orotate

**Pathway (de novo pyrimidine synthesis):** Glutamine + CO2 + 2 ATP → carbamoyl phosphate (CPS II, cytosolic; rate-limiting; inhibited by UTP, activated by PRPP) → + aspartate → carbamoyl aspartate (aspartate transcarbamoylase) → dihydroorotate (dihydroorotase) → **orotate** (dihydroorotate dehydrogenase, mitochondrial inner membrane; inhibited by leflunomide and teriflunomide) → orotidine-5'-monophosphate (OMP) (orotate phosphoribosyltransferase, uses PRPP) → UMP (OMP decarboxylase). The last two steps are catalyzed by the bifunctional enzyme **UMP synthase**.

**Hereditary orotic aciduria:** - Autosomal recessive UMP synthase deficiency. - Presents in infancy with megaloblastic anemia that does not respond to B12 or folate, failure to thrive, developmental delay, and orotic acid crystals in the urine. - There is no hyperammonemia, which distinguishes it from OTC deficiency. - Treatment is oral uridine (or triacetyluridine), which bypasses the block and also provides negative feedback by inhibiting CPS II.

**OTC deficiency (X-linked recessive urea cycle disorder):** - Carbamoyl phosphate accumulates in mitochondria and spills into the cytosol, where it enters the pyrimidine pathway. This increases orotic acid. - Findings: hyperammonemia, increased orotic acid in blood and urine, decreased BUN, and neurologic symptoms (lethargy, vomiting, cerebral edema), often after protein intake. - Treatment: low-protein diet, nitrogen scavengers (sodium benzoate, phenylbutyrate), and arginine or citrulline in some cases.

**Differentiating high orotic acid:** - Orotic aciduria: megaloblastic anemia, normal ammonia, normal BUN. - OTC deficiency: high ammonia, low BUN, no megaloblastic anemia.

**Other associations:** - Allopurinol and other drugs that inhibit OMP decarboxylase can raise orotate or orotidine levels. This is a classic test-writer link between purine and pyrimidine metabolism. - Leflunomide inhibits dihydroorotate dehydrogenase, which blocks pyrimidine synthesis in rapidly dividing lymphocytes (used in RA). - Mnemonic: with orotic aciduria, "no hyperammonemia."