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Doctoral Thesis
DOI
10.11606/T.76.2004.tde-09042008-100756
Document
Author
Full name
Artur Torres Cordeiro
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2004
Supervisor
Committee
Thiemann, Otavio Henrique (President)
Arni, Raghuvir Krishnaswamy
Beltramini, Leila Maria
Degrave, Wim Maurits Sylvain
Polikarpov, Igor
Title in Portuguese
Determinação da estrutura cristalográfica da enzima glicose-6-fosfato isomerase de Leishmania mexicana e comparação com a enzima homóloga de humanos
Keywords in Portuguese
Estrutura cristalográfica
Glicose-6-fosfato
Isomerase
Leishmania
Abstract in Portuguese
Esta tese apresenta em sua introdução uma revisão bibliográfica sobre a leishmaniose no Brasil e no mundo, com dados atuais de documentos do Ministério da Saúde e da Organização Mundial da Saúde. Discute também, com base em revisões bibliográficas recentes, os mecanismos que o parasita (Leishmania) possui para escapar da resposta imunológica e obter abrigo no interior das células de defesa dos humanos; os tratamentos atualmente empregados para a leishmaniose; a importância de uma abordagem racional para o desenvolvimento de novas drogas e a falta de interesse das industrias farmacêuticas em direcionar a pesquisa & desenvolvimento para doenças tropicais. Ainda na introdução ressalta-se a importância da identificação e validação de potenciais alvos metabólicos antes de se investir na busca por compostos com potencial quimioterápico. Como exemplo discute-se o papel das enzimas do metabolismo energético, entre elas a fosfoglicose isomerase (PGI), na sobrevivência e homeostase do parasita Leismanin. Os experimentos descritos nesta tese visam a determinação da estrutura cristalográfica da PGI de L. mexicana e a comparação cinética e estrutural com a PGI humana. O mapeamento das diferenças estruturais entres as duas enzimas é fundamental para a validação da PGI como potencial alvo metabólico e serve de guia para a idealização de inibidores seletivos da enzima dos parasitas.
Title in English
Determination of the crystallographic structure of Leishmania mexicana glucose-6-phosphate isomerase and comparision to the human enzyme
Keywords in English
Crystallographic structure
Glicose-6-phosphate
Isomerase
Abstract in English
This thesis presents a review about the occurrence of leishmaniasis in Brazil and all over the world. The main data sources were documents from Brazilian Health Ministry and the World Health Organization. The introduction presents actual information about strategies adopt by the parasite to evade the human immune response, the common drugs used in actual treatment, the need for new drugs based on a rational approach and the lack of interest from pharmaceutic industry to invest in research & development for tropical diseases. It also highlights the importance to identify, and validate possible metabolic targets before spending time and money in searching potential compounds that blocks a non validated parasite target. The enzymes that participate in the energy metabolism are considered good target. An example is the glicosomal enzyme phosphoglucose isomerase (PGI), which was recently validated by RNA interference experiments in T. brucei as a good target. The experiments described here intend to elucidate the crystallographic structure from L. mexicana PGI and compare its kinetic and structural proprieties to the human PGI. The mapping of the differences between both enzymes is crucial for the validation of PGI as a metabolic target and will assist in the design of inhibitors with high selectivity against the parasite enzyme.
 
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ArturCordeiro_D.pdf (4.09 Mbytes)
Publishing Date
2008-04-17
 
WARNING: The material described below relates to works resulting from this thesis or dissertation. The contents of these works are the author's responsibility.
  • CORDEIRO, A T, et al. Crystallographic structure of native human phosphoglucose isomerase (PGI) and a novel insight on its enzimatic mechanism. In 7th International Conference on Biology and Synchrotron Radiation, Sao Pedro, 2001. Resumo.
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