Dihydroorotate dehydrogenase (fumarate)

Dihydroorotate dehydrogenase (fumarate), often abbreviated as DHODH (fumarate), is an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidines. Specifically, it oxidizes dihydroorotate to orotate, using fumarate as the electron acceptor. This reaction is essential for the production of the pyrimidine nucleotides uridine monophosphate (UMP), cytidine monophosphate (CMP), thymidine monophosphate (TMP), and their phosphorylated derivatives, which are crucial building blocks for RNA and DNA.

In many organisms, including Escherichia coli and other bacteria, DHODH is a membrane-associated enzyme, typically bound to the cytoplasmic membrane. This membrane association allows for efficient electron transfer to quinones in the respiratory chain, which are used in energy generation. The enzyme in these organisms utilizes ubiquinone (coenzyme Q) as the electron acceptor, and is sometimes classified as Dihydroorotate dehydrogenase (quinone).

DHODH (fumarate), on the other hand, is a soluble, cytosolic enzyme found in eukaryotic organisms, including humans. It directly reduces fumarate to succinate during the oxidation of dihydroorotate. The reduced fumarate plays a role in cellular metabolism.

The reaction catalyzed by DHODH is:

Dihydroorotate + Fumarate -> Orotate + Succinate

Inhibition of DHODH can block pyrimidine biosynthesis, making it a potential target for therapeutic intervention. Several drugs, such as leflunomide and teriflunomide, are DHODH inhibitors used in the treatment of autoimmune diseases like rheumatoid arthritis and multiple sclerosis. These drugs reduce the proliferation of lymphocytes by limiting pyrimidine availability. The inhibition of pyrimidine synthesis can lead to a decrease in DNA and RNA synthesis, thus suppressing the immune response. The selectivity of these inhibitors for mammalian DHODH over bacterial DHODH makes them useful as therapeutic agents with reduced impact on the gut microbiome.