A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity.
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.
Bello
Angelica M
AM
Center for Molecular Design and Preformulations, Toronto General Research Institute, Toronto General Hospital, Toronto, ON M5G 2C4 Canada.
Poduch
Ewa
E
Fujihashi
Masahiro
M
Amani
Merhnaz
M
Li
Yan
Y
Crandall
Ian
I
Hui
Raymond
R
Lee
Ping I
PI
Kain
Kevin C
KC
Pai
Emil F
EF
Kotra
Lakshmi P
LP
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D013058:Mass Spectrometry; D017014:Methanobacterium / Q000201:enzymology; D008958:Models, Molecular; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C581210:6-iodouridine; C518981:6-iodouridine 5'-monophosphate; D000962:Antimalarials; D014542:Uridine Monophosphate; D009964:Orotidine-5'-Phosphate Decarboxylase; D014529:Uridine