Cytochrome P-450 Polymorphism

描述（由申请人提供）：细胞色素P450单加氧酶通常决定候选药物的清除率，限制其疗效。这些酶也可能是脱靶毒性的来源。我们的长期目标是了解P450酶识别底物的结构决定因素。人类药物代谢的p450可以代谢多种结构不同的底物，这可能部分反映了每种酶的灵活性和底物结合的结构适应性。这强调了确定结构不同药物复合物中单个酶的多种结构的必要性，以了解构象灵活性对药物结合的贡献。P450s 1B1、1A2、2D6和2C19的活性位点结构通过单独或联合与化学上不同的底物、抑制剂和活化剂相互作用引起的特异性变化将被确定，以描绘每种酶可能发生的适应性变化的范围。此外，还将确定P450s 2J2、3A5和3A7以及具有代表性的家族4酶的活性位点拓扑结构，以确定控制这些酶对药物代谢和清除外源和过量内源化合物的重要功能贡献的结构特征。总的来说，这些研究将填补我们对P450结构与功能相关知识的重大空白，并为预测药物代谢提供重要的信息和工具。

DESCRIPTION (provided by applicant): Cytochrome P450 monooxygenases often determine the clearance of candidate drugs limiting their efficacy. These enzymes can also be sources for off-target toxicity. Our long term objective is to understand the structural determinants of substrate recognition by P450 enzymes. Collectively and individually the human drug metabolizing P450s can metabolize structurally diverse range of substrates, and this is likely to reflect in part the flexibility of each enzyme and structural adaptations for substrate binding. This underscores the necessity to determine multiple structures of individual enzymes in complex with structurally dissimilar drugs to understand the contribution of conformational flexibility to drug binding. Specific changes in the active site architectures of P450s 1B1, 1A2, 2D6, and 2C19 induced by interaction with chemically diverse substrates, inhibitors and activators, alone or in combination, will be identified to delineate the range of adaptive changes that can occur for each enzyme. Additionally, the active site topologies of P450s 2J2, 3A5 and 3A7 as well as representative family 4 enzymes will also be determined to identify structural characteristics that control the important functional contribution made by these enzymes to drug metabolism and the clearance of xenobiotics and excess endogenous compounds. Collectively, these studies will address significant gaps in our knowledge of P450 structure as it relates to function, and provide important information and tools for the prediction of drug metabolism.