Mitochondrial dihydroorotate dehydrogenase (DHODH)

Mitochondrial dihydroorotate dehydrogenase (DHODH) is a critical enzyme in the de novo pyrimidine biosynthesis pathway of Eimeria species, which are apicomplexan parasites responsible for coccidiosis in poultry and livestock (PubMed: 11445235). This enzyme is located on the inner mitochondrial membrane and catalyzes the fourth step of the pyrimidine biosynthetic pathway: the oxidation of dihydroorotate to orotate. This reaction is coupled to the reduction of ubiquinone, thereby linking nucleotide synthesis to the mitochondrial electron transport chain (PubMed: 25650095). Because Eimeria parasites lack the ability to salvage preformed pyrimidines from their environment, they are entirely dependent on this de novo pathway for DNA and RNA production (UniProt). Consequently, DHODH is a validated therapeutic target; its inhibition leads to the depletion of intracellular pyrimidine pools, resulting in the cessation of parasite growth and replication. Research focuses on developing selective inhibitors, such as triazolopyrimidines, that exploit structural differences between the parasite enzyme and the host versions to minimize toxicity and overcome resistance to existing anticoccidials (PubMed: 30204105).

Other names

Dihydroorotate oxidaseDihydroorotate:ubiquinone oxidoreductaseDHODEmDHODHEtDHODHEimeria tenella dihydroorotate dehydrogenase

Inhibition of the de novo pyrimidine biosynthetic pathway by blocking the oxidation of dihydroorotate to orotate, leading to nucleotide depletion and inhibition of DNA/RNA synthesis.