3G3M

Crystal Structure of Human Orotidine 5'-monophosphate Decarboxylase Covalently Modified by 5-fluoro-6-iodo-UMP

3G3M の概要

• エントリーDOI: 10.2210/pdb3g3m/pdb
• 関連するPDBエントリー: 3G3D
• 分子名称: Uridine 5'-monophosphate synthase, 5-FLUORO-URIDINE-5'-MONOPHOSPHATE (3 entities in total)
• 機能のキーワード: human, orotidine 5'-monophosphate decarboxylase, c-terminal domain, 5-fluoro-6-iodo-ump, alternative splicing, decarboxylase, disease mutation, glycosyltransferase, lyase, multifunctional enzyme, phosphoprotein, polymorphism, pyrimidine biosynthesis, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30830.33

構造登録者

Liu, Y.,Tang, H.L.,Bello, A.M.,Poduch, E.,Kotra, L.P.,Pai, E.F. (登録日: 2009-02-02, 公開日: 2009-03-03, 最終更新日: 2023-09-06)

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 (1.4 Å)