Apicomplexan protozoal dihydroorotate dehydrogenase (DHODH)

Apicomplexan protozoal dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme essential for the de novo biosynthesis of pyrimidines in parasites such as Plasmodium falciparum and Toxoplasma gondii (Phillips et al., 2008, J. Biol. Chem.). Unlike human cells, which can utilize salvage pathways to acquire pyrimidines, these protozoal parasites rely almost exclusively on the de novo pathway for DNA and RNA synthesis, making DHODH a critical metabolic bottleneck (Ross et al., 2014, Nature Communications). The enzyme catalyzes the fourth step of the pathway, the oxidation of dihydroorotate to orotate, coupled with the reduction of ubiquinone in the mitochondrial electron transport chain. Because of significant structural differences between the parasite and human versions of the enzyme—specifically in the ubiquinone-binding tunnel—highly selective inhibitors like DSM265 have been developed to target the parasite without affecting the host (Booker et al., 2010, J. Biol. Chem.). This selectivity is vital for treating infections like malaria while minimizing side effects related to human pyrimidine depletion (McCarthy et al., 2017, Lancet Infect Dis).

Other names

Dihydroorotate dehydrogenase (quinone)Dihydroorotate oxidasePlasmodium falciparum dihydroorotate dehydrogenasePfDHODHToxoplasma gondii dihydroorotate dehydrogenaseTgDHODH

Inhibition of the enzyme prevents the conversion of dihydroorotate to orotate, thereby halting de novo pyrimidine synthesis which is essential for DNA and RNA production in parasites that lack salvage pathways (Coteron et al., 2011, J. Med. Chem.).