X-ray structure of Salmonella typhimurium uridine phosphorylase complexed with 5-fluorouracil and molecular modelling of the complex of 5-fluorouracil with uridine phosphorylase from Vibrio cholerae

Uridine phosphorylase (UPh), which is a key enzyme in the reutilization pathway of pyrimidine nucleoside metabolism, is a validated target for the treatment of infectious diseases and cancer. A detailed analysis of the interactions of UPh with the therapeutic ligand 5‐fluorouracil (5‐FUra) is import...

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Published in:Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2012-08, Vol.68 (8), p.968-974
Main Authors: Lashkov, Alexander A., Sotnichenko, Sergey E., Prokofiev, Igor I., Gabdulkhakov, Azat G., Agapov, Igor I., Shtil, Alexander A., Betzel, Christian, Mironov, Alexander S., Mikhailov, Al'bert M.
Format: Article
Language:English
Subjects:
5-fluorouracil
Atomic structure
bacterial uridine phosphorylases
Catalysis
Catalytic Domain
Cholera
Cluster Analysis
Design engineering
Enzyme Inhibitors - pharmacology
Enzymes
Fluorouracil - pharmacology
Inhibitors
Ligands
Microbiology
molecular docking
Phosphorylases
Protein Binding
Protein Conformation
Protein Structure, Secondary
Protein Structure, Tertiary
Salmonella
Salmonella typhimurium
Salmonella typhimurium - enzymology
Solvents
Uridine Phosphorylase - chemistry
Vibrio
Vibrio cholerae
Vibrio cholerae - enzymology
X-rays
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Summary:Uridine phosphorylase (UPh), which is a key enzyme in the reutilization pathway of pyrimidine nucleoside metabolism, is a validated target for the treatment of infectious diseases and cancer. A detailed analysis of the interactions of UPh with the therapeutic ligand 5‐fluorouracil (5‐FUra) is important for the rational design of pharmacological inhibitors of these enzymes in prokaryotes and eukaryotes. Expanding on the preliminary analysis of the spatial organization of the active centre of UPh from the pathogenic bacterium Salmonella typhimurium (StUPh) in complex with 5‐FUra [Lashkov et al. (2009), Acta Cryst. F65, 601–603], the X‐ray structure of the StUPh–5‐FUra complex was analysed at atomic resolution and an in silico model of the complex formed by the drug with UPh from Vibrio cholerae (VchUPh) was generated. These results should be considered in the design of selective inhibitors of UPhs from various species.
ISSN:1399-0047
0907-4449
1399-0047
DOI:10.1107/S090744491201815X