Dihydro-orotate dehydrogenase (DHODH)

Dihydro-orotate dehydrogenase (DHODH) is a mitochondrial enzyme that catalyzes the fourth step in the *de novo* synthesis of pyrimidines, specifically converting dihydroorotate to orotate using quinone as an electron acceptor. This reaction is essential for generating uridine monophosphate (UMP), a precursor for all pyrimidine nucleotides required for DNA and RNA synthesis. In humans, DHODH is encoded by the *DHODH* gene on chromosome 16 and localizes to the outer surface of the inner mitochondrial membrane[1][7]. Structurally, DHODH exists in two main classes—Class 1 enzymes are cytosolic and use fumarate or NAD+ as electron acceptors; Class 2 enzymes are membrane-bound and use coenzyme Q/ubiquinones. The human enzyme belongs to Class 2. The active site contains flavin mononucleotide (FMN) as a cofactor[1][4]. DHODH plays a critical role in rapidly proliferating cells due to its function in nucleotide biosynthesis. It has emerged as an important therapeutic target for autoimmune diseases such as rheumatoid arthritis—where inhibitors like leflunomide suppress lymphocyte proliferation—and certain cancers where cell growth depends on robust nucleotide production[3][5]. Additionally, it has been explored as a target against infectious diseases including malaria and viral infections. Several small-molecule inhibitors have been developed targeting DHODH’s active site or ubiquinone-binding pocket; these include leflunomide/teriflunomide, brequinar, atovaquone, BAY2402234, and experimental compounds such as H‐006/furocoumavirin[2][5][6]. Mechanistically, these drugs block pyrimidine synthesis leading to S-phase arrest and apoptosis in susceptible cells. Therapeutic challenges include immunosuppression-related risks due to impaired lymphocyte function when inhibiting this enzyme systemically[3]. No widely used biomarkers exist specifically for patient selection or efficacy monitoring with current clinical DHODH inhibitors. In summary, Dihydro-orotate dehydrogenase is an essential mitochondrial flavoenzyme involved in nucleotide metabolism with established roles both physiologically—in cell growth—and pathologically—as a druggable target in cancer therapy and immune modulation[1][3].

Other names

Dihydroorotate dehydrogenaseDHODdihydroorotate oxidasedihydroorotic acid dehydrogenase

Inhibition of pyrimidine biosynthesis by blocking the oxidation of dihydroorotate to orotate