Dihydroorotase (DHOase) catalyzes the reversible cyclization of N-carbamyl-l-aspartate (CA-asp) to l-dihydroorotate (DHO), which is third step in the de novo biosynthesis of pyrimidine nucleotides. The pathway is subject to diverse regulatory mechanisms including allosteric inhibition and activation, phosphorylation, and perhaps changes in intracellular location. Understanding the operation and interplay of these controls in the cell remains a fascinating challenge. Modulating the pyrimidine metabolism pharmacologically has therapeutical uses.
Pyrimidine synthesis inhibitors are used in active moderate to severe rheumatoid and psoriatic arthritis.
Each subunit of the homodimeric enzyme folds into a TIM barrel with eight parallel beta strands in the center and alpha-helices on the outer surface of the molecule. Each subunit contains a binuclear zinc center and carboxylated Lys-103 serving as a bridging ligand between the two cations. Structural studies of apo- and different complexes with ligands and inhibitors revealed importance of the surface loop (residues 106-116), which is involved in the ligand binding.