2E6Y

Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP

Summary for 2E6Y

• Entry DOI: 10.2210/pdb2e6y/pdb
• Related: 1dv7 1dvj 1kly 1klz 1km0 1km1 1km2 1km3 1km4 1km5 1km6 1lol 1loq 1lor 1los 1lp6 1x1z
• Descriptor: Orotidine 5'-phosphate decarboxylase, URIDINE-5'-MONOPHOSPHATE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: tim-barrel, lyase
• Biological source: Methanothermobacter thermautotrophicus
• Total number of polymer chains: 2
• Total formula weight: 55775.54

Authors

Fujihashi, M.,Bello, A.M.,Kotra, L.P.,Pai, E.F. (deposition date: 2007-01-05, release date: 2007-02-27, Last modification date: 2024-10-23)

Primary citation

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.
A Potent, Covalent Inhibitor of Orotidine 5'-Monophosphate Decarboxylase with Antimalarial Activity.
J.Med.Chem., 50:915-921, 2007

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.

PubMed: 17290979
DOI: 10.1021/jm060827p

Experimental method

X-RAY DIFFRACTION (1.6 Å)