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| {{STRUCTURE_2qcd| PDB=2qcd | SCENE= }} | | {{STRUCTURE_2qcd| PDB=2qcd | SCENE= }} |
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| '''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to UMP'''
| | ===Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to UMP=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_18184586}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 18184586 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_18184586}} |
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| ==Disease== | | ==Disease== |
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| [[Category: Lyase]] | | [[Category: Lyase]] |
| [[Category: Ump synthase]] | | [[Category: Ump synthase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 14:43:13 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 18:53:56 2008'' |