Download MendeleyStructures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design.
Wittmann, J.G., Heinrich, D., Gasow, K., Frey, A., Diederichsen, U., Rudolph, M.G.(2008) Structure 16: 82-92
- PubMed: 18184586
- DOI: https://doi.org/10.1016/j.str.2007.10.020
- Primary Citation of Related Structures:
2QCC, 2QCD, 2QCE, 2QCF, 2QCG, 2QCH, 2QCL, 2QCM, 2QCN - PubMed 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.
Organizational Affiliation:
Department of Molecular Structural Biology, University of G?ttingen, G?ttingen, Germany.
