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Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress
Author(s) -
Ghosh Ayan K.,
Sardar Abul H.,
Mandal Abhishek,
Saini Savita,
Abhishek Kumar,
Kumar Ashish,
Purkait Bidyut,
Singh Ruby,
Das Sushmita,
Mukhopadhyay Rupkatha,
Roy Syamal,
Das Pradeep
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-258624
Subject(s) - pentose phosphate pathway , leishmania donovani , oxidative stress , biochemistry , biology , carbohydrate metabolism , glucose uptake , glycolysis , metabolism , oxidative phosphorylation , chemistry , immunology , insulin , leishmaniasis , endocrinology , visceral leishmaniasis
Understanding the mechanism that allows the intracellular protozoan parasite Leishmania donovani ( Ld ) to respond to reactive oxygen species (ROS) is of increasing therapeutic importance because of the continuing resistance toward antileishmanial drugs and for determining the illusive survival strategy of these parasites. A shift in primary carbon metabolism is the fastest response to oxidative stress. A 14 CO 2 evolution study, expression of glucose transporters together with consumption assays, indicated a shift in metabolic flux of the parasites from glycolysis toward pentose phosphate pathway (PPP) when exposed to different oxidants in vitro/ex vivo. Changes in gene expression, protein levels, and enzyme activities all pointed to a metabolic reconfiguration of the central glucose metabolism in response to oxidants. Generation of glucose‐6‐phosphate dehydrogenase (G6PDH) (~5‐fold) and transaldolase (TAL) (~4.2‐fold) overexpressing Ld cells reaffirmed that lethal doses of ROS were counterbalanced by effective manipulation of NADPH:NADP + ratio and stringent maintenance of reduced thiol content. The extent of protein carbonylation and accumulation of lipid peroxidized products were also found to be less in overexpressed cell lines. Interestingly, the LD 50 of sodium antimony gluconate (SAG), amphotericin‐B (AmB), and miltefosine were significantly high toward overexpressing parasites. Consequently, this study illustrates that Ld strategizes a metabolic reconfiguration for replenishment of NADPH pool to encounter oxidative challenges.—Ghosh, A. K., Sardar, A. H., Mandal, A., Saini, S., Abhishek, K., Kumar, A., Purkait, B., Singh, R., Das, S., Mukhopadhyay, R., Roy, S., Das, P. Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress. FASEB J. 29, 2081‐2098 (2015). www.fasebj.org