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Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress

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Title Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress
 
Creator 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
 
Subject Infectious Diseases and Immunology
 
Description 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 14CO2 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 LD50 of sodiumantimony 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.
 
Publisher Federation of American Society of Experimental Biology
 
Date 2015
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2216/1/FASEB_JOURNAL__V._29__(_5__)_2081%2D2098;2015[18].pdf
Ghosh, Ayan K. and Sardar, Abul H. and Mandal, Abhishek and Saini, Savita and Abhishek, Kumar and Kumar, Ashish and Purkait, Bidyut and Singh, Ruby and Das, Sushmita and Mukhopadhyay, Rupkatha and Roy, Syamal and Das, Pradeep (2015) Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress. The FASEB Journal, 29 (5). pp. 2081-2089. ISSN 0892-6638
 
Relation http://dx.doi.org/10.1096/fj.14-258624
http://www.eprints.iicb.res.in/2216/