A Potent, Covalent Inhibitor of Orotidine 5'-Monophosphate Decarboxylase with Antimalarial Activity
详细信息 查看全文
- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 8, 2007
- 年：2007
- 卷：50
- 期：5
- 页码：915 - 921
- 全文大小：319K
- 年卷期：v.50,no.5(March 8, 2007)
- ISSN：1520-4804
文摘
Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine5'-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in anextensive hydrogen-bonding network. We discovered that 6-iodouridine 5'-monophosphate (6-iodo-UMP)irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum andPlasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalentattachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. TheX-ray crystal structure (1.6 Å resolution) of the complex of the inhibitor and ODCase clearly shows thecovalent bond formation with the active site Lys-42 residue. 6-Iodo-UMP inhibits ODCase in a time- andconcentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potentantiplasmodial activity, with IC50s of 4.4 ± 1.3 
M and 6.2 ± 0.7 M against P. falciparum ItG and 3D7isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and itsnucleoside analogue paves the way to a new class of inhibitors against malaria.
M and 6.2 ± 0.7 M against P. falciparum ItG and 3D7isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and itsnucleoside analogue paves the way to a new class of inhibitors against malaria.