Lewis David F V
Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, UK.
Arch Biochem Biophys. 2003 Jan 1;409(1):32-44. doi: 10.1016/s0003-9861(02)00349-1.
A detailed analysis of substrate selectivity within the cytochrome P450 2 (CYP2) family is reported. From a consideration of specific interactions between drug substrates for human CYP2 family enzymes and the putative active sites of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, it is likely that the number and disposition of hydrogen bond donor/acceptors and aromatic rings within the various P450 substrate molecules determines their enzyme selectivity and binding affinity, together with directing their preferred routes of metabolism by the CYP2 enzymes concerned. Although many aliphatic residues are present in most P450 active sites, it would appear that their main contribution centers around hydrophobic interactions and desolvation processes accompanying substrate binding. Molecular modeling studies based on the recent CYP2C5 crystal structure appear to show close agreement with site-directed mutagenesis experiments and with information on substrate metabolism and selectivity within the CYP2 family.
本文报道了对细胞色素P450 2（CYP2）家族底物选择性的详细分析。通过考虑人类CYP2家族酶的药物底物与CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6和CYP2E1假定活性位点之间的特定相互作用，各种P450底物分子中氢键供体/受体和芳香环的数量及位置可能决定了它们的酶选择性和结合亲和力，同时也决定了相关CYP2酶的首选代谢途径。尽管大多数P450活性位点存在许多脂肪族残基，但它们的主要作用似乎集中在底物结合时的疏水相互作用和去溶剂化过程。基于最近CYP2C5晶体结构的分子模拟研究似乎与定点诱变实验以及CYP2家族内底物代谢和选择性信息密切一致。
