Cooperative properties of cytochromes P450

作者：Denisov Ilia G; Frank Daniel J; Sligar Stephen G^*

来源：Pharmacology & Therapeutics, 2009, 124(2): 151-167.

DOI：10.1016/j.pharmthera.2009.05.011

• P450
• Allosteric effects
• Cooperativity
• Drug-drug interactions

Cytochromes P450 form a large and important class of heme monooxygenases with a broad spectrum of substrates and corresponding functions, from steroid hormone biosynthesis to the metabolism of xenobiotics. Despite decades of study, the molecular mechanisms responsible for the complex non-Michaelis behavior observed with many members of this superfamily during metabolism, often termed 'cooperativity', remain to be fully elucidated. Although there is evidence that oligomerization may play an important role in defining the observed cooperativity, some monomeric cytochromes P450, particularly those involved in xenobiotic metabolism, also display this behavior due to their ability to simultaneously bind several substrate molecules. As a result, formation of distinct enzyme-substrate complexes with different stoichiometry and functional properties can give rise to homotropic and heterotropic cooperative behavior. This review aims to summarize the current understanding of cooperativity in cytochromes P450, with a focus on the nature of cooperative effects in monomeric enzymes.

• 出版日期2009-11