Fungal dihydroorotate dehydrogenase (DHODH)

Fungal dihydroorotate dehydrogenase (DHODH) is a mitochondrial (class II) flavoenzyme and oxidoreductase that catalyzes the fourth and rate-limiting step in the de novo biosynthesis of pyrimidine nucleotides: the ubiquinone-dependent oxidation of dihydroorotate to orotate. This enzyme is essential for RNA and DNA synthesis in fungi and is critical for fungal growth and cell wall integrity. Fungal DHODH shows significant sequence and structural divergence from mammalian DHODH, enabling selective inhibition by small molecules and making it an attractive and validated target for antifungal drug development. Drugs such as olorofim demonstrate potent inhibition of fungal DHODH with minimal activity against human isoforms, providing effective antifungal activity with a potentially favorable safety profile. Fungal DHODH inhibitors represent a new therapeutic class to counter resistance to existing antifungals[2][3][4][5][6][7].

Other names

Dihydroorotate dehydrogenase (class II in most pathogenic fungi)Pyr4 (gene in some fungal species)AfDHODH (*Aspergillus fumigatus* DHODH)

Selective inhibition of fungal DHODH enzyme, blocking conversion of dihydroorotate to orotate, thereby halting de novo pyrimidine biosynthesis. Starvation of RNA and DNA precursors causes inhibition of fungal cell proliferation, resulting in antifungal effects[2][3][5]