Glyoxylate cycle (GS)

The glyoxylate cycle, also known as the glyoxylate shunt, is a metabolic pathway found in plants, bacteria, and fungi, but it is notably absent in mammals. This pathway functions as an anabolic variant of the tricarboxylic acid (TCA) cycle, bypassing the two carbon-dioxide-generating decarboxylation steps to convert two-carbon acetyl-CoA units into four-carbon succinate and malate. In pathogenic microorganisms, such as Mycobacterium tuberculosis and Candida albicans, the glyoxylate cycle is essential for carbon assimilation and gluconeogenesis when simple sugars are unavailable, particularly during survival inside host macrophages. Because the key enzymes of the cycle, isocitrate lyase and malate synthase, have no human counterparts, they represent high-value therapeutic targets for the development of selective antimicrobial and antifungal agents. Inhibiting this cycle effectively disrupts the ability of latent pathogens to maintain energy levels and synthesize essential biomass from host-derived lipids. Current research focuses on developing selective inhibitors like phenyl-diketo acids and itaconate derivatives to combat persistent and drug-resistant infections. Despite its potential, therapeutic development is challenged by the need for high enzyme specificity to avoid off-target effects on the host's central metabolism.

Other names

Glyoxylate shuntGlyoxylate bypassGlyoxylate pathway

Inhibition of key enzymes isocitrate lyase and malate synthase to disrupt the bypass of the tricarboxylic acid (TCA) cycle, thereby preventing the conversion of 2-carbon compounds into 4-carbon dicarboxylic acids required for gluconeogenesis and energy production in pathogens.