Dihydroorotate dehydrogenase (mitochondrial) (DHODH) (DHODH)

Dihydroorotate dehydrogenase (DHODH) is a rate-limiting mitochondrial enzyme that catalyzes the fourth step of the de novo pyrimidine biosynthesis pathway, converting dihydroorotate to orotate (UniProt: Q02127). This enzyme is uniquely positioned in the inner mitochondrial membrane, where it couples the production of uridine monophosphate (UMP) to the mitochondrial electron transport chain via the reduction of ubiquinone (PubMed: 25605871). While most cells can maintain nucleotide pools through salvage pathways, activated T and B lymphocytes are critically dependent on de novo synthesis to support rapid proliferation (StatPearls: Teriflunomide). Consequently, DHODH serves as a major therapeutic target for immunomodulatory drugs like teriflunomide, which is used to treat relapsing forms of multiple sclerosis by limiting the expansion of pathogenic neuroreactive lymphocytes (FDA: Aubagio Label). Beyond its role in autoimmunity, DHODH is an emerging target in oncology, as many cancer cells exhibit a "pyrimidine addiction" to support uncontrolled growth (PubMed: 32814843). The inhibition of DHODH leads to a depletion of intracellular pyrimidine pools, resulting in cytostatic effects rather than cytotoxic ones in most contexts.

Other names

Dihydroorotate oxidaseDHODPYRDDihydroorotate dehydrogenase

Non-competitive inhibition of the enzyme dihydroorotate dehydrogenase (DHODH), which blocks the de novo synthesis of pyrimidine nucleotides (specifically UMP), leading to cell cycle arrest in rapidly dividing cells like activated lymphocytes.