Oxidation of alpha-meso-formylmesoheme by heme oxygenase. Electronic control of the reaction regiospecificity.
The oxidation of heme to biliverdin IXalpha by heme oxygenase involves regiospecific alpha-meso-hydroxylation followed by extrusion of the alpha-meso-carbon as CO. In an earlier study, enzymatic oxidation of the four meso-methylmesoheme isomers suggested that the reaction regiospecificity is sensitive to the electronic properties of the meso-methyl group (Torpey, J. W., and Ortiz de Montellano, P. R. (1996) J. Biol. Chem. 271, 26067-26073), although we could not exclude the possibility that the altered reaction regiochemistry was due to perturbation of the porphyrin structure by the meso-substituent. To examine this possibility, we have synthesized the four meso-formylmesoporphyrin isomers and have examined their oxidation by heme oxygenase. The meso-formyl and meso-methyl substituents differ in that the former is electron withdrawing and the latter is electron donating. In contrast to alpha-meso-methylmesoheme, which is exclusively oxidized at the methyl-substituted position, alpha-meso-formylmesoheme is exclusively oxidized at a non-formyl-substituted meso-carbon. The finding that the methyl and formyl groups channel the reaction regiospecificity in opposite directions establishes that the regiochemistry of the heme oxygenase reaction is primarily under electronic rather than steric control. It also confirms that the oxidation involves electrophilic addition of the oxygen to the porphyrin ring.
Torpey
J
J
Department of Pharmaceutical Chemistry, School of Pharmacy, and Liver Center, University of California, San Francisco, California 94143-0446, USA.
Ortiz de Montellano
P R
PR
D001664:Biliverdine / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007536:Isomerism; D008652:Mesoporphyrins / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase; D010084:Oxidation-Reduction; D013054:Spectrophotometry, Atomic
D008652:Mesoporphyrins; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D009247:NADH, NADPH Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D001664:Biliverdine