3S9Y

Crystal Structure of P. falciparum orotidine 5'-monophosphate decarboxylase complexed with 5-fluoro-6-amino-UMP in space group P21, produced from 5-fluoro-6-azido-UMP

Summary for 3S9Y

• Entry DOI: 10.2210/pdb3s9y/pdb
• Related: 2Q8L 2Q8Z 2QAF 3BAR 3BPW 3MWA 3N34
• Descriptor: Orotidine 5'-phosphate decarboxylase, 6-amino-5-fluorouridine 5'-(dihydrogen phosphate), SULFATE ION, ... (7 entities in total)
• Functional Keywords: p. falciparum, orotidine 5'-monophosphate decarboxylase, 5-fluoro-6-amino-ump, 5-fluoro-6-azido-ump, decarboxylase, lyase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 4
• Total formula weight: 161943.59

Authors

Liu, Y.,Kotra, L.P.,Pai, E.F. (deposition date: 2011-06-02, release date: 2012-04-18, Last modification date: 2023-09-13)

Primary citation

Bello, A.M.,Konforte, D.,Poduch, E.,Furlonger, C.,Wei, L.,Liu, Y.,Lewis, M.,Pai, E.F.,Paige, C.J.,Kotra, L.P.
Structure-activity relationships of orotidine-5'-monophosphate decarboxylase inhibitors as anticancer agents.
J.Med.Chem., 52:1648-1658, 2009

PubMed Abstract: A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorouridine derivatives. The mononucleotide derivatives were used for enzyme inhibition investigations against ODCase. Anticancer activities of all the synthesized derivatives were evaluated using the nucleoside forms of the inhibitors. 5-Fluoro-UMP was a very weak inhibitor of ODCase. 6-Azido-5-fluoro and 5-fluoro-6-iodo derivatives are covalent inhibitors of ODCase, and the active site Lys145 residue covalently binds to the ligand after the elimination of the 6-substitution. Among the synthesized nucleoside derivatives, 6-azido-5-fluoro, 6-amino-5-fluoro, and 6-carbaldehyde-5-fluoro derivatives showed potent anticancer activities in cell-based assays against various leukemia cell lines. On the basis of the overall profile, 6-azido-5-fluoro and 6-amino-5-fluoro uridine derivatives exhibited potential for further investigations.

PubMed: 19260677
DOI: 10.1021/jm801224t

Experimental method

X-RAY DIFFRACTION (1.7 Å)