Isocitrate Lyase - Disease Relevance

Disease Relevance

ICL has found to be important in human, animal, and plant pathogenesis. For several agricultural crops including cereals, cucumbers, and melons, increased expression of the gene encoding ICL is important for fungal virulence. For instance, increased gene expression of icl1 has been seen in the fungus Leptosphaeria maculans upon infection of canola. Inactivation of the icl1 gene leads to reduced pathogenicity of the fungus, which is thought to be a result of the inability of the fungus to use carbon sources provided by the plant.

Additionally, upregulation of the glyoxylate cycle has been seen for pathogens that attack humans. This is the case for fungi such as Candida albicans, which inhabits the skin, mouth, GI tract, gut and vagina of mammals and can lead to systemic infections of immunocompromised patients; as well as for the bacterium Mycobacterium tuberculosis, the major causative agent of tuberculosis. In this latter case, ICL has been found to be essential for survival in the host.

Because of its use by pathogenic fungi and bacteria, specific inhibitors are being sought for ICL and malate synthase. Although some inhibitors have already been identified, including itaconate, itaconic anhydride, bromopyruvate, nitropropionate, oxalate and malate, these are non-specific and would also inhibit other enzymes essential for host function. More research is needed to identify inhibitors that selectively target enzymes in the glyoxylate cycle.