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'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP''' | '''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP''' | ||
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[[Category: Rudolph, M.]] | [[Category: Rudolph, M.]] | ||
[[Category: Wittmann, J.]] | [[Category: Wittmann, J.]] | ||
[[Category: | [[Category: Catalytic proficiency]] | ||
[[Category: | [[Category: Decarboxylase]] | ||
[[Category: | [[Category: Lyase]] | ||
[[Category: | [[Category: Ump synthase]] | ||
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Revision as of 14:43, 4 May 2008
Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Oroticaciduria OMIM:[258900]
About this StructureAbout this Structure
2QCF is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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:18184586 Page seeded by OCA on Sun May 4 14:43:27 2008