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The expression of gluconeogenic enzymes is typically repressed when glucose is available. The protozoan parasite Toxoplasma gondii utilizes host glucose to sustain high rates of intracellular replication. However, despite their preferential utilization of glucose, intracellular parasites constitutively express two isoforms of the gluconeogenic enzyme fructose 1,6-bisphosphatase (TgFBP1 and TgFBP2). The rationale for constitutive expression of FBPases in T. gondii remains unclear. We find that conditional knockdown of TgFBP2 results in complete loss of intracellular growth in vitro under glucose-replete conditions and loss of acute virulence in mice. TgFBP2 deficiency was rescued by expression of catalytically active FBPase and was associated with altered glycolytic and mitochondrial TCA cycle fluxes, as well as dysregulation of glycolipid, amylopectin, and fatty acid biosynthesis. Futile cycling between …