Structures of the Human Orotidine-5′-Monophosphate Decarboxylase Support a Covalent Mechanism and Provide a Framework for Drug Design

• Published in: Structure (London) 2008-01, Vol.16 (1), p.82-92
• Main Authors: Wittmann, Julia G., Heinrich, Daniel, Gasow, Kathrin, Frey, Alexandra, Diederichsen, Ulf, Rudolph, Markus G.
• Format: Article
• Language: English
• Subjects: Drug Design; Humans; Kinetics; Models, Molecular; Multienzyme Complexes - chemistry; Multienzyme Complexes - metabolism; Orotate Phosphoribosyltransferase - chemistry; Orotate Phosphoribosyltransferase - metabolism; Orotidine-5'-Phosphate Decarboxylase - chemistry; Orotidine-5'-Phosphate Decarboxylase - drug effects; Orotidine-5'-Phosphate Decarboxylase - metabolism; Protein Conformation; PROTEINS; Uracil Nucleotides - chemistry; Uracil Nucleotides - metabolism
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2007.10.020

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 CO2 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.