Azole drugs trap cytochrome P450 EryK in alternative conformational states.
Summary of "Azole drugs trap cytochrome P450 EryK in alternative conformational states."
EryK is a bacterial cytochrome P450 that catalyzes the last hydroxylation occurring during the biosynthetic pathway of erythromycin A in Streptomyces erythraeus. We report the crystal structures of EryK in complex with two widely used azole inhibitors: ketoconazole and clotrimazole. Both of these ligands use their imidazole moiety to coordinate the heme iron of P450s. Nevertheless, because of the different chemical and structural properties of their N1-substituent group, ketoconazole and clotrimazole trap EryK, respectively, in a closed and in an open conformation that resemble the two structures previously described for the ligand-free EryK. Indeed, ligands induce a distortion of the internal helix I that affects the accessibility of the binding pocket by regulating the kink of the external helix G via a network of interactions that involves helix F. The data presented thus constitute an example of how a cytochrome P450 may be selectively trapped in different conformational states by inhibitors.
Department of Biochemical Sciences, Sapienza University of Rome and CNR Institute of Molecular Biology and Pathology, Piazzale A. Moro 5, Rome, Italy.
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Medical and Biotech [MESH] Definitions
Cytochrome P-450 Cyp2d6
A cytochrome P450 enzyme that catalyzes the hydroxylation of many drugs and environmental chemicals, such as DEBRISOQUINE; ADRENERGIC RECEPTOR ANTAGONISTS; and TRICYCLIC ANTIDEPRESSANTS. This enzyme is deficient in up to 10 percent of the Caucasian population.
Cytochrome P-450 Cyp2e1
An ethanol-inducible cytochrome P450 enzyme that metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Substrates include alcohol; NITROSAMINES; BENZENE; URETHANE; and other low molecular weight compounds. CYP2E1 has been used as an enzyme marker in the study of alcohol abuse.
Cytochrome P-450 Cyp27a1
An NAPH-dependent cytochrome P450 enzyme that catalyzes the oxidation of the side chain of sterol intermediates such as the 27-hydroxylation of 5-beta-cholestane-3-alpha,7-alpha, 12-alpha-triol. Cytochrome P-450 CYP27A1 is a mitochondrial enzyme; however microsomal-derived homologs of the enzyme have been identified and are included under this heading.
An allylic compound that acts as a suicide inactivator of CYTOCHROME P450 by covalently binding to its heme moiety or surrounding protein.
An NADPH-dependent P450 enzyme that plays an essential role in the sterol biosynthetic pathway by catalyzing the demethylation of 14-methyl sterols such as lanosterol. The enzyme acts via the repeated hydroxylation of the 14-methyl group, resulting in its stepwise conversion into an alcohol, an aldehyde and then a carboxylate, which is removed as formic acid. Sterol 14-demethylase is an unusual cytochrome P450 enzyme in that it is found in a broad variety of organisms including ANIMALS; PLANTS; FUNGI; and protozoa.
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