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3eww

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D312N mutant of human orotidyl-5'-monophosphate decarboxylase in complex with 6-cyano-UMP, covalent adduct

Structural highlights

3eww is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.1Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

UMPS_HUMAN Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM: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.^[1]

Function

UMPS_HUMAN

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Suchi M, Mizuno H, Kawai Y, Tsuboi T, Sumi S, Okajima K, Hodgson ME, Ogawa H, Wada Y. Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. Am J Hum Genet. 1997 Mar;60(3):525-39. PMID:9042911
↑ Heinrich D, Diederichsen U, Rudolph MG. Lys314 is a nucleophile in non-classical reactions of orotidine-5'-monophosphate decarboxylase. Chemistry. 2009 Jul 6;15(27):6619-25. PMID:19472232 doi:10.1002/chem.200900397

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3eww"

@@ Line 3: / Line 3: @@
 <StructureSection load='3eww' size='340' side='right'caption='[[3eww]], [[Resolution|resolution]] 1.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3eww]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EWW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3eww]] 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=3EWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EWW FirstGlance]. <br>
-</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=U1P:6-[(E)-IMINOMETHYL]URIDINE+5-PHOSPHATE'>U1P</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.1&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ewu|3ewu]], [[3ewx|3ewx]], [[3ewy|3ewy]], [[3ewz|3ewz]], [[3ex0|3ex0]], [[3ex1|3ex1]], [[3ex2|3ex2]], [[3ex3|3ex3]], [[3ex4|3ex4]], [[3ex5|3ex5]], [[3ex6|3ex6]]</div></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=U1P:6-[(E)-IMINOMETHYL]URIDINE+5-PHOSPHATE'>U1P</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UMPS ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] </span></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=3eww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eww OCA], [https://pdbe.org/3eww PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3eww RCSB], [https://www.ebi.ac.uk/pdbsum/3eww PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3eww 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>
+[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]]
@@ Line 35: / Line 35: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Orotidine-5'-phosphate decarboxylase]]
+[[Category: Diederichsen U]]
-[[Category: Diederichsen, U]]
+[[Category: Heinrich D]]
-[[Category: Heinrich, D]]
+[[Category: Rudolph M]]
-[[Category: Rudolph, M]]
+[[Category: Wittmann J]]
-[[Category: Wittmann, J]]
-[[Category: Decarboxylase]]
-[[Category: Disease mutation]]
-[[Category: Glycosyltransferase]]
-[[Category: Lyase]]
-[[Category: Multifunctional enzyme]]
-[[Category: Pyrimidine biosynthesis]]
-[[Category: Tim barrel]]
-[[Category: Transferase]]
-[[Category: Unusual catalysis]]

3eww

From Proteopedia

Current revision

D312N mutant of human orotidyl-5'-monophosphate decarboxylase in complex with 6-cyano-UMP, covalent adduct

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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