Hypoxanthine-Guanine Phosphoribosyltransferase Is Dispensable for Mycobacterium smegmatis Viability

Purine metabolism plays a ubiquitous role in the physiology of and other mycobacteria. The purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is essential for growth ; however, its precise role in physiology is unclear. Membrane-permeable prodrugs of specifically designed H...

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Bibliographic Details
Published in:Journal of bacteriology 2020-02, Vol.202 (5)
Main Authors: Knejzlík, Zdeněk, Herkommerová, Klára, Hocková, Dana, Pichová, Iva
Format: Article
Language:English
Subjects:
Antimicrobial activity
Bacteriology
Chemical compounds
Data points
Drugs
Enzymes
Guanine
Hypoxanthine
Inhibitors
Metabolism
Mycobacterium smegmatis
Phosphoribosyltransferase
Physiology
Prodrugs
Tuberculosis
Viability
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Summary:Purine metabolism plays a ubiquitous role in the physiology of and other mycobacteria. The purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is essential for growth ; however, its precise role in physiology is unclear. Membrane-permeable prodrugs of specifically designed HGPRT inhibitors arrest the growth of and represent potential new antituberculosis compounds. Here, we investigated the purine salvage pathway in the model organism Using genomic deletion analysis, we confirmed that HGPRT is the only guanine and hypoxanthine salvage enzyme in but is not required for growth of this mycobacterium or survival under long-term stationary-phase conditions. We also found that prodrugs of HGPRT inhibitors displayed an unexpected antimicrobial activity against that is independent of HGPRT. Our data point to a different mode of mechanism of action for these inhibitors than was originally proposed. Purine bases, released by the hydrolytic and phosphorolytic degradation of nucleic acids and nucleotides, can be salvaged and recycled. The hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which catalyzes the formation of guanosine-5'-monophosphate from guanine and inosine-5'-monophosphate from hypoxanthine, represents a potential target for specific inhibitor development. Deletion of the HGPRT gene ( ) in the model organism confirmed that this enzyme is not essential for growth. Prodrugs of acyclic nucleoside phosphonates (ANPs), originally designed against HGPRT from , displayed anti- activities comparable to those obtained for but also inhibited the strain. These results confirmed that ANPs act in by a mechanism independent of HGPRT.
ISSN:0021-9193
1098-5530
DOI:10.1128/JB.00710-19