2qcn
From Proteopedia
(New page: 200px<br /><applet load="2qcn" size="350" color="white" frame="true" align="right" spinBox="true" caption="2qcn, resolution 1.85Å" /> '''Covalent complex of ...) |
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==Overview== | ==Overview== | ||
| - | UMP synthase (UMPS) catalyzes the last two steps of de novo pyrimidine | + | 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. |
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| + | ==Disease== | ||
| + | Known disease associated with this structure: Oroticaciduria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=258900 258900]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: ump synthase]] | [[Category: ump synthase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:38:10 2008'' |
Revision as of 16:38, 21 February 2008
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Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP
Contents |
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:[258900]
About this Structure
2QCN is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Full crystallographic information is available from 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:18184586
Page seeded by OCA on Thu Feb 21 18:38:10 2008
Categories: Homo sapiens | Orotidine-5'-phosphate decarboxylase | Single protein | Rudolph, M. | Wittmann, J. | GOL | SO4 | U5P | Alternative splicing | Catalytic proficiency | Decarboxylase | Disease mutation | Glycosyltransferase | Lyase | Multifunctional enzyme | Polymorphism | Pyrimidine biosynthesis | Transferase | Ump synthase
