A771726 (Teriflunomide), Active metabolite of leflunomide. Dihydroorotate dehydrogenase inhibitor.

Supplementary information

This supplementary information is collated from multiple sources and compiled automatically.

Dihydroorotate dehydrogenase (DHODH) also known as URA1 is an enzyme weighing approximately 43 kDa. It plays a critical role in the de novo pyrimidine biosynthesis pathway. DHODH is mainly expressed in the inner mitochondrial membrane where it catalyzes the conversion of dihydroorotate to orotate. This reaction involves ubiquinone as an electron acceptor making DHODH an important player in cellular respiration. Its functionality is essential for the synthesis of nucleotides particularly in rapidly proliferating cells.

Biological function summary

Dihydroorotate dehydrogenase is involved in establishing the pyrimidine pool necessary for DNA and RNA synthesis. It is a single-component enzyme but its activity supports the function of other enzymes in the pathway such as carbamoyl-phosphate synthetase. The proper regulation of DHODH is integral to cellular proliferation and immune responses. Cells that synthesize nucleotides at high rates such as immune cells and cancer cells heavily depend on its activity.

Pathways

Dihydroorotate dehydrogenase is an important player in the pyrimidine biosynthesis pathway and links to the mitochondrial electron transport chain. Its interaction with ubiquinone underlines its role in energy production connecting it to respiratory complexes. DHODH works alongside proteins such as orotate phosphoribosyltransferase which further transforms orotate to orotidine-5'-monophosphate in pyrimidine biosynthesis. These pathways are vital for maintaining the balance of nucleotide levels impacting processes like DNA replication.

Dihydroorotate dehydrogenase is relevant to autoimmune diseases like rheumatoid arthritis and cancers. Inhibitors such as leflunomide and brequinar target DHODH to disrupt the proliferation of rapidly dividing cells. Leflunomide which is metabolized to teriflunomide reduces immune cell turnover in rheumatoid arthritis illustrating DHODH's therapeutic importance. Similarly it is a target in cancer treatment where its inhibition can slow down tumor growth interfacing with other metabolic regulators active in malignancies.