View source for 1xk2


==NADPH- and Ascorbate-Supported Heme Oxygenase Reactions are Distinct. Regiospecificity of Heme Cleavage by the R183E Mutant==
<StructureSection load='1xk2' size='340' side='right'caption='[[1xk2]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1xk2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XK2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XK2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1xk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xk2 OCA], [https://pdbe.org/1xk2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xk2 RCSB], [https://www.ebi.ac.uk/pdbsum/1xk2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xk2 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HMOX1_HUMAN HMOX1_HUMAN] Defects in HMOX1 are the cause of heme oxygenase 1 deficiency (HMOX1D) [MIM:[https://omim.org/entry/614034 614034]. A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly.<ref>PMID:9884342</ref> 
== Function ==
[https://www.uniprot.org/uniprot/HMOX1_HUMAN HMOX1_HUMAN] Heme oxygenase cleaves the heme ring at the alpha methene bridge to form biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under physiological conditions, the activity of heme oxygenase is highest in the spleen, where senescent erythrocytes are sequestrated and destroyed.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xk/1xk2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1xk2 ConSurf].
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== Publication Abstract from PubMed ==
The ability of the human heme oxygenase-1 (hHO-1) R183E mutant to oxidize heme in reactions supported by either NADPH-cytochrome P450 reductase or ascorbic acid has been compared. The NADPH-dependent reaction, like that of wild-type hHO-1, yields exclusively biliverdin IXalpha. In contrast, the R183E mutant with ascorbic acid as the reductant produces biliverdin IXalpha (79 +/- 4%), IXdelta (19 +/- 3%), and a trace of IXbeta. In the presence of superoxide dismutase and catalase, the yield of biliverdin IXdelta is decreased to 8 +/- 1% with a corresponding increase in biliverdin IXalpha. Spectroscopic analysis of the NADPH-dependent reaction shows that the R183E ferric biliverdin complex accumulates, because reduction of the iron, which is required for sequential iron and biliverdin release, is impaired. Reversal of the charge at position 183 makes reduction of the iron more difficult. The crystal structure of the R183E mutant, determined in the ferric and ferrous-NO bound forms, shows that the heme primarily adopts the same orientation as in wild-type hHO-1. The structure of the Fe(II).NO complex suggests that an altered active site hydrogen bonding network supports catalysis in the R183E mutant. Furthermore, Arg-183 contributes to the regiospecificity of the wild-type enzyme, but its contribution is not critical. The results indicate that the ascorbate-dependent reaction is subject to a lower degree of regiochemical control than the NADPH-dependent reaction. Ascorbate may be able to reduce the R183E ferric and ferrous dioxygen complexes in active site conformations that cannot be reduced by NADPH-cytochrome P450 reductase.

Regiospecificity determinants of human heme oxygenase: differential NADPH- and ascorbate-dependent heme cleavage by the R183E mutant.,Wang J, Lad L, Poulos TL, Ortiz de Montellano PR J Biol Chem. 2005 Jan 28;280(4):2797-806. Epub 2004 Nov 3. PMID:15525643<ref>PMID:15525643</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Heme oxygenase 3D structures|Heme oxygenase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lad L]]
[[Category: Ortiz de montellano PR]]
[[Category: Poulos TL]]
[[Category: Wang J]]