Hydrogenosomal redox activation system

The hydrogenosomal redox activation system is a specialized metabolic pathway located within the hydrogenosomes of anaerobic protozoan parasites, such as Trichomonas vaginalis, Giardia lamblia, and Entamoeba histolytica (Müller, 1993). This system is primarily composed of the enzyme pyruvate:ferredoxin oxidoreductase (PFOR) and the electron carrier ferredoxin, which facilitate the oxidative decarboxylation of pyruvate to acetyl-CoA (Leitsch, 2017). The process generates low-redox-potential electrons that are typically used to produce molecular hydrogen via hydrogenase enzymes. However, this system also serves as the primary site for the activation of 5-nitroimidazole drugs, such as metronidazole, which act as prodrugs (Upcroft & Upcroft, 2001). These drugs are reduced by the system's electron donors, resulting in the formation of short-lived, highly reactive nitro radical anions that cause lethal damage to the parasite's DNA and other cellular components. Resistance to these therapies often arises through the downregulation or loss of components within this redox system, highlighting its central role in antiparasitic drug efficacy (Land & Johnson, 1999).

Other names

Hydrogenosomal electron transport chainPFOR-ferredoxin systemHydrogenosomal metabolic pathwayAnaerobic redox system

Reductive activation of 5-nitroimidazole prodrugs into toxic radical intermediates via low-potential electron transfer from ferredoxin.