title: Oxidation of the meso-methylmesoheme regioisomers by heme oxygenase. Electronic control of the reaction regiospecificity.
abstract: The oxidation of heme by heme oxygenase (HO-1) results in highly regiospecific extrusion of the alpha-meso-carbon as CO and the formation of biliverdin IXalpha. The first step in the accepted mechanism for this process is alpha-meso-hydroxylation of the heme. To define further the reaction mechanism, the oxidations of the four isomers of meso-methylmesoheme by human truncated HO-1 supported by NADPH-cytochrome P450 reductase, H2O2, or ascorbate have been examined. Surprisingly, the results establish that (a) HO-1 can oxidize an alpha-meso-methyl-substituted heme to biliverdin IXalpha without proceeding via the alpha-meso-hydroxy intermediate; (b) the normal HO-1 alpha-regiospecificity is inverted in favor of the substituted gamma-position by introduction of a gamma-meso methyl group; and (c) the beta- and delta-meso-methylmesohemes are oxidized less regiospecifically to mixtures of methyl-substituted and -unsubstituted mesobiliverdins. The results indicate that electronic rather than steric effects primarily control the regiospecificity of heme cleavage by HO-1.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, and Liver Center, University of California, San Francisco, 94143-0446, USA.
authors.forename: J
authors.initials: J
authors.lastname: Torpey
authors.forename: P R
authors.initials: PR
authors.lastname: Ortiz de Montellano
mesh_terms: D001205:Ascorbic Acid / Q000378:metabolism; D001664:Biliverdine / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006418:Heme / Q000031:analogs & derivatives* / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007536:Isomerism; D008652:Mesoporphyrins / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D013054:Spectrophotometry, Atomic
chemical_list: D008652:Mesoporphyrins; C101873:methylmesoheme; C065420:N-methylmesoporphyrin IX; D006418:Heme; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D009251:NADPH-Ferrihemoprotein Reductase; D001664:Biliverdine; D001205:Ascorbic Acid