View source for 2qcf

[[Image:2qcf.jpg|left|200px]]

 {{Structure
|PDB= 2qcf |SIZE=350|CAPTION= <scene name='initialview01'>2qcf</scene>, resolution 1.22&Aring;
|SITE= <scene name='pdbsite=AC1:5fu+Binding+Site+For+Residue+A+501'>AC1</scene> and <scene name='pdbsite=AC2:Gol+Binding+Site+For+Residue+A+502'>AC2</scene>
|LIGAND= <scene name='pdbligand=S:SULFUR+ATOM'>S</scene>, <scene name='pdbligand=5FU:5-FLUORO-URIDINE-5'-MONOPHOSPHATE'>5FU</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
|ACTIVITY= [http://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] 
|GENE= UMPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
}}

'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP'''


==Overview==
UMP synthase (UMPS) catalyzes the last two steps of de novo pyrimidine nucleotide synthesis and is a potential cancer drug target. The C-terminal domain of UMPS is orotidine-5'-monophosphate decarboxylase (OMPD), a cofactor-less yet extremely efficient enzyme. Studies of OMPDs from micro-organisms led to the proposal of several noncovalent decarboxylation mechanisms via high-energy intermediates. We describe nine crystal structures of human OMPD in complex with substrate, product, and nucleotide inhibitors. Unexpectedly, simple compounds can replace the natural nucleotides and induce a closed conformation of OMPD, defining a tripartite catalytic site. The structures outline the requirements drugs must meet to maximize therapeutic effects and minimize cross-species activity. Chemical mimicry by iodide identified a CO(2) product binding site. Plasticity of catalytic residues and a covalent OMPD-UMP complex prompt a reevaluation of the prevailing decarboxylation mechanism in favor of covalent intermediates. This mechanism can also explain the observed catalytic promiscuity of OMPD.

==Disease==
Known disease associated with this structure: Oroticaciduria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=258900 258900]]

==About this Structure==
2QCF is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCF OCA]. 

==Reference==
Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design., Wittmann JG, Heinrich D, Gasow K, Frey A, Diederichsen U, Rudolph MG, Structure. 2008 Jan;16(1):82-92. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18184586 18184586]
[[Category: Homo sapiens]]
[[Category: Orotidine-5'-phosphate decarboxylase]]
[[Category: Single protein]]
[[Category: Rudolph, M.]]
[[Category: Wittmann, J.]]
[[Category: 5FU]]
[[Category: GOL]]
[[Category: S]]
[[Category: catalytic proficiency]]
[[Category: decarboxylase]]
[[Category: lyase]]
[[Category: ump synthase]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:24:20 2008''