Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions.
Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions.
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DOI：
10.1002/jlcr.3031
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发表时间：
2013-07
影响因子：
1.8
通讯作者：
Guengerich FP
中科院分区：
文献类型：
--
作者：
Guengerich FP
细胞色素P450(P450)酶约占药物代谢的75%。P450催化的大多数反应都是混合官能团的氧化反应，C-H键(通常)被破坏。这一步骤的限速性质可以用动力学同位素效应(KIE)方法来分析。最相关的KIE类型是一种称为分子间非竞争性的，表明限速C-H键断裂。几个P450的Kie与kcat的相关系数(R2)为0.62。在某些情况下，氢替代被认为是一种潜在的减缓药物新陈代谢或改变代谢部位的方法，根据对P450Kies的了解，可以对在药物设计/开发中应用氢的潜力提出几个一般性的观点。
Cytochrome P450 (P450) enzymes account for ~ 75% of the metabolism of drugs. Most of the reactions catalyzed by P450s are mixed-function oxidations, and a C-H bond is (usually) broken. The rate-limiting nature of this step can be analyzed using the kinetic isotope effect (KIE) approach. The most relevant type of KIE is one termed intermolecular non-competitive, indicative of rate-limiting C-H bond breaking. A KIE vs. kcat for several P450s showed a correlation coefficient (r2) of 0.62. Deuterium substitution has been considered as a potential means of slowing drug metabolism or redirecting sites of metabolism in some cases, and several general points can be made regarding the potential for application of deuterium in drug design/development based on what is known about P450 KIEs.