Dihydroorotate dehydrogenase (mitochondrial) (DHODH)

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidines, converting dihydroorotate to orotate as part of nucleotide biosynthesis required for DNA and RNA production. Human DHODH is localized on the outer surface of the mitochondrial inner membrane and links mitochondrial energy metabolism with nucleotide synthesis; it requires ubiquinone as an electron acceptor, associating its action with redox processes. As a critical node in both cellular proliferation and immune function, DHODH is a validated therapeutic target for autoimmune diseases, some cancers (notably acute myeloid leukemia), viral and parasitic infections, and rare developmental disorders such as Miller syndrome arising from DHODH mutations. Multiple clinically approved and investigational drugs act by inhibiting DHODH, leading to disruption of the cellular pyrimidine pool, interference with nucleic acid synthesis, and antiproliferative or immunomodulatory effects. The enzyme contains an FMN cofactor, binds within a complex channel in its membrane domain, and is structurally targeted by diverse inhibitor classes with distinct pharmacological profiles.

Other names

Dihydroorotate dehydrogenaseDHOdehasedihydroorotate dehydrogenase, mitochondrialPOADSURA1 (used for the yeast enzyme)

Inhibition of de novo pyrimidine biosynthesis by blocking conversion of dihydroorotate to orotate, thereby reducing nucleotide pools and impairing DNA/RNA synthesis needed for cell proliferation and immune cell activity; Disruption of mitochondrial function and electron transport connected to redox metabolism; Induction of differentiation and apoptosis in rapidly proliferating cells (e.g., AML)