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2e6y
From Proteopedia
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Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP
Overview
Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5'-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5'-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 A resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-72 [corrected] residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC50s of 4.4 +/- 1.3 microM and 6.2 +/- 0.7 microM against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.
About this Structure
2E6Y is a Single protein structure of sequence from Methanothermobacter thermautotrophicus with and as ligands. Active as Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Full crystallographic information is available from OCA.
Reference
A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity., Bello AM, Poduch E, Fujihashi M, Amani M, Li Y, Crandall I, Hui R, Lee PI, Kain KC, Pai EF, Kotra LP, J Med Chem. 2007 Mar 8;50(5):915-21. Epub 2007 Feb 10. PMID:17290979
Page seeded by OCA on Thu Feb 21 17:06:43 2008
