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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2018.tde-22022018-164355
Document
Author
Full name
Nubia Carolina Manchola Varon
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Silber, Ariel Mariano (President)
Cordeiro, Artur Torres
Festuccia, William Tadeu Lara
Martínez, Luis Alberto Luévano
Tonelli, Renata Rosito
Title in Portuguese
Metabolismo dos aminoácidos ramificados e sua participação na modulação da diferenciação em Trypanosoma cruzi.
Keywords in Portuguese
Trypanosma cruzi
Aminoácidos
Diferenciação
Doença de Chagas
Isoleucina
Leucina
Metaciclogênesis
Transporte
Valina
Abstract in Portuguese
A doença de Chagas é uma doença negligenciada com aproximadamente 8 milhões de pessoas cronicamente infectadas e mais de 40 milhões sob risco de infecção. Atualmente as poucas drogas disponíveis para o tratamento da doença são limitadas em relação à eficácia e tolerância, o que evidencia a necessidade de novos alvos terapêuticos visando o desenvolvimento de drogas eficazes para o tratamento da doença. Estudos têm descrito a importância dos aminoácidos no ciclo de vida do T. cruzi, que além de atuarem na síntese proteica e no metabolismo energético, estão relacionados a diferentes funções no parasito. Apesar de estudos anteriores indicarem os aminoácidos de cadeia ramificada (BCAA - leucina, isoleucina e valina) como integrantes do metabolismo em T. cruzi é curioso o fato de ainda haver poucos estudos na literatura sobre a identificação de funções relevantes dos BCAA para a biologia do parasita, bem como associados a outros aminoácidos do T. cruzi. Esse projeto teve o propósito de: (1) Avaliar o papel biológico que os BCAA tem ao longo do ciclo de vida do parasita, com especial enfase nos processos de diferenciação, (2) Avaliar o transporte dos BCAA em T. cruzi. (2) Caracterizar cinéticamente se as enzimas transaminases tirosina aminotransferase TAT e aspartato aminotransferase ASAT catalisam a reação de desaminação/aminação dos derivados de BCAA. (3) Avaliar o papel funcional do complexo enzimático desidrogenase de alfa-cetoácidos ramificados BCAKDH. (4) Estudar a localização intracelular do complexo enzimático nas formas do parasita. (5) Avaliar os o potencial terapêutico. (6) Investigar a funcionalidade do mesmo e as proteinas associadas ao complexo enzimático BCAKDH.
Title in English
Branched chain amino acids metabolism and their participation in the diferentiation modulation of Trypanosoma cruzi.
Keywords in English
Trypanosma cruzi
Amino acids
Chagas\' disease
Differentiation
Isoleucine
Leucine
Metacyclogenesis
Transport
Valine
Abstract in English
Chagas disease is a neglected disease with approximately 8 million people chronically infected and more than 40 million at risk of infection. Currently the few drugs available for the treatment of the disease are limited in relation to efficacy and tolerance, which highlights the need for new therapeutic targets aimed at the development of drugs effective for the treatment of the disease. Studies have described the importance of amino acids in the life cycle of T. cruzi, which in addition to acting on protein synthesis and energetic metabolism, are related to different functions in the parasite. Although previous studies indicate branched chain amino acids (BCAA - leucine, isoleucine and valine) as components of metabolism in T. cruzi, it is curious that there are still few studies in the literature on the identification of relevant BCAA functions for the biology of parasite, as well as associated with other T. cruzi amino acids. The purpose of this project was to: (1) Evaluate the biological role of BCAAs in the life cycle of the parasite, with special emphasis on differentiation processes; (2) Evaluate BCAA transport in T. cruzi. (2) Kinetically characterize whether the enzymes transaminases tyrosine aminotransferase TAT and aspartate aminotransferase ASAT catalyze the deamination / amination reaction of the BCAA derivatives. (3) To evaluate the functional role of the enzymatic complex dehydrogenase of branched alpha-ketoacids BCAKDH. (4) To study the intracellular localization of the enzymatic complex in the forms of the parasite. (5) Evaluate the therapeutic potential. (6) Investigate the functionality of the proteins associated with the enzymatic complex BCAKDH.
 
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Release Date
2020-02-22
Publishing Date
2018-02-22
 
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