Cytochrome P450 flexibility.

Abstract

Cytochrome P450 refers to a group of enzymes that catalyze the monooxygenation of various organic molecules in the following reaction: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*} \begin{matrix}{\mathrm{RH}}+{\mathrm{O}}\_{2}+2{\mathrm{e}}^{-}+2{\mathrm{H}}^{+}{\rightarrow} {\mathrm{R}}-{\mathrm{OH}}+{\mathrm{H}}\_{2}{\mathrm{O}}.\end{matrix} \end{equation*}\end{document} P450s are best known for their role in drug metabolism and detoxification. Humans have 57 functional P450 genes and 46 pseudogenes (http://drnelson.utmem.edu/human.genecount.html), and several of these, located in liver microsomes, are induced by a variety of foreign organic molecules. Hydroxylation of these substances by P450s renders these relatively insoluble organic compounds more soluble for easier elimination. In addition, P450s participate in the metabolism of sex hormones, vitamin D, and bile acids in mammals (1, 2); ecdysones in insects (3); and terpenes in plants (4). P450s also play an important role in microorganisms in the use of various organic compounds as carbon sources and in the production of important natural products such as antibiotics. P450s range in size from 40 to 50 kDa and contain a single heme group. Oxygen binds to the heme iron where the enzyme catalyzes cleavage of the oxygen O—O bond, leaving behind an iron-linked oxygen atom that provides a potent oxidant. The substrate is held precisely in place such that the correct carbon atom is close to the iron-linked O atom for regio- and stereoselective hydroxylation. In general, those P450s involved in the production of important intermediates such as in steroid metabolism are highly specific. However, many of the drug-metabolizing P450s are not specific and are capable of hydroxylating a variety of diverse and unrelated compounds. Several P450 crystal structures now are known, and it was not too surprising, based on sequence alignments, that the overall fold is maintained in all P450s (Fig. 1). A particularly challenging problem, however, is to understand how …