Dihydroorotate dehydrogenase (DHODH) (DHODH)

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent enzyme located on the inner mitochondrial membrane that catalyzes the fourth step of the de novo pyrimidine synthesis pathway [1, 4]. It facilitates the oxidation of dihydroorotate to orotate, transferring electrons to ubiquinone and thereby linking nucleotide metabolism to the mitochondrial respiratory chain [2, 3]. Because rapidly proliferating cells, such as activated T-lymphocytes and cancer cells, rely heavily on de novo pyrimidine synthesis rather than the salvage pathway, DHODH serves as a critical therapeutic target [5, 9]. Drugs like leflunomide and its active metabolite teriflunomide inhibit DHODH to treat autoimmune conditions like rheumatoid arthritis and multiple sclerosis by suppressing immune cell expansion [7, 13]. Beyond immunology, DHODH inhibition is being explored for its potential to induce differentiation in myeloid leukemia and sensitize solid tumors to ferroptosis [3, 17, 20]. However, clinical use is often associated with safety concerns such as hepatotoxicity and potential teratogenic effects [8, 15, 18].

Other names

Dihydroorotate oxidaseDHO_dhPYRDDihydroorotate dehydrogenase (quinone), mitochondrial

Inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase, which catalyzes the fourth step of de novo pyrimidine biosynthesis (oxidation of dihydroorotate to orotate), leading to depletion of intracellular pyrimidine pools and subsequent suppression of cell proliferation and immune responses [1, 4, 7, 9].