A Toxoplasma gondii Gluconeogenic Enzyme Contributes to Robust Central Carbon Metabolism and Is Essential for Replication and Virulence

Martin Blume, Richard Nitzsche, Ulrich Sternberg, Motti Gerlic, Seth L. Masters, Nishith Gupta, Malcolm J. McConville

Cell Host & Microbe 2015 August 12: 18, 210–220

Speaker: Shung-Hao Ku (顧聲豪)                                Time: 15:00~16:00, Nov, 25 2015

Commentator: Dr. Wei Chen Lin (林威辰 老師)       Place: Room 601

Abstract:

        Toxoplasma gondii, an obligate intracellular protozoan, is capable of infecting virtually all warm-blooded animals like humans. Roughly one-third of the world's population is infected with T. gondii, which may lead to a mononucleosis-like syndrome with fever, asthenia and headache.  In host cell, T. gondii utilize glucose to generate energy and essential anabolic precursors via glycolysis, the pentose phosphate pathway, and mitochondrial respiration. Although preferentially utilizing glucose under standard growth conditions, T. gondii still express a number of enzymes involved in gluconeogenesis. It contains two isomers of the enzymes fructose 1,6-bisphosphatase, T. gondii isomer FBPase1 and 2 (TgFBP1, TgFBP2), which catalyze the conversion of fructose 1,6-bisphosphate (FBP) to fructose 6-phosphate. While the rationale for constitutive expression of FBPases in T. gondii remains unclear, it may affect growth and virulence phenotype in T. gondii mutants lacking the major glucose transporter and the capacity to replicate within host cells [1]. In this study, the authors show that the constitutive expression of TgFBP2 is required for parasite intracellular replication in host cells. TgFBP2, but not TgFBP1, was shown to be active in vivo and to support parasite growth under both glucose-limiting and glucose-replete conditions. They further demonstrated that repression of TgFBP2 results in attenuated virulence in mice. In conclusion, TgFBP2 is more important than TgFBP1, and it can regulatory function of early glycolytic flux. Even without glucose, TgFBP2 is able to survive by sustaining gluconeogenesis. This research raises the possibility that key enzymes in central carbon metabolism are potential drug targets.

Reference:

1.    Blume, M., Rodriguez-Contreras, D., Landfear, S., Fleige, T., Soldati-Favre, D.,Lucius, R., and Gupta, N. (2009). Host-derived glucose and its transporter inthe obligate intracellular pathogen Toxoplasma gondii are dispensable by glutaminolysis. Proc. Natl. Acad. Sci. USA106, 12998–13003.