Substrate specificity of pyrimidine nucleoside phosphorylases of NP-II family probed by X-ray crystallography and molecular modeling
- Авторлар: Balaev V.1, Lashkov A.1, Prokofev I.1, Gabdulkhakov A.1, Seregina T.2, Mironov A.2, Betzel C.3, Mikhailov A.1
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Мекемелер:
- Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”
- State Research Institute of Genetics and Selection of Industrial Microorganisms
- University of Hamburg
- Шығарылым: Том 61, № 5 (2016)
- Беттер: 830-841
- Бөлім: Structure of Macromolecular Compounds
- URL: https://journals.rcsi.science/1063-7745/article/view/190316
- DOI: https://doi.org/10.1134/S1063774516050023
- ID: 190316
Дәйексөз келтіру
Аннотация
Pyrimidine nucleoside phosphorylases, which are widely used in the biotechnological production of nucleosides, have different substrate specificity for pyrimidine nucleosides. An interesting feature of these enzymes is that the three-dimensional structure of thymidine-specific nucleoside phosphorylase is similar to the structure of nonspecific pyrimidine nucleoside phosphorylase. The three-dimensional structures of thymidine phosphorylase from Salmonella typhimurium and nonspecific pyrimidine nucleoside phosphorylase from Bacillus subtilis in complexes with a sulfate anion were determined for the first time by X-ray crystallography. An analysis of the structural differences between these enzymes demonstrated that Lys108, which is involved in the phosphate binding in pyrimidine nucleoside phosphorylase, corresponds to Met111 in thymidine phosphorylases. This difference results in a decrease in the charge on one of the hydroxyl oxygens of the phosphate anion in thymidine phosphorylase and facilitates the catalysis through SN2 nucleophilic substitution. Based on the results of X-ray crystallography, the virtual screening was performed for identifying a potent inhibitor (anticancer agent) of nonspecific pyrimidine nucleoside phosphorylase, which does not bind to thymidine phosphorylase. The molecular dynamics simulation revealed the stable binding of the discovered compound—2-pyrimidin-2-yl-1H-imidazole-4-carboxylic acid—to the active site of pyrimidine nucleoside phosphorylase.
Авторлар туралы
V. Balaev
Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”
Email: alashkov83@gmail.com
Ресей, Leninskii pr. 59, Moscow, 119333
A. Lashkov
Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”
Хат алмасуға жауапты Автор.
Email: alashkov83@gmail.com
Ресей, Leninskii pr. 59, Moscow, 119333
I. Prokofev
Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”
Email: alashkov83@gmail.com
Ресей, Leninskii pr. 59, Moscow, 119333
A. Gabdulkhakov
Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”
Email: alashkov83@gmail.com
Ресей, Leninskii pr. 59, Moscow, 119333
T. Seregina
State Research Institute of Genetics and Selection of Industrial Microorganisms
Email: alashkov83@gmail.com
Ресей, Pervyi Dorozhnyi proezd 1, Moscow, 117545
A. Mironov
State Research Institute of Genetics and Selection of Industrial Microorganisms
Email: alashkov83@gmail.com
Ресей, Pervyi Dorozhnyi proezd 1, Moscow, 117545
C. Betzel
University of Hamburg
Email: alashkov83@gmail.com
Германия, Mittelweg 177, Hamburg, 20148
A. Mikhailov
Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”
Email: alashkov83@gmail.com
Ресей, Leninskii pr. 59, Moscow, 119333