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PDBsum entry 3ewu

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protein ligands Protein-protein interface(s) links
Lyase PDB id
3ewu
Jmol
Contents
Protein chains
257 a.a. *
Ligands
GOL
UEP ×2
SO4
Waters ×513
* Residue conservation analysis
PDB id:
3ewu
Name: Lyase
Title: D312n mutant of human orotidyl-5'-monophosphate decarboxylas complex with 6-acetyl-ump, covalent adduct
Structure: Orotidine-5'-phosphate decarboxylase. Chain: a, b. Fragment: unp residues 224-480. Synonym: ompdecase. Engineered: yes. Mutation: yes
Source: Homo sapiens. Organism_taxid: 9606. Gene: umps. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.60Å     R-factor:   0.165     R-free:   0.196
Authors: D.Heinrich,J.Wittmann,U.Diederichsen,M.Rudolph
Key ref: D.Heinrich et al. (2009). Lys314 is a nucleophile in non-classical reactions of orotidine-5'-monophosphate decarboxylase. Chemistry, 15, 6619-6625. PubMed id: 19472232
Date:
16-Oct-08     Release date:   07-Apr-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P11172  (UMPS_HUMAN) -  Uridine 5'-monophosphate synthase
Seq:
Struc:
480 a.a.
257 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.2.4.2.10  - Orotate phosphoribosyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Pyrimidine Biosynthesis
      Reaction: Orotidine 5'-phosphate + diphosphate = orotate + 5-phospho-alpha-D-ribose 1-diphosphate
Orotidine 5'-phosphate
Bound ligand (Het Group name = UEP)
matches with 88.00% similarity
+ diphosphate
= orotate
+ 5-phospho-alpha-D-ribose 1-diphosphate
   Enzyme class 2: E.C.4.1.1.23  - Orotidine-5'-phosphate decarboxylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: Orotidine 5'-phosphate = UMP + CO2
Orotidine 5'-phosphate
=
UMP
Bound ligand (Het Group name = UEP)
matches with 91.30% similarity
+ CO(2)
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   3 terms 
  Biochemical function     catalytic activity     2 terms  

 

 
    reference    
 
 
Chemistry 15:6619-6625 (2009)
PubMed id: 19472232  
 
 
Lys314 is a nucleophile in non-classical reactions of orotidine-5'-monophosphate decarboxylase.
D.Heinrich, U.Diederichsen, M.G.Rudolph.
 
  ABSTRACT  
 
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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20424759 S.Thirumalairajan, B.Mahaney, and S.L.Bearne (2010).
Interrogation of the active site of OMP decarboxylase from Escherichia coli with a substrate analogue bearing an anionic group at C6.
  Chem Commun (Camb), 46, 3158-3160.  
20498911 Y.J.Wu, C.C.Liao, C.H.Jen, Y.C.Shih, and T.C.Chien (2010).
Chemical models and their mechanistic implications for the transformation of 6-cyanouridine 5'-monophosphate catalyzed by orotidine 5'-monophosphate decarboxylase.
  Chem Commun (Camb), 46, 4821-4823.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.