Abstract
Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and thus drugs that inhibit human PNP activity have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Besides, the purine salvage pathway is the only possible way for apicomplexan parasites to obtain the building blocks for RNA and DNA synthesis, which makes PNP from these parasites an attractive target for drug development against diseases such as malaria. Hence, a number of research groups have made efforts to elucidate the mechanism of action of PNP based on structural and kinetic studies. It is conceivable that the mechanism may be different for PNPs from diverse sources, and influenced by the oligomeric state of the enzyme in solution. Furthermore, distinct transition state structures can make possible the rational design of specific inhibitors for human and apicomplexan enzymes. Here, we review the current status of these research efforts to elucidate the mechanism of PNP-catalyzed chemical reaction, focusing on the mammalian and Plamodium falciparum enzymes, targets for drug development against, respectively, T-Cell- and Apicomplexan parasites-mediated diseases.
Keywords: Purine nucleoside phosphorylase, protein structure, malaria, drug design, autoimmune diseases, enzyme inhibition
Current Drug Targets
Title: Purine Nucleoside Phosphorylase: A Potential Target for the Development of Drugs to Treat T-Cell- and Apicomplexan Parasite-Mediated Diseases
Volume: 8 Issue: 3
Author(s): R. G. Silva, J. E. S. Nunes, F. Canduri, J. C. Borges, L. M. Gava, F. B. Moreno, L. A. Basso and D. S. Santos
Affiliation:
Keywords: Purine nucleoside phosphorylase, protein structure, malaria, drug design, autoimmune diseases, enzyme inhibition
Abstract: Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and thus drugs that inhibit human PNP activity have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Besides, the purine salvage pathway is the only possible way for apicomplexan parasites to obtain the building blocks for RNA and DNA synthesis, which makes PNP from these parasites an attractive target for drug development against diseases such as malaria. Hence, a number of research groups have made efforts to elucidate the mechanism of action of PNP based on structural and kinetic studies. It is conceivable that the mechanism may be different for PNPs from diverse sources, and influenced by the oligomeric state of the enzyme in solution. Furthermore, distinct transition state structures can make possible the rational design of specific inhibitors for human and apicomplexan enzymes. Here, we review the current status of these research efforts to elucidate the mechanism of PNP-catalyzed chemical reaction, focusing on the mammalian and Plamodium falciparum enzymes, targets for drug development against, respectively, T-Cell- and Apicomplexan parasites-mediated diseases.
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Silva G. R., S. Nunes E. J., Canduri F., Borges C. J., Gava M. L., Moreno B. F., Basso A. L. and Santos S. D., Purine Nucleoside Phosphorylase: A Potential Target for the Development of Drugs to Treat T-Cell- and Apicomplexan Parasite-Mediated Diseases, Current Drug Targets 2007; 8 (3) . https://dx.doi.org/10.2174/138945007780058997
DOI https://dx.doi.org/10.2174/138945007780058997 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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