Mechanisms of Cytochrome P450-Catalyzed Oxidations
Mechanisms of Cytochrome P450-Catalyzed Oxidations
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DOI：
10.1021/acscatal.8b03401
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发表时间：
2018-12-01
期刊：
影响因子：
12.9
通讯作者：
Guengerich, F. Peter
中科院分区：
文献类型：
--
作者：
Guengerich, F. Peter
酶是复杂的生物催化剂，对生命至关重要。大多数化学物质的氧化由细胞色素P450（P450，CH 3）酶催化，其通常利用混合功能氧化酶化学计量，利用吡啶核苷酸作为电子供体：NAD（P）H + O-2 R -> NAD（P）（+）+ RO + H2O（其中R是碳底物，RO是氧化产物）。氧化的催化作用在很大程度上是在血红素铁-氧复合物的背景下理解的，通常称为化合物I，形式上为FeO 3+，其基础是过氧化物酶化学。现在有许多P450的X射线晶体结构可用（来自>= 146种不同P450的>= 822种结构），并有助于理解催化特异性。除了羟基化，P450还催化更复杂的氧化，包括C-C键的形成和裂解。通过定向进化从P450衍生的酶甚至可以催化更不寻常的反应，例如，环丙烷化。目前正在研究的P450问题包括中间体化合物0的潜在作用（形式为Fe-III-O-2（-））在某些反应的催化中的作用，化合物I的高自旋和低自旋形式的作用，去饱和的机理，P450的开放和闭合结构在催化中的作用，多步氧化中的持续合成能力的程度，以及辅助蛋白细胞色素B的作用（5）。更多的全球性问题包括结构如何驱动功能、催化作用的预测以及多种蛋白质构象的作用。
Enzymes are complex biological catalysts and are critical to life. Most oxidations of chemicals are catalyzed by cytochrome P450 (P450, CYP) enzymes, which generally utilize mixed-function oxidase stoichiometry, utilizing pyridine nucleotides as electron donors: NAD(P)H + O-2 R -> NAD(P)(+) + RO + H2O (where R is a carbon substrate and RO is an oxidized product). The catalysis of oxidations is largely understood in the context of the heme iron-oxygen complex generally termed Compound I, formally FeO3+, whose basis was in peroxidase chemistry. Many X-ray crystal structures of P450s are now available (>= 822 structures from >= 146 different P450s) and have helped in understanding catalytic specificity. In addition to hydroxylations, P450s catalyze more complex oxidations, including C-C bond formation and cleavage. Enzymes derived from P450s by directed evolution can even catalyze more unusual reactions, e.g., cyclopropanation. Current P450 questions under investigation include the potential role of the intermediate Compound 0 (formally Fe-III-O-2(-)) in catalysis of some reactions, the roles of high- and low-spin forms of Compound I, the mechanism of desaturation, the roles of open and closed structures of P450s in catalysis, the extent of processivity in multistep oxidations, and the role of the accessory protein cytochrome b(5). More global questions include exactly how structure drives function, prediction of catalysis, and roles of multiple protein conformations.