Oxidation of the meso-methylmesoheme regioisomers by heme oxygenase. Electronic control of the reaction regiospecificity.

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.