Dihydroorotate dehydrogenase

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Dihydroorotate dehydrogenase

Dihydroorotate dehydrogenase (DHODH) is an enzyme that plays a crucial role in the de novo synthesis of pyrimidines. It catalyzes the fourth step in the pyrimidine biosynthesis pathway, which is the conversion of dihydroorotate to orotate. This reaction is essential for the production of uridine monophosphate (UMP), a precursor for all pyrimidine nucleotides.

Function

DHODH is a flavoprotein that uses flavin mononucleotide (FMN) as a cofactor. The enzyme is located in the inner mitochondrial membrane in eukaryotes and in the cytoplasm of prokaryotes. The reaction catalyzed by DHODH involves the oxidation of dihydroorotate to orotate, with the concomitant reduction of quinone to quinol in eukaryotes or the reduction of NAD+ to NADH in prokaryotes.

Structure

The structure of DHODH varies between species. In humans, DHODH is a monomeric enzyme composed of a single polypeptide chain. The active site of the enzyme contains a binding pocket for dihydroorotate and FMN. The enzyme also has a hydrophobic domain that anchors it to the inner mitochondrial membrane.

Clinical Significance

DHODH is a target for several immunosuppressive and antiproliferative drugs. Inhibitors of DHODH, such as leflunomide and teriflunomide, are used in the treatment of rheumatoid arthritis and multiple sclerosis, respectively. These drugs work by depleting pyrimidine pools, which inhibits the proliferation of rapidly dividing cells, including lymphocytes.

Genetic Disorders

Mutations in the DHODH gene can lead to Miller syndrome, a rare genetic disorder characterized by craniofacial abnormalities and limb defects. This condition is inherited in an autosomal recessive manner.

Research Applications

DHODH is studied extensively in the context of cancer and infectious diseases. Inhibitors of DHODH are being investigated as potential treatments for various types of cancer, as well as for malaria and viral infections.

See Also

• Pyrimidine metabolism
• Enzyme
• Mitochondrion
• Flavoprotein
• Leflunomide
• Teriflunomide