3BAR

Crystal structure of Plasmodium falciparum orotidine 5'-phosphate decarboxylase covalently modified by 6-azido-UMP

Summary for 3BAR

• Entry DOI: 10.2210/pdb3bar/pdb
• Related: 2Q8L 2Q8Z 2QAF
• Descriptor: Orotidine 5'-phosphate decarboxylase, URIDINE-5'-MONOPHOSPHATE (3 entities in total)
• Functional Keywords: plasmodium falciparum, orotidine 5'-phosphate decarboxylase, covalently, 6-azido-ump, lyase, pyrimidine biosynthesis
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 80447.28

Authors

Liu, Y.,Bello, A.M.,Poduch, E.,Lau, W.,Kotra, L.P.,Pai, E.F. (deposition date: 2007-11-08, release date: 2008-01-29, Last modification date: 2024-11-20)

Primary citation

Bello, A.M.,Poduch, E.,Liu, Y.,Wei, L.,Crandall, I.,Wang, X.,Dyanand, C.,Kain, K.C.,Pai, E.F.,Kotra, L.P.
Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate Decarboxylase.
J.Med.Chem., 51:439-448, 2008

PubMed Abstract: Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities.

PubMed: 18189347
DOI: 10.1021/jm7010673

Experimental method

X-RAY DIFFRACTION (1.9 Å)