Dihydroorotate dehydrogenase, mitochondrial (DHODH)

Dihydroorotate dehydrogenase, mitochondrial (DHODH), is a flavin mononucleotide-dependent enzyme located on the outer surface of the inner mitochondrial membrane. It catalyzes the fourth step in the de novo pyrimidine biosynthetic pathway—the ubiquinone-mediated oxidation of dihydroorotate to orotate—which is essential for generating pyrimidines required for DNA and RNA synthesis. Unlike other enzymes in this pathway that are cytosolic, DHODH uniquely resides within mitochondria. Its activity links nucleotide metabolism with cellular energy status and redox balance. DHODH is a validated therapeutic target; its inhibition suppresses lymphocyte proliferation—making it useful for treating autoimmune diseases such as rheumatoid arthritis—and has shown promise as an anti-cancer strategy due to its role in supporting rapid cell division. Genetic mutations in *DHODH* cause Miller syndrome, a rare developmental disorder affecting craniofacial structures and limb formation. Clinically used inhibitors include leflunomide/teriflunomide; experimental compounds such as brequinar and furocoumavirin have also been studied. Safety concerns primarily relate to immunosuppression from long-term enzyme inhibition[1][3][5][6].

Other names

Dihydroorotate dehydrogenaseDHODHDHOdehasePOADSURA1[3][5]

Inhibition of DHODH blocks de novo pyrimidine biosynthesis, leading to reduced DNA/RNA synthesis and cell proliferation; this is cytostatic or cytotoxic in rapidly dividing cells such as lymphocytes or cancer cells[1][6].