InterPro domain: IPR005719

Dihydroorotate dehydrogenase (DHOD), also known as dihydroorotate oxidase, catalyses the fourth step in de novo pyrimidine biosynthesis, the stereospecific oxidation of (S)-dihydroorotate to orotate, which is the only redox reaction in this pathway. DHODs can be divided into two mains classes: class 1 cytosolic enzymes found primarily in Gram-positive bacteria, and class 2 membrane-associated enzymes found primarily in eukaryotic mitochondria and Gram-negative bacteria [ 1 ].

The class 1 DHODs can be further divided into subclasses 1A and 1B, which differ in their structural organisation and use of electron acceptors. The 1A enzyme is a homodimer of two PyrD subunits where each subunit forms a TIM barrel fold with a bound FMN cofactor located near the top of the barrel [ 2 ]. Fumarate is the natural electron acceptor for this enzyme. The 1B enzyme, in contrast is a heterotetramer composed of a central, FMN-containing, PyrD homodimer resembling the 1A homodimer, and two additional PyrK subunits which contain FAD and a 2Fe-2S cluster [ 3 ]. These additional groups allow the enzyme to use NAD(+) as its natural electron acceptor.

The class 2 membrane-associated enzymes are monomers which have the FMN-containing TIM barrel domain found in the class 1 PyrD subunit, and an additional N-terminal alpha helical domain [ 4 , 5 ]. These enzymes use respiratory quinones as the physiological electron acceptor.

This entry represents the enzyme protein dihydroorotate dehydrogenase (also called quinone) exclusively for class 2. It includes members from bacteria, yeast, plants etc. The subfamilies 1 and 2 share extensive homology, particularly toward the C terminus. This subfamily has a longer N-terminal region.

1. Active site of dihydroorotate dehydrogenase A from Lactococcus lactis investigated by chemical modification and mutagenesis. Biochemistry 36, 16197-205
2. The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A complexed with the enzyme reaction product throws light on its enzymatic function. Protein Sci. 7, 1269-79
3. Structure of dihydroorotate dehydrogenase B: electron transfer between two flavin groups bridged by an iron-sulphur cluster. Structure 8, 1227-38
4. Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure 8, 25-33
5. E. coli dihydroorotate dehydrogenase reveals structural and functional distinctions between different classes of dihydroorotate dehydrogenases. Structure 10, 1211-23