Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases.

Autor: Scholte LLS; René Rachou Institute, Oswaldo Cruz Foundation - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil; Instituto Tecnológico Vale, Belém, PA 66055-090, Brazil. Electronic address: larissa@cpqrr.fiocruz.br., Mourão MM; René Rachou Institute, Oswaldo Cruz Foundation - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil. Electronic address: marinamm@cpqrr.fiocruz.br., Pais FS; René Rachou Institute, Oswaldo Cruz Foundation - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil; Promove College of Technology, Belo Horizonte, MG 30140-061, Brazil., Melesina J; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, 06120 Halle/Saale, Germany. Electronic address: jelena.melesina@pharmazie.uni-halle.de., Robaa D; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, 06120 Halle/Saale, Germany. Electronic address: dina.robaa@pharmazie.uni-halle.de., Volpini AC; René Rachou Institute, Oswaldo Cruz Foundation - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil. Electronic address: avolpini@cpqrr.fiocruz.br., Sippl W; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, 06120 Halle/Saale, Germany. Electronic address: wolfgang.sippl@pharmazie.uni-halle.de., Pierce RJ; 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. Electronic address: raymond.pierce@pasteur-lille.fr., Oliveira G; Instituto Tecnológico Vale, Belém, PA 66055-090, Brazil. Electronic address: guilherme.oliveira@itv.org., Nahum LA; René Rachou Institute, Oswaldo Cruz Foundation - FIOCRUZ, Belo Horizonte, MG 30190-002, Brazil; Promove College of Technology, Belo Horizonte, MG 30140-061, Brazil. Electronic address: laila@cpqrr.fiocruz.br.
Jazyk: angličtina
Zdroj: Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases [Infect Genet Evol] 2017 Sep; Vol. 53, pp. 175-188. Date of Electronic Publication: 2017 May 13.
DOI: 10.1016/j.meegid.2017.05.011
Abstrakt: 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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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