Dihydroorotate dehydrogenase (DHODH) is an enzyme required for de novo pyrimidine synthesis. In humans, it is a mitochondrial protein identified as a drug target in cancer and immunological disorders. Prokaryotic DHODH is also a target for antiviral and antibacterial compounds.
Dihydroorotate dehydrogenase (DHODH) EC 188.8.131.52 is a flavoenzyme responsible for the fourth step of de novo pyrimidine synthesis, required to produce DNA and RNA. In humans, DHODH is a monomeric protein found on the inner mitochondrial membrane, encoded by the DHODH gene.
DHODH is conserved across eukatyotes and prokaryotes, with proteins designated as Class 1 or Class 2 depending on sequence similarity, subcellular location and preference for substrate. Class 1 DHODH are soluble, cytosolic proteins, further split into class 1A and class 1B. Class 1A DHODH are encoded by the pyrD gene and are found in lower eukaryotes and gram-positive bacteria, while class 1B DHODH are heterotetrameric proteins composed of subunits encoded by the pyrD and pyrK genes, also found in gram-positive bacteria. Class 2 DHODH, of which human DHODH is an example, are monomeric proteins found on the inner membrane of mitochondria in eukaryotes and the cytosolic membrane of some prokaryotes.
The activity of DHODH is essential throughout mammalian facial and limb development. Mutations in the DHODH gene in humans cause Miller syndrome (also known as post axial acrofacial dystosis, POADS); a rare genetic disorder resulting in craniofacial malformation with abnormality of the arms, hands and/or feet.
DHODH is a potential drug target in cancer, immunological disorders, bacterial and viral infections and parasitic diseases. Inhibitors of DHODH, and therefore pyrimidine synthesis, are clinically available for the treatment of rheumatoid and psoriatic arthritis and multiple sclerosis. Inhibitors have also been developed to combat malaria, targeting Plasmodium DHODH.
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