The pentose phosphate pathway in Trypanosoma cruzi: a potential target for the chemotherapy of Chagas disease

Anais da Academia Brasileira de Ciências

Mariana Igoillo-esteve¹  Dante Maugeri¹  Ana L. Stern¹  Paula Beluardi¹  Juan J. Cazzulo¹ 

[1] ,Instituto Tecnologico de Chascomus Instituto de Investigaciones Biotecnologicas Provincia de Buenos Aires,Argentina

关键词: Trypanosoma cruzi;    Chagas disease;    pentose phosphate pathway;    oxidative stress;    NADPH generation;    Trypanosoma cruzi;    doença de Chagas;    via das pentoses fosfato;    estresse oxidativo;    produção de NADPH;   

DOI  :  10.1590/S0001-37652007000400007

来源: SciELO

【 摘 要 】

Trypanosoma cruzi is highly sensitive to oxidative stress caused by reactive oxygen species. Trypanothione, the parasite's major protection against oxidative stress, is kept reduced by trypanothione reductase, using NADPH; the major source of the reduced coenzyme seems to be the pentose phosphate pathway. Its seven enzymes are present in the four major stages in the parasite's biological cycle; we have cloned and expressed them in Escherichia coli as active proteins. Glucose 6-phosphate dehydrogenase, which controls glucose flux through the pathway by its response to the NADP/NADPH ratio, is encoded by a number of genes per haploid genome, and is induced up to 46-fold by hydrogen peroxide in metacyclic trypomastigotes. The genes encoding 6-phosphogluconolactonase, 6-phosphogluconate dehydrogenase, transaldolase and transketolase are present in the CL Brener clone as a single copy per haploid genome. 6-phosphogluconate dehydrogenase is very unstable, but was stabilized introducing two salt bridges by site-directed mutagenesis. Ribose-5-phosphate isomerase belongs to Type B; genes encoding Type A enzymes, present in mammals, are absent. Ribulose-5-phosphate epimerase is encoded by two genes. The enzymes of the pathway have a major cytosolic component, although several of them have a secondary glycosomal localization, and also minor localizations in other organelles.

【 授权许可】

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