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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
Advancements in Proteomic and Peptidomic Approaches in Cancer Immunotherapy: Unveiling the Immune Microenvironment
The scope of this thematic issue centers on the integration of proteomic and peptidomic technologies into the field of cancer immunotherapy, with a particular emphasis on exploring the tumor immune microenvironment. This issue aims to gather contributions that illustrate the application of these advanced methodologies in unveiling the complex interplay ...read more
Artificial Intelligence for Protein Research
Protein research, essential for understanding biological processes and creating therapeutics, faces challenges due to the intricate nature of protein structures and functions. Traditional methods are limited in exploring the vast protein sequence space efficiently. Artificial intelligence (AI) and machine learning (ML) offer promising solutions by improving predictions and speeding up ...read more
Nutrition and Metabolism in Musculoskeletal Diseases
The musculoskeletal system consists mainly of cartilage, bone, muscles, tendons, connective tissue and ligaments. Balanced metabolism is of vital importance for the homeostasis of the musculoskeletal system. A series of musculoskeletal diseases (for example, sarcopenia, osteoporosis) are resulted from the dysregulated metabolism of the musculoskeletal system. Furthermore, metabolic diseases (such ...read more
Protein Folding, Aggregation and Liquid-Liquid Phase Separation
Protein folding, misfolding and aggregation remain one of the main problems of interdisciplinary science not only because many questions are still open, but also because they are important from the point of view of practical application. Protein aggregation and formation of fibrillar structures, for example, is a hallmark of a ...read more
Related Journals
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Using Measured pKa, LogP and Solubility to Investigate Supersaturation and Predict BCS Class
Current Drug Metabolism Improving Nutritional Quality of Plant Proteins Through Genetic Engineering
Current Genomics Characterization of Seven New Polystyrene Plates Binding Peptides from a Phage-Displayed Random 12-Peptide Library
Combinatorial Chemistry & High Throughput Screening A Rapid and Sensitive HPLC-FLD Method for the Determination of Retinol and Vitamin E Isomers in Human Serum
Current Pharmaceutical Analysis Molecular Mechanisms of Drug Photodegradation and Photosensitization
Current Pharmaceutical Design Advanced Nanomedicines for the Treatment and Diagnosis of Myocardial Infarction and Heart Failure
Current Drug Targets Meet Our Editor
Current Metabolomics Synthesis, Molecular Docking and Anticancer Evaluation of New Arylazothiazoles
Current Organic Synthesis Multidrug Resistance Phenotype Mediated by the P-Glycoprotein-Like Transporter in Leishmania: A Search for Reversal Agents
Current Drug Targets Empyema and Bronchopleural Fistula Following Lung Resection
Current Respiratory Medicine Reviews Application of Nanotechnology in Miniaturized Systems and its Use for Advanced Analytics and Diagnostics – an Updated Review
Recent Patents on Food, Nutrition & Agriculture Recent Advances on the Enantioselective Synthesis of C-Nucleosides Inhibitors of Inosine Monophosphate Dehydrogenase (IMPDH)
Current Topics in Medicinal Chemistry Evaluation of the Biological Fate and the Transport Through Biological Barriers of Nanosilver in Mice
Current Pharmaceutical Design Feature Clustering and Ensemble Learning Based Approach for Software Defect Prediction
Recent Advances in Computer Science and Communications A Novel Hydroxysteroid-Sulfating Cytosolic Sulfotransferase, SULT3 ST3, from Zebrafish: Identification, Characterization, and Ontogenic Study
Drug Metabolism Letters A Neural Network-Based QSAR Approach for Exploration of Diverse Multi-Tyrosine Kinase Inhibitors and its Comparison with a Fragment- Based Approach
Current Computer-Aided Drug Design Combining In Silico Protein Stability Calculations with Structure-Function Relationships to Explore the Effect of Polymorphic Variation on Cytochrome P450 Drug Metabolism
Current Drug Metabolism New Fabrication and Applications of Carbohydrate Arrays
Current Medicinal Chemistry 3-(Adamantan-1-yl)-4-hydroxybenzyl Substituted Purines and Pyrimidines: Synthesis and Cytotoxic Activity
Letters in Drug Design & Discovery Lentisk (<i>Pistacia lentiscus L.</i>) a Renewable Source of Pure Shikimic Acid and its Antioxidant Activity
Current Bioactive Compounds