Pyrimidine biosynthesis, in which orotic acid is a major intermediate, is regulated at the level of carbamylphosphate synthetase II (CPS II), the enzyme catalyzing the first reaction in this pathway. The isoenzyme CPS I (a mitochondrial enzyme) catalyzes the production of carbamylphophate during the process of urea synthesis. Under conditions in which mitochondrial carbamylphosphate accumulates (e.g. in urea cycle disorders), cytosolic carbamylphosphate levels rise and urine orotic acid excretion increases. This may be recognised in organic acid analysis, but orotic acid is a charged nitrogen species which has very limited solubility in organic solvents and the amount detected by routine GC-MS is a fraction of the actual concentration. Therefore accurate quantification of orotic acid requires LC-MS/MS analysis.
Urine orotic acid analysis is one of the key investigations in significant hyperammonaemia. Increased urinary excretion of orotic acid is a feature of four IMDs involving the urea cycle:
In the past, an allopurinol loading test has been used to tests heterozygous female carriers for OTC deficiency however, this is no longer used as mutational analysis provides more accurate information.
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