| Structural highlights
2e6y is a 2 chain structure with sequence from Methanothermobacter thermautotrophicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | ,
| | Related: | 1dv7, 1dvj, 1kly, 1klz, 1km0, 1km1, 1km2, 1km3, 1km4, 1km5, 1km6, 1lol, 1loq, 1lor, 1los, 1lp6, 1x1z |
| Gene: | pyrF (Methanothermobacter thermautotrophicus) |
| Activity: | Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity.,Bello AM, Poduch E, Fujihashi M, Amani M, Li Y, Crandall I, Hui R, Lee PI, Kain KC, Pai EF, Kotra LP J Med Chem. 2007 Mar 8;50(5):915-21. Epub 2007 Feb 10. PMID:17290979[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bello AM, Poduch E, Fujihashi M, Amani M, Li Y, Crandall I, Hui R, Lee PI, Kain KC, Pai EF, Kotra LP. A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity. J Med Chem. 2007 Mar 8;50(5):915-21. Epub 2007 Feb 10. PMID:17290979 doi:10.1021/jm060827p
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