2QCN

Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP

Summary for 2QCN

• Entry DOI: 10.2210/pdb2qcn/pdb
• Related: 2JGY 2QCC 2QCD 2QCE 2QCF 2QCG 2QCH 2QCL 2QCM 2V30
• Descriptor: Uridine 5'-monophosphate synthase, SULFATE ION, URIDINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: ump synthase, decarboxylase, catalytic proficiency, disease mutation, glycosyltransferase, lyase, multifunctional enzyme, pyrimidine biosynthesis, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 57528.10

Authors

Wittmann, J.,Rudolph, M. (deposition date: 2007-06-19, release date: 2007-11-13, Last modification date: 2024-10-30)

Primary citation

Wittmann, J.G.,Heinrich, D.,Gasow, K.,Frey, A.,Diederichsen, U.,Rudolph, M.G.
Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design.
Structure, 16:82-92, 2008

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.

PubMed: 18184586
DOI: 10.1016/j.str.2007.10.020

Experimental method

X-RAY DIFFRACTION (1.85 Å)