InterPro domain: IPR004721

Dihydroorotase belongs to MEROPS peptidase family M38 (clan MJ), where it is classified as a non-peptidase homologue. DHOase catalyses the third step in the de novo biosynthesis of pyrimidine, the conversion of ureidosuccinic acid (N-carbamoyl-L-aspartate) into dihydroorotate. Dihydroorotase binds a zinc ion which is required for its catalytic activity [ 1 ].

In bacteria, DHOase is a dimer of identical chains of about 400 amino-acid residues (gene pyrC). In the metazoa, DHOase is part of a large multi-functional protein known as 'rudimentary' in Drosophila melanogaster and CAD in mammals and which catalyzes the first three steps of pyrimidine biosynthesis [ 2 ]. The DHOase domain is located in the central part of this polyprotein. In yeast, DHOase is encoded by a monofunctional protein (gene URA4). However, a defective DHOase domain [ 3 ] is found in a multifunctional protein (gene URA2) that catalyzes the first two steps of pyrimidine biosynthesis.

The comparison of DHOase sequences from various sources shows [ 4 ] that there are two highly conserved regions. The first located in the N-terminal extremity contains two histidine residues suggested [ 5 ] to be involved in binding the zinc ion. The second is found in the C-terminal part. Members of this family of proteins are predicted to adopt a TIM barrel fold [ 5 ].

This family represents the homodimeric form of dihydroorotase 3.5.2.3 . It is found in bacteria, plants and fungi; URA4 of yeast is a member of this group of sequences.

1. Dihydroorotase from Escherichia coli. Substitution of Co(II) for the active site Zn(II). J. Biol. Chem. 266, 1597-604
2. The evolutionary history of the first three enzymes in pyrimidine biosynthesis. Bioessays 15, 157-64
3. Organization of the yeast URA2 gene: identification of a defective dihydroorotase-like domain in the multifunctional carbamoylphosphate synthetase-aspartate transcarbamylase complex. Gene 79, 59-70
4. Structure of the Saccharomyces cerevisiae URA4 gene encoding dihydroorotase. Mol. Gen. Genet. 212, 134-41
5. An evolutionary treasure: unification of a broad set of amidohydrolases related to urease. Proteins 28, 72-82