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Identifica????o in silico de enzimas isofuncionais n??o-hom??logas, um potencial reservat??rio de alvos terap??uticos.

By Ana Carolina Ramos Guimar??es

Abstract

O estudo da reconstru????o metab??lica em diversos organismos exp??e a exist??ncia de compostos cruciais para a sua sobreviv??ncia. Dentre estes compostos, est??o as enzimas, respons??veis pela cat??lise das rea????es bioqu??micas em vias metab??licas. Diferentemente das enzimas hom??logas, as enzimas an??logas (tamb??m conhecidas como enzimas isofuncionais n??o hom??logas) s??o capazes de catalisar as mesmas rea????es, mas sem apresentar similaridade de sequ??ncia significativa no n??vel prim??rio e, possivelmente, com diferentes estruturas tridimensionais. Um estudo detalhado destas enzimas pode desvendar novos mecanismos catal??ticos, adicionar informa????es sobre a origem e evolu????o de vias bioqu??micas e revelar alvos potenciais para o desenvolvimento de drogas. Para muitas enfermidades causadas por parasitas, as op????es terap??uticas permanecem ineficientes ou inexistentes, exigindo a busca de novos alvos. Estes podem ser prote??nas espec??ficas do parasita ausentes no hospedeiro ou compostos presentes em ambos, mas com estrutura tridimensional substancialmente diferente, como as enzimas an??logas. A ferramenta AnEnPi, capaz de identificar, anotar e comparar enzimas hom??logas e an??logas, foi desenvolvida e utilizada para reconstruir computacionalmente as vias metab??licas de alguns organismos modelo, como os tripanossomat??deos. Uma an??lise mais focada no metabolismo de amino??cidos de Trypanosoma cruzi identificou alvos promissores para o desenvolvimento de novas drogas. Al??m disso, uma revis??o do metabolismo geral de T. cruzi foi realizada em outras vias metab??licas, levando em considera????o esta nova abordagem de busca por potenciais alvos terap??uticos. Uma vez que a estrutura tridimensional ?? importante no estudo de analogia, a ferramenta MHOLline foi utilizada para a obten????o de modelos 3D a partir de hom??logos, an??logos e prote??nas espec??ficas de T. cruzi versus Homo sapiens. As estrat??gias utilizadas nesse trabalho ap??iam o conceito de an??lise estrutural, juntamente com a an??lise funcional de prote??nas, como uma interessante metodologia computacional para detectar potenciais alvos para o desenvolvimento de novas drogas.The study of metabolic reconstruction in different organisms exposes the existence of crucial compounds for its survival. Examples of these compounds are the enzymes that are responsible for the catalysis of biochemical reactions in metabolic pathways. Unlike the homologous enzymes, the analogous enzymes (also known as non- homologous isofunctional enzymes) are able to catalyze the same reactions, but without significant sequence similarity at the primary level and possibly with different three-dimensional structures. A detailed study of these enzymes may exhibit new catalytic mechanisms, add information about the origin and evolution of biochemical pathways and reveal potential targets for drug development. For many diseases caused by parasites, therapeutic options remain inefficient or nonexistent, requiring the search for new drug targets. These targets may be specific proteins of the parasite (absent in the host) or compounds present in the both organisms but with different three-dimensional structure, like analogous enzymes. The tool AnEnPi approach was able to identify, annotate and compare homologous and analogous enzymes. It was developed and used to reconstruct computationally the metabolic pathways of some model organisms such as trypanosomes. A more focused analysis on the amino acids metabolism of Trypanosoma cruzi identified promising targets for the development of new drugs. Furthermore, a review of the general metabolism of T. cruzi was carried out in other metabolic pathways, taking into account this new approach in the search for potential therapeutic targets. Since the three-dimensional structure is important in the study of analogy, the tool MHOLline was used to obtain 3D models for homologous, analogous and specific proteins of T. cruzi versus Homo sapiens. The strategies used in this study support the concept that structural analysis together with protein functional analysis could be an interesting computational methodology to detect potential targets for structure-based rational drug design

Topics: Enzimas Isofuncionais, AnEnPi, Enzimas /an??lise, Catalisador, Simula????o de Din??mica Molecular/utiliza????o, Biologia Computacional/m??todos, Trypanosoma cruzi /enzimologia, Trypanosoma cruzi /metabolismo, Amino??cidos /metabolismo, Rea????es Bioqu??micas/an??lise, Descoberta de Drogas /m??todos
Year: 2010
OAI identifier: oai:agregador.ibict.br.RI_FIOCRUZ:oai:localhost:icict/5672
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