1s13
From Proteopedia
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Human Heme Oxygenase Oxidatition of alpha- and gamma-meso-Phenylhemes
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Overview
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.
Disease
Known diseases associated with this structure: Epiphyseal dysplasia, multiple, 5 OMIM:[602109], Heme oxygenase-1 deficiency OMIM:[141250], Osteoarthritis, hand, susceptibility to OMIM:[602109], Spondyloepimetaphyseal dysplasia OMIM:[602109]
About this Structure
1S13 is a Single protein structure of sequence from Homo sapiens with 2FH as ligand. Active as Heme oxygenase, with EC number 1.14.99.3 Full crystallographic information is available from OCA.
Reference
Human heme oxygenase oxidation of 5- and 15-phenylhemes., Wang J, Niemevz F, Lad L, Huang L, Alvarez DE, Buldain G, Poulos TL, de Montellano PR, J Biol Chem. 2004 Oct 8;279(41):42593-604. Epub 2004 Aug 5. PMID:15297453
Page seeded by OCA on Mon Nov 12 19:09:04 2007
