Isocitrate lyase (ICL)

Isocitrate lyase (ICL) is a critical enzyme in the glyoxylate cycle, a metabolic pathway that allows bacteria, fungi, and plants to utilize fatty acids or acetate as their sole carbon source by bypassing the decarboxylation steps of the citric acid cycle (McKinney et al., 2000, Nature; UniProt P9WNK3). The enzyme catalyzes the reversible cleavage of isocitrate into succinate and glyoxylate, a process essential for gluconeogenesis and energy production when glucose is scarce (Munoz-Elias & McKinney, 2005, Science). Because ICL is absent in mammals but vital for the survival and persistence of pathogens like Mycobacterium tuberculosis within host macrophages, it is a highly attractive target for the development of selective antimicrobial therapies (Sharma et al., 2013, J. Biol. Chem.). In the context of infectious disease, ICL is particularly important for the latent phase of tuberculosis, where the bacterium shifts its metabolism to utilize host-derived lipids for long-term survival (Eoh & Rhee, 2014, Nat. Commun.). Pharmacological inhibition of ICL aims to effectively starve the pathogen during its dormant state, potentially shortening treatment durations and overcoming antibiotic resistance (Hogan et al., 2011, Microbiology). Although several small-molecule inhibitors such as itaconate and 3-nitropropionate have been identified in research settings, the primary challenge in clinical development is achieving high specificity to avoid interference with other metabolic enzymes in the host, such as those in the mitochondrial respiratory chain.

Other names

Isocitrate glyoxylate-lyaseIsocitritaseIsocitrate lyase 1Isocitrate lyase 2ICL1ICL2AceA

Inhibition of the glyoxylate cycle by blocking the cleavage of isocitrate into succinate and glyoxylate, preventing the pathogen from utilizing host-derived lipids as a carbon source for energy and biomass production during chronic infection phases.