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

J Med Chem. 2007 Mar 8;50(5):915-21. doi: 10.1021/jm060827p. Epub 2007 Feb 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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


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