A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity.

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.

• Authors: Angelica M Bello, Ewa Poduch, Masahiro Fujihashi, Merhnaz Amani, Yan Li, Ian Crandall, Raymond Hui, Ping I Lee, Kevin C Kain, Emil F Pai, Lakshmi P Kotra
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 5 Pg. 915-21 (Mar 08 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17290979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 6-iodouridine
• 6-iodouridine 5'-monophosphate
• Antimalarials
• Uridine Monophosphate
• Orotidine-5'-Phosphate Decarboxylase
• Uridine

Topics

• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• CHO Cells
• Cricetinae
• Cricetulus
• Crystallography, X-Ray
• Mass Spectrometry
• Methanobacterium (enzymology)
• Models, Molecular
• Orotidine-5'-Phosphate Decarboxylase (antagonists & inhibitors, chemistry)
• Plasmodium falciparum (drug effects, enzymology, isolation & purification)
• Stereoisomerism
• Structure-Activity Relationship
• Uridine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Uridine Monophosphate (analogs & derivatives, chemical synthesis, chemistry, pharmacology)