A Potent, Covalent Inhibitor of Orotidine 5'-Monophosphate Decarboxylase with Antimalarial Activity.
Bello, A.M., Poduch, E., Fujihashi, M., Amani, M., Li, Y., Crandall, I., Hui, R., Lee, P.I., Kain, K.C., Pai, E.F., Kotra, L.P.(2007) J Med Chem 50: 915-921
- PubMed: 17290979 
- DOI: https://doi.org/10.1021/jm060827p
- Primary Citation of Related Structures:  
2E6Y - PubMed 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 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.
Organizational Affiliation: 
Center for Molecular Design and Preformulations, Toronto General Research Institute, Toronto General Hospital, Toronto, ON M5G 2C4 Canada.