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

3S9Y の概要

• エントリーDOI: 10.2210/pdb3s9y/pdb
• 関連するPDBエントリー: 2Q8L 2Q8Z 2QAF 3BAR 3BPW 3MWA 3N34
• 分子名称: Orotidine 5'-phosphate decarboxylase, 6-amino-5-fluorouridine 5'-(dihydrogen phosphate), SULFATE ION, ... (7 entities in total)
• 機能のキーワード: p. falciparum, orotidine 5'-monophosphate decarboxylase, 5-fluoro-6-amino-ump, 5-fluoro-6-azido-ump, decarboxylase, lyase
• 由来する生物種: Plasmodium falciparum
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 161943.59

構造登録者

Liu, Y.,Kotra, L.P.,Pai, E.F. (登録日: 2011-06-02, 公開日: 2012-04-18, 最終更新日: 2023-09-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)