Influence of 6-aminonicotinamide (6AN) on Leishmania promastigotes evaluated by metabolomics: Beyond the pentose phosphate pathway

Chemico-biological Interactions
Shawgi Hago AlmugadamStefania Hanau

Abstract

6-Aminonicotinamide (6AN) is an antimetabolite used to inhibit the NADPH-producing pentose phosphate pathway (PPP) in many cellular systems, making them more susceptible to oxidative stress. It is converted by a NAD(P)+ glycohydrolase to 6-aminoNAD and 6-aminoNADP, causing the accumulation of PPP intermediates, due to their inability to participate in redox reactions. Some parasites like Plasmodium falciparum and Coccidia are highly sensitive but not all cell types showed a strong responsiveness to 6AN, probably due to the different targeted pathway. For instance, in bacteria the main target is the Preiss-Handler salvage pathway for NAD+ biosynthesis. We were interested in testing 6AN on the kinetoplastid protozoan Leishmania as another model to clarify the mechanisms of action of 6AN, by using metabolomics. Leishmania promastigotes, the life-cycle stage residing in the sandfly, demonstrated a three order of magnitude higher EC50 (mM) compared to P. falciparum and mammalian cells (μM), although pre-treatment with 100 μM 6AN prior to sub-lethal oxidative challenge induced a supra-additive cell kill in L. infantum. By metabolomics, we did not detect 6ANAD/P suggesting that NAD+ glycohydrolases in Leishmania may not be highly effi...Continue Reading

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Citations

Jul 1, 2020·Microorganisms·Magali Van den KerkhofGuy Caljon
Aug 26, 2019·Free Radical Biology & Medicine·N Rocco-MachadoJ R Meyer-Fernandes

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