Helminth-specific fumarate reductase (FRD)

Helminth-specific fumarate reductase is a critical enzyme in the anaerobic energy metabolism of many parasitic worms, including nematodes and trematodes. Unlike their mammalian hosts, which primarily utilize oxygen-dependent respiration, many helminths rely on a specialized electron transport chain where fumarate serves as the terminal electron acceptor. This enzyme, often referred to as mitochondrial complex II acting in reverse, catalyzes the reduction of fumarate to succinate using rhodoquinol as a cofactor. This process is essential for ATP generation in the low-oxygen environments of the host's intestines or tissues. Because this rhodoquinone-dependent pathway is absent in humans, the enzyme represents a highly selective target for anthelmintic therapy. Drugs such as benzimidazoles and experimental inhibitors like flutolanil have been shown to target this system, leading to metabolic exhaustion and death of the parasite. Targeting this enzyme is a cornerstone of treating various helminthic infections, although the emergence of resistance remains a significant clinical challenge.

Other names

Rhodoquinol-fumarate reductaseNADH-fumarate reductaseParasite-specific fumarate reductaseSuccinate reductaseMitochondrial complex II (reverse)

Inhibition of the fumarate reductase enzyme prevents the reduction of fumarate to succinate, thereby disrupting the parasite's anaerobic electron transport chain and halting ATP production.