1s13: Difference between revisions
New page: left|200px<br /> <applet load="1s13" size="450" color="white" frame="true" align="right" spinBox="true" caption="1s13, resolution 2.29Å" /> '''Human Heme Oxygenas... |
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[[Image:1s13.gif|left|200px]]<br /> | [[Image:1s13.gif|left|200px]]<br /><applet load="1s13" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1s13, resolution 2.29Å" /> | caption="1s13, resolution 2.29Å" /> | ||
'''Human Heme Oxygenase Oxidatition of alpha- and gamma-meso-Phenylhemes'''<br /> | '''Human Heme Oxygenase Oxidatition of alpha- and gamma-meso-Phenylhemes'''<br /> | ||
==Overview== | ==Overview== | ||
Human heme oxygenase-1 (hHO-1) catalyzes the O2-dependent oxidation of | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1S13 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 2FH as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Heme_oxygenase Heme oxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.3 1.14.99.3] Full crystallographic information is available from [http:// | 1S13 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=2FH:'>2FH</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Heme_oxygenase Heme oxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.3 1.14.99.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1S13 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Buldain, G.]] | [[Category: Buldain, G.]] | ||
[[Category: Lad, L.]] | [[Category: Lad, L.]] | ||
[[Category: Montellano, P | [[Category: Montellano, P R.Ortiz de.]] | ||
[[Category: Niemevz, F.]] | [[Category: Niemevz, F.]] | ||
[[Category: Poulos, T | [[Category: Poulos, T L.]] | ||
[[Category: Wang, J.]] | [[Category: Wang, J.]] | ||
[[Category: 2FH]] | [[Category: 2FH]] | ||
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[[Category: heme oxyhenase-1]] | [[Category: heme oxyhenase-1]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:56:45 2008'' | ||
Revision as of 15:56, 21 February 2008
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Human Heme Oxygenase Oxidatition of alpha- and gamma-meso-Phenylhemes
OverviewOverview
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.
DiseaseDisease
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 StructureAbout this Structure
1S13 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Heme oxygenase, with EC number 1.14.99.3 Full crystallographic information is available from OCA.
ReferenceReference
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
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