PDBsum entry 2qcc

Lyase

PDB id: 2qcc

Contents

Protein chains

248 a.a. *

Ligands

SO4 ×2

GOL ×2

Waters ×305

* Residue conservation analysis

PDB id:

2qcc

Name:

Lyase

Title:

Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human ump synthase, apo form

Structure:

Orotidine 5'- phosphate decarboxylase (ompdecase). Chain: a, b. Fragment: c-terminal domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: umps. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.85Å R-factor: 0.200 R-free: 0.258

Authors:

J.Wittmann,M.Rudolph

Key ref:

J.G.Wittmann et al. (2008). Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design. Structure, 16, 82-92. PubMed id: 18184586 DOI: 10.1016/j.str.2007.10.020

Date:

19-Jun-07 Release date: 06-Nov-07

Protein chains

P11172  (UMPS_HUMAN) -  Uridine 5'-monophosphate synthase from Homo sapiens

Seq: 480 a.a.

Struc: 248 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.4.2.10 - orotate phosphoribosyltransferase.
• Pathway: Pyrimidine Biosynthesis
• Reaction: orotidine 5'-phosphate + diphosphate = orotate + 5-phospho-alpha-D-ribose 1-diphosphate
• Enzyme class 2: E.C.4.1.1.23 - orotidine-5'-phosphate decarboxylase.

Pathway:

• Reaction: orotidine 5'-phosphate + H⁺ = UMP + CO2

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.str.2007.10.020

Structure 16:82-92 (2008)

PubMed id: 18184586

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

J.G.Wittmann, D.Heinrich, K.Gasow, A.Frey, U.Diederichsen, M.G.Rudolph.

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.

Selected figure(s)

Figure 1.
Figure 1. UMPS Domain Structure and OMPD Biochemistry
(A) Reaction catalyzed by OMPD.
(B) Turnover of OMP substrate by wild-type OMPD (black) is abolished in the Asp312Asn mutant (red). If the detection limit of the assay is assumed to be 5% of the total signal over 4000 s, the Asp312Asn mutant is at least 1300-fold less active than the wild-type.
(C) Michaelis-Menten kinetics of wild-type OMPD at 25°C.
(D) OMPD is an obligatory dimer of high affinity.

Figure 4.
Figure 4. Substrate Binding to OMPD
(A and B) Stereo representation of the Asp312Asn OMPD-OMP complex showing a bent carboxylate group.
(C and D) Stereo representation of the Asp312Asn 6-HMUMP-OMPD complex. The hydroxymethyl group is also bent out of plane, indicating that electrostatic repulsion by Asp317b is not responsible for substrate deformation.

The above figures are reprinted by permission from Cell Press: Structure (2008, 16, 82-92) copyright 2008.

Figures were selected by an automated process.