Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases
Autor: | Jelena Melesina, Fabiano Sviatopolk-Mirsky Pais, Marina de Moraes Mourão, Laila A. Nahum, A. C. Volpini, Dina Robaa, Guilherme Oliveira, Wolfgang Sippl, Larissa L. S. Scholte, Raymond J. Pierce |
---|---|
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Microbiology (medical) Trypanosoma Histone-modifying enzymes Protein Conformation Plasmodium falciparum Antiprotozoal Agents Helminthiasis Protozoan Proteins Gene Expression Biology Microbiology Genome Histone Deacetylases Homology (biology) Epigenesis Genetic Evolution Molecular 03 medical and health sciences 0302 clinical medicine RNA interference Databases Genetic Genetics Animals Humans Homology modeling Epigenetics Molecular Biology Gene Phylogeny Ecology Evolution Behavior and Systematics Anthelmintics Leishmania Protozoan Infections Neglected Diseases Helminth Proteins Chromatin Histone Deacetylase Inhibitors Molecular Docking Simulation 030104 developmental biology Infectious Diseases Structural Homology Protein 030220 oncology & carcinogenesis Schistosoma |
Zdroj: | Infection, Genetics and Evolution. 53:175-188 |
ISSN: | 1567-1348 |
Popis: | The availability of the genomic data of diverse parasites provides an opportunity to identify new drug candidates against neglected tropical diseases affecting people worldwide. Histone modifying enzymes (HMEs) are potential candidates since they play key roles in the regulation of chromatin modifications, thus globally regulating gene expression. Furthermore, aberrant epigenetic states are often associated with human diseases, leading to great interest in HMEs as therapeutic targets. Our work focused on two families of protein lysine deacetylases (HDACs and sirtuins). First, we identified potential homologues in the predicted proteomes of selected taxa by using hidden Markov model profiles. Then, we reconstructed the evolutionary relationships of protein sequences by Bayesian inference and maximum likelihood method. In addition, we constructed homology models for five parasite HDACs to provide information for experimental validation and structure-based optimization of inhibitors. Our results showed that parasite genomes code for diverse HDACs and sirtuins. The evolutionary pattern of protein deacetylases with additional experimental data points to these enzymes as common drug targets among parasites. This work has improved the functional annotation of approximately 63% HDACs and 51% sirtuins in the selected taxa providing insights for experimental design. Homology models pointed out structural conservation and differences among parasite and human homologues and highlight potential candidates for further inhibitor development. Some of these parasite proteins are undergoing RNA interference or knockout analyses to validate the function of their corresponding genes. In the future, we will investigate the main functions performed by these proteins, related phenotypes, and their potential as therapeutic targets. |
Databáze: | OpenAIRE |
Externí odkaz: |