A Potent, Covalent Inhibitor of Orotidine 5‘-Monophosphate Decarboxylase with Antimalarial Activity

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Abstract
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 Å resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-42 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 μM and 6.2 ± 0.7 μM 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.