Glycerol suppresses glucose consumption in trypanosomes through metabolic contest

Author:

Allmann Stefan,Wargnies Marion,Plazolles NicolasORCID,Cahoreau EdernORCID,Biran MarcORCID,Morand PaulineORCID,Pineda ErikaORCID,Kulyk Hanna,Asencio Corinne,Villafraz OrianaORCID,Rivière Loïc,Tetaud EmmanuelORCID,Rotureau BriceORCID,Mourier Arnaud,Portais Jean-CharlesORCID,Bringaud FrédéricORCID

Abstract

Microorganisms must make the right choice for nutrient consumption to adapt to their changing environment. As a consequence, bacteria and yeasts have developed regulatory mechanisms involving nutrient sensing and signaling, known as “catabolite repression,” allowing redirection of cell metabolism to maximize the consumption of an energy-efficient carbon source. Here, we report a new mechanism named “metabolic contest” for regulating the use of carbon sources without nutrient sensing and signaling. Trypanosoma brucei is a unicellular eukaryote transmitted by tsetse flies and causing human African trypanosomiasis, or sleeping sickness. We showed that, in contrast to most microorganisms, the insect stages of this parasite developed a preference for glycerol over glucose, with glucose consumption beginning after the depletion of glycerol present in the medium. This “metabolic contest” depends on the combination of 3 conditions: (i) the sequestration of both metabolic pathways in the same subcellular compartment, here in the peroxisomal-related organelles named glycosomes; (ii) the competition for the same substrate, here ATP, with the first enzymatic step of the glycerol and glucose metabolic pathways both being ATP-dependent (glycerol kinase and hexokinase, respectively); and (iii) an unbalanced activity between the competing enzymes, here the glycerol kinase activity being approximately 80-fold higher than the hexokinase activity. As predicted by our model, an approximately 50-fold down-regulation of the GK expression abolished the preference for glycerol over glucose, with glucose and glycerol being metabolized concomitantly. In theory, a metabolic contest could be found in any organism provided that the 3 conditions listed above are met.

Funder

centre national de la recherche scientifique

université de bordeaux

agence nationale de la recherche

h2020 marie skłodowska-curie actions

frm

institut pasteur

Publisher

Public Library of Science (PLoS)

Subject

General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Neuroscience

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