Allosteric phenomena in cytochrome P450-catalyzed monooxygenations

被引:64
作者
Hlavica, P
Lewis, DFV
机构
[1] Univ Munich, Walther Straub Inst Pharmakol & Toxikol, D-80336 Munich, Germany
[2] Univ Surrey, Sch Biol Sci, Mol Toxicol Grp, Guildford GU2 5XH, Surrey, England
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 2001年 / 268卷 / 18期
关键词
cytochrome P450; allosteric activation; conformer equilibria; kinetic models; substrate binding; electron transfer; dioxygen association;
D O I
10.1046/j.1432-1327.2001.02412.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Allosteric regulation of monooxygenase activity is shown to occur with diverse cytochrome P450 isoforms and is characterized by kinetic patterns deviating from the Michaelis-Menten model. Homotropic and heterotropic phenomena are encountered in both substrate activation and productive coupling of the electron donors NADPH-cytochrome P450 reductase and cytochrome b(5), and the lipid environment of the system also appears to play a role as an effector. Circumstantial analysis reveals the components of the electron transfer chain to be mutually beneficial in interactions with each other depending on the substrate used and type of cytochrome P450 operative. It is noteworthy that association of diatomic gaseous ligands may be amenable to allosteric regulation as well. Thus, dioxygen binding to cytochrome P450 displays nonhyperbolic kinetic profiles in the presence of certain substrates; the latter, together with redox proteins such as cytochrome b(5), can exert efficient control of the abortive breakdown of the oxyferrous intermediates formed. Similarly, substrates may modulate the structural features of the access channel for solutes such as carbon monoxide in specific cytochrome P450 isozymes to either facilitate or impair ligand diffusion to the heme iron. The in vivo importance of allosteric regulation of enzyme activity is discussed in detail.
引用
收藏
页码:4817 / 4832
页数:16
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