Davydov Dmitri R, Halpert James R
Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, 9500 Gilman Drive, La Jolla, CA 9209, USA.
Expert Opin Drug Metab Toxicol. 2008 Dec;4(12):1523-35. doi: 10.1517/17425250802500028.
According to the initial hypothesis on the mechanisms of cooperativity in drug-metabolizing cytochromes P450, a loose fit of a single substrate molecule in the P450 active site results in a requirement for the binding of multiple ligand molecules for efficient catalysis. Although simultaneous occupancy of the active site by multiple ligands is now well established, there is increasing evidence that the mechanistic basis of cooperativity also involves an important ligand-induced conformational transition. Moreover, recent studies demonstrate that the conformational heterogeneity of the enzyme is stabilized by ligand-dependent interactions of several P450 molecules. Application of the concept of an oligomeric allosteric enzyme to microsomal cytochromes P450 in combination with a general paradigm of multiple ligand occupancy of the active site provides an excellent explanation for complex manifestations of the atypical kinetic behavior of the enzyme.
根据关于药物代谢细胞色素P450协同作用机制的最初假说，单个底物分子在P450活性位点的松散结合导致需要多个配体分子结合才能进行有效催化。尽管现在已经充分证实多个配体可同时占据活性位点，但越来越多的证据表明，协同作用的机制基础还涉及重要的配体诱导构象转变。此外，最近的研究表明，该酶的构象异质性通过几个P450分子的配体依赖性相互作用得以稳定。将寡聚别构酶的概念应用于微粒体细胞色素P450，并结合活性位点多个配体占据的一般模式，可为该酶非典型动力学行为的复杂表现提供一个很好的解释。
