View source for 3ewu


==D312N mutant of human orotidyl-5'-monophosphate decarboxylase in complex with 6-acetyl-UMP, covalent adduct==
<StructureSection load='3ewu' size='340' side='right'caption='[[3ewu]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3ewu]] 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=3EWU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EWU 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]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UEP:6-ETHYLURIDINE+5-PHOSPHATE'>UEP</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=3ewu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ewu OCA], [https://pdbe.org/3ewu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ewu RCSB], [https://www.ebi.ac.uk/pdbsum/3ewu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ewu ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:[https://omim.org/entry/258900 258900]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies.<ref>PMID:9042911</ref> 
== Function ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN] 
== 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/ew/3ewu_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=3ewu ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Orotidine-5'-monophosphate decarboxylase (OMPD) catalyzes the decarboxylation of orotidine-5'-monophosphate (OMP) to uridine-5'-monophosphate (UMP) in an extremely proficient manner. The reaction does not require any cofactors and proceeds by an unknown mechanism. In addition to decarboxylation, OMPD is able to catalyze other reactions. We show that several C6-substituted UMP derivatives undergo hydrolysis or substitution reactions that depend on a lysine residue (Lys314) in the OMPD active site. 6-Cyano-UMP is converted to UMP, and UMP derivatives with good leaving groups inhibit OMPD by a suicide mechanism in which Lys314 covalently binds to the substrate. These non-classical reactivities of human OMPD were characterized by cocrystallization and freeze-trapping experiments with wild-type OMPD and two active-site mutants by using substrate and inhibitor nucleotides. The structures show that the C6-substituents are not coplanar with the pyrimidine ring. The extent of this substrate distortion is a function of the substituent geometry. Structure-based mechanisms for the reaction of 6-substituted UMP derivatives are extracted in accordance with results from mutagenesis, mass spectrometry, and OMPD enzyme activity. The Lys314-based mechanisms explain the chemodiversity of OMPD, and offer a strategy to design mechanism-based inhibitors that could be used for antineoplastic purposes for example.

Lys314 is a nucleophile in non-classical reactions of orotidine-5'-monophosphate decarboxylase.,Heinrich D, Diederichsen U, Rudolph MG Chemistry. 2009 Jul 6;15(27):6619-25. PMID:19472232<ref>PMID:19472232</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3ewu" style="background-color:#fffaf0;"></div>

==See Also==
*[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Diederichsen U]]
[[Category: Heinrich D]]
[[Category: Rudolph M]]
[[Category: Wittmann J]]