2和CYP1B1酶具有功能上的异同，但其结构基础尚不清楚。我们用α -萘黄酮抑制剂测定了人CYP1A1蛋白的2.6埃结构。-萘黄酮结合在一个封闭的活性位点内，平面苯并-4- 1核心与构成活性位点一壁的I螺旋平装，2-苯基取代基指向催化血红素铁。与先前确定的相关细胞色素P450 1A2和1B1酶的结构进行比较，揭示了活性位点之间的不同特征，这些特征可能是这些酶功能变异的基础。最后，对接研究探索了CYP1A结构的能力，以帮助理解它们与几种典型底物和抑制剂的已知体外相互作用。
Cytochrome P450 (CYP) 1A1 is an extrahepatic monooxygenase involved in the metabolism of endogenous substrates and drugs, as well as the activation of certain toxins and environmental pollutants. CYP1A1 is particularly well known for its ability to biotransform polycyclic aromatic hydrocarbons, such as benzo[a] pyrene in tobacco smoke, into carcinogens. CYP1A1 possesses functional similarities and differences with human CYP1A2 and CYP1B1 enzymes, but the structural basis for this has been unclear. We determined a 2.6 angstrom structure of human CYP1A1 with the inhibitor alpha-naphthoflavone. alpha-Naphthoflavone binds within an enclosed active site, with the planar benzochromen-4-one core packed flat against the I helix that composes one wall of the active site, and the 2-phenyl substituent oriented toward the catalytic heme iron. Comparisons with previously determined structures of the related cytochrome P450 1A2 and 1B1 enzymes reveal distinct features among the active sites that may underlie the functional variability of these enzymes. Finally, docking studies probed the ability of CYP1A structures to assist in understanding their known in vitro interactions with several typical substrates and inhibitors.