1S13

Human Heme Oxygenase Oxidatition of alpha- and gamma-meso-Phenylhemes

Summary for 1S13

• Entry DOI: 10.2210/pdb1s13/pdb
• Descriptor: Heme oxygenase 1, 2-PHENYLHEME (3 entities in total)
• Functional Keywords: heme oxygenase-1, heme degradation, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Microsome: P09601
• Total number of polymer chains: 2
• Total formula weight: 55182.40

Authors

Wang, J.,Niemevz, F.,Lad, L.,Buldain, G.,Poulos, T.L.,Ortiz de Montellano, P.R. (deposition date: 2004-01-05, release date: 2004-08-24, Last modification date: 2023-08-23)

Primary citation

Wang, J.,Niemevz, F.,Lad, L.,Huang, L.,Alvarez, D.E.,Buldain, G.,Poulos, T.L.,Ortiz de Montellano, P.R.
Human heme oxygenase oxidation of 5- and 15-phenylhemes.
J.Biol.Chem., 279:42593-42604, 2004

PubMed Abstract: Human heme oxygenase-1 (hHO-1) catalyzes the O2-dependent oxidation of heme to biliverdin, CO, and free iron. Previous work indicated that electrophilic addition of the terminal oxygen of the ferric hydroperoxo complex to the alpha-meso-carbon gives 5-hydroxyheme. Earlier efforts to block this reaction with a 5-methyl substituent failed, as the reaction still gave biliverdin IXalpha. Surprisingly, a 15-methyl substituent caused exclusive cleavage at the gamma-meso-rather than at the normal, unsubstituted alpha-meso-carbon. No CO was formed in these reactions, but the fragment cleaved from the porphyrin eluded identification. We report here that hHO-1 cleaves 5-phenylheme to biliverdin IXalpha and oxidizes 15-phenylheme at the alpha-meso position to give 10-phenylbiliverdin IXalpha. The fragment extruded in the oxidation of 5-phenylheme is benzoic acid, one oxygen of which comes from O2 and the other from water. The 2.29- and 2.11-A crystal structures of the hHO-1 complexes with 1- and 15-phenylheme, respectively, show clear electron density for both the 5- and 15-phenyl rings in both molecules of the asymmetric unit. The overall structure of 15-phenylheme-hHO-1 is similar to that of heme-hHO-1 except for small changes in distal residues 141-150 and in the proximal Lys18 and Lys22. In the 5-phenylheme-hHO-1 structure, the phenyl-substituted heme occupies the same position as heme in the heme-HO-1 complex but the 5-phenyl substituent disrupts the rigid hydrophobic wall of residues Met34, Phe214, and residues 26-42 near the alpha-meso carbon. The results provide independent support for an electrophilic oxidation mechanism and support a role for stereochemical control of the reaction regiospecificity.

PubMed: 15297453
DOI: 10.1074/jbc.M406346200

Experimental method

X-RAY DIFFRACTION (2.29 Å)