Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/26451
Title: Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases
Authors: Scholte, Larissa Lopes Silva
Mourão, Marina de Morais
Pais, Fabiano Sviatopolk Mirsky
Melesina, Jelena
Roba, Dina
Volpini, Angela Cristina
Sippl, Wolfgang
Pierce, Raymond J.
Oliveira, Guilherme Correa de
Nahum, Laila Alves
Affilliation: Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil/Instituto Tecnológico Vale. Belém, PA, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil/ Promove Colegio de Tecnologia. Belo Horizonte, MG, Brazil
Institute of Pharmacy. Martin Luther University of Halle-Wittenberg. Halle/Saale, Germany
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil/ Institute of Pharmacy. Martin Luther University of Halle-Wittenberg. Halle/Saale, Germany
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil
Institute of Pharmacy. Martin Luther University of Halle-Wittenberg. Halle/Saale, Germany
Univ. Lille. CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France
Instituto Tecnológico Vale. Belém, PA, Brazil
Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil/ Promove Colegio de Tecnologia. Belo Horizonte, MG, Brazil
Abstract: 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
Keywords: Histone modifying enzymes
Epigenetics
Phylogenomics
Functional annotation
keywords: Enzimas modificadoras de histona
epigenetica
Issue Date: 2017
Publisher: Elsevier
Citation: SCHOLTE, Larissa Lopes Silva et al. Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases. Infect Genet Evol., v. 53, p. 175-188, 2017.
DOI: 10.1016/j.meegid.2017.05.011
ISSN: 1567-1348
Copyright: restricted access
Appears in Collections:MG - IRR - Artigos de Periódicos

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