Guengerich F P
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Curr Drug Metab. 2001 Jun;2(2):93-115. doi: 10.2174/1389200013338694.
Cytochrome P450 (P450) enzymes play major roles in the metabolism of drugs, carcinogens, steroids, eicosanoids, alkaloids, pesticides, and other important xenobiotics, as well as chemicals normally endogenous to the body. P450s are generally considered in a classical catalytic reduction-oxidation cycle and an odd-electron abstraction/rebound chemical mechanism that can be used to rationalize carbon hydroxylation, dealkylation of heteroatomic substrates, heteroatom oxygenation, and the oxidation of unsaturated compounds to epoxides and phenols. However, many other reactions are catalyzed by P450s but not generally appreciated. The classical catalytic mechanism requires some expansion to explain all of these reactions. Reactions discussed here include mechanism-based heme inactivation, mechanism-based protein modification, 1,2-shifts, 1- and 2-electron reductions, 1-electron oxidation, oxidative cleavage of carboxylic acid esters, desaturation, deformylation of aldehydes, ring formation, ipso mechanisms for aryl dehalogenation and O- and N-dearylation, cis-trans bond isomerization, several rearrangements of oxidized eicosanoids, aldoxime dehydration, and hydrolysis of phosphatidylcholine.
细胞色素P450（P450）酶在药物、致癌物、类固醇、类二十烷酸、生物碱、农药及其他重要的外源性物质以及体内正常内源性化学物质的代谢中发挥着主要作用。P450通常被认为参与经典的催化还原-氧化循环以及奇数电子提取/反弹化学机制，该机制可用于解释碳羟基化、杂原子底物的脱烷基化、杂原子氧化以及不饱和化合物氧化为环氧化物和酚类。然而，P450还催化许多其他反应，但通常未得到充分认识。经典的催化机制需要进一步扩展以解释所有这些反应。这里讨论的反应包括基于机制的血红素失活、基于机制的蛋白质修饰、1,2-迁移、1-和2-电子还原、1-电子氧化、羧酸酯的氧化裂解、去饱和、醛的脱甲酰基化、环化、芳基脱卤和O-及N-脱芳基化的原位机制、顺反键异构化、氧化类二十烷酸的几种重排、醛肟脱水以及磷脂酰胆碱的水解。
