细胞色素P450配体通道的研究进展

Advances in the ligand channels of cytochrome P450s

细胞色素P450(CYP)是一类含亚铁血红素的酶,不但能催化内源性底物的生物合成和代谢,而且对外源性化合物的代谢、激活以及降解毒性等起着重要作用.P450也是人体内最主要的药物代谢酶,能催化代谢约75%的临床药物.已有的P450酶晶体结构显示,绝大多数酶呈现闭合的构象,其催化活性位点位于血红素上方且深埋于蛋白质的中心,没有明显的通道用于配体进出活性中心.因此一个有趣而重要的问题是,配体如何进出酶的活性中心达到被氧化或发生抑制作用?近年来,关于P450酶配体通道的研究取得了显著进展.本文重点综述了通道研究的实验方法及6类P450酶可能存在的通道和作用机制,并对其未来的发展方向进行了展望.

Cytochrome P450s（CYPs） are heme-containing monooxygenases that play critical roles in the biosynthesis and degradation of many physiologically important compounds,and in the metabolism and detoxification of xenobiotics.Currently,the available crystal structures of CYPs exhibit similar three-dimensional structural folds at the gross level.The active site of CYPs is buried deep within the center of the protein and above the heme cofactor.Because the active site is inaccessible to the surrounding bulk solvent,the question of how the ligand enters/exits the buried active site remains unresolved.The issue of the ligand access/egress channel in P450s has attracted significant attention in recent years.A complete review of major experimental methods and possible ligand channels of 6 typical P450 enzymes is presented in this review,and further research focuses are also discussed.