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Abstract
Parasites of the Trypanosomatidae family are responsible for diseases that afflict several million people worldwide. Currently there is an urgent need for new drugs against these diseases and an approach to drug discovery is the study of biochemical and structural properties of a potential target and the subsequent design of specific compounds. Trypanosomatid genes coding for enzymes which distinctively hydrolyze dUTP have been isolated by genetic complementation in Escherichia coli mutants defective in dUTPase activity. An analysis of these sequences from Leishmania major and Trypanosoma cruzi showed that no significant similarity could be established with the family of known dUTPases and that the five consensus motifs were absent. However, limited similarity was identified for three motifs present in an enzyme related in function the dCTPase-dUTPase from T phages and 35percent identity with a putative dUTPase identified in the eubacteria Campylobacter jejuni. T. cruzi and L. major dUTPases were hig hly similar and catalyzed in a specific fashion the hydrolysis of dUTP. A detailed kinetic study of both enzymes revealed that dUDP is also an efficient substrate of the enzyme while other nucleotides are poorly hydrolyzed. The enzyme is essential for viability in Leishmania and is up-regulated by inhibitors of dTMP synthesis. Thus, a new family of dUTPases might exist in certain organisms that bear no sequence or structure similarity with eukaryotic enzymes accomplishing the same function and that may constitute potential drug targets for the development of specific inhibitors.
Keywords: Trypanosomal dUTPases, Leishmania major, Trypanosoma cruzi, Campylobacter jejuni, DUT GENES, RECOMBINANT PROTOZOAN dUTPases, INHIBITION, Dihydrofolate reductase, Thymidylate synthase
Current Protein & Peptide Science
Title: Trypanosomal dUTPases as Potential Targets for Drug Design
Volume: 2 Issue: 4
Author(s): Fernando Hidalgo-zarco and Dolores Gonzalez-pacnowska
Affiliation:
Keywords: Trypanosomal dUTPases, Leishmania major, Trypanosoma cruzi, Campylobacter jejuni, DUT GENES, RECOMBINANT PROTOZOAN dUTPases, INHIBITION, Dihydrofolate reductase, Thymidylate synthase
Abstract: Parasites of the Trypanosomatidae family are responsible for diseases that afflict several million people worldwide. Currently there is an urgent need for new drugs against these diseases and an approach to drug discovery is the study of biochemical and structural properties of a potential target and the subsequent design of specific compounds. Trypanosomatid genes coding for enzymes which distinctively hydrolyze dUTP have been isolated by genetic complementation in Escherichia coli mutants defective in dUTPase activity. An analysis of these sequences from Leishmania major and Trypanosoma cruzi showed that no significant similarity could be established with the family of known dUTPases and that the five consensus motifs were absent. However, limited similarity was identified for three motifs present in an enzyme related in function the dCTPase-dUTPase from T phages and 35percent identity with a putative dUTPase identified in the eubacteria Campylobacter jejuni. T. cruzi and L. major dUTPases were hig hly similar and catalyzed in a specific fashion the hydrolysis of dUTP. A detailed kinetic study of both enzymes revealed that dUDP is also an efficient substrate of the enzyme while other nucleotides are poorly hydrolyzed. The enzyme is essential for viability in Leishmania and is up-regulated by inhibitors of dTMP synthesis. Thus, a new family of dUTPases might exist in certain organisms that bear no sequence or structure similarity with eukaryotic enzymes accomplishing the same function and that may constitute potential drug targets for the development of specific inhibitors.
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Cite this article as:
Hidalgo-zarco Fernando and Gonzalez-pacnowska Dolores, Trypanosomal dUTPases as Potential Targets for Drug Design, Current Protein & Peptide Science 2001; 2 (4) . https://dx.doi.org/10.2174/1389203013381026
DOI https://dx.doi.org/10.2174/1389203013381026 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
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