De novo pyrimidine synthesis (glutamine -> UMP); orotic aciduria, Miller syndrome, CAD-DEE

De novo pyrimidine biosynthesis is the six-step pathway that builds uridine monophosphate (UMP) — the parent pyrimidine ribonucleotide from which CTP, UTP, dTTP and the other pyrimidines derive — from glutamine, bicarbonate, ATP, aspartate and PRPP. Unlike de novo purine synthesis, the ring is assembled first and only attached to ribose-phosphate at the fifth step. The large multifunctional cytosolic protein CAD performs the first three steps: carbamoyl-phosphate synthetase II (glutamine + 2 ATP + HCO3- -> carbamoyl phosphate; the cytosolic pyrimidine CPS, distinct from the mitochondrial urea-cycle CPS1), aspartate transcarbamylase (-> N-carbamoyl-aspartate) and dihydroorotase (-> dihydroorotate). Dihydroorotate dehydrogenase (DHODH) — the only membrane-bound, mitochondrial step — then oxidises dihydroorotate to orotate using FMN and ubiquinone, coupling pyrimidine synthesis to the respiratory chain. Finally the bifunctional UMP synthase (UMPS) attaches PRPP (orotate phosphoribosyltransferase -> OMP) and decarboxylates OMP to UMP. Inherited defects: UMPS deficiency causes hereditary orotic aciduria (megaloblastic anemia, uridine-responsive); DHODH deficiency causes Miller syndrome (postaxial acrofacial dysostosis); and CAD deficiency causes a uridine-responsive developmental and epileptic encephalopathy. DHODH is the target of the immunosuppressant leflunomide/teriflunomide.