Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design.

Abstract

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.

• Authors: Julia G Wittmann, Daniel Heinrich, Kathrin Gasow, Alexandra Frey, Ulf Diederichsen, Markus G Rudolph
• Journal: Structure (London, England : 1993) (Structure) Vol. 16 Issue 1 Pg. 82-92 (Jan 2008) ISSN: 0969-2126 [Print] United States
• PMID: 18184586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Multienzyme Complexes
• Uracil Nucleotides
• uridine 5'-monophosphate synthase
• Orotate Phosphoribosyltransferase
• Orotidine-5'-Phosphate Decarboxylase

Topics

• Drug Design
• Humans
• Kinetics
• Models, Molecular
• Multienzyme Complexes (chemistry, metabolism)
• Orotate Phosphoribosyltransferase (chemistry, metabolism)
• Orotidine-5'-Phosphate Decarboxylase (chemistry, drug effects, metabolism)
• Protein Conformation
• Uracil Nucleotides (chemistry, metabolism)