Coon M J, Vaz A D, McGinnity D F, Peng H M
Department of Biological Chemistry, Medical School, The University of Michigan, Ann Arbor 48109-0606, USA.
Drug Metab Dispos. 1998 Dec;26(12):1190-3.
A hypervalent iron-oxene species has been widely proposed as the "active oxygen" in cytochrome P450 (P450)-catalyzed reactions. We recently examined the effect of mutation of the highly conserved threonine residue in P450s 2B4 and 2E1 to alanine, a change that is believed to interfere with proton delivery to the active site, and have determined the change in rates of deformylation of aldehydes, epoxidation of olefins, and hydroxylation of various substrates. The results support the concept that three distinct oxidants are functional in P450 catalysis: nucleophilic peroxo-iron, nucleophilic or electrophilic hydroperoxo-iron, and electrophilic oxenoid-iron. The occurrence of multiple oxidizing species may contribute to the remarkable versatility of the P450 family of isozymes in the modification of drugs and other substrates. Furthermore, the relative concentrations of these oxidants in a particular P450 isozyme may contribute to substrate specificity and govern the type of reaction catalyzed.
高价铁氧物种已被广泛认为是细胞色素P450（P450）催化反应中的“活性氧”。我们最近研究了将P450 2B4和2E1中高度保守的苏氨酸残基突变为丙氨酸的影响，据信这种变化会干扰质子向活性位点的传递，并确定了醛的脱甲酰化、烯烃的环氧化以及各种底物的羟基化反应速率的变化。结果支持了这样一种概念，即三种不同的氧化剂在P450催化中起作用：亲核过氧铁、亲核或亲电氢过氧铁以及亲电氧烯铁。多种氧化物种的存在可能有助于P450同工酶家族在药物和其他底物修饰方面具有显著的多功能性。此外，这些氧化剂在特定P450同工酶中的相对浓度可能有助于底物特异性，并决定所催化反应的类型。
