Substrate Spectra of Nucleoside Phosphorylases and their Potential in the Production of Pharmaceutically Active Compounds

Author(s): Heba Yehia, Sarah Kamel, Katharina Paulick, Peter Neubauer, Anke Wagner*.

Journal Name: Current Pharmaceutical Design

Volume 23 , Issue 45 , 2017

Abstract:

Background: Nucleoside phosphorylases catalyze the reversible phosphorolysis of pyrimidine and purine nucleosides in the presence of phosphate. They are relevant to the appropriate function of the immune system in mammals and interesting drug targets for cancer treatment. Next to their role as drug targets nucleoside phosphorylases are used as catalysts in the synthesis of nucleosides and their analogs that are widely applied as pharmaceuticals.

Methods: Based on their substrates nucleoside phosphorylases are classified as pyrimidine and purine nucleoside phosphorylases. This article describes the substrate spectra of nucleoside phosphorylases and structural properties that influence their activity. Substrate ranges are summarized and relations between members of pyrimidine or purine nucleoside phosphorylases are elucidated.

Results: Nucleoside phosphorylases accept a broad spectrum of substrates: they accept both base and sugar modified nucleosides. The most widely studied nucleoside phosphorylases are those of Escherichia coli, mammals and pathogens. However, recently the attention has been shifted to thermophilic nucleoside phosphorylases due to several advantages. Nucleoside phosphorylases have been applied to produce drugs like ribavirin or fludarabine. However, limitations were observed when drugs show an open ring structure. Site-directed mutagenesis approaches were shown to alter the substrate specificity of nucleoside phosphorylases.

Conclusion: Nucleoside phosphorylases are valuable tools to produce modified nucleosides with therapeutic or diagnostic potential with high affinity and specificity. A wide variety of nucleoside phosphorylases are available in nature which differ in their protein sequence and show varying substrate spectra. To overcome limitations of the naturally occurring enzymes site-directed mutagenesis approaches can be used.

Keywords: Nucleoside phosphorylase, pyrimidine analog, purine analog, catalytic mechanism, structure, function, mutagensesis.

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Article Details

VOLUME: 23
ISSUE: 45
Year: 2017
Page: [6913 - 6935]
Pages: 23
DOI: 10.2174/1381612823666171024155811
Price: $58

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