Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase

Abstract

Mice with the X-chromosomal sparse-fur (spf) mutation are an animal model of some hereditary deficiencies of ornithine carbamoyltransferase (OCT) in man. Orotic aciduria and hyperammonaemia are the most conspicuous metabolic changes in these diseases. Selective inactivation of ornithine aminotransferase (OAT) by 5-fluoromethylornithine raises endogenous ornithine concentrations so that citrulline formation is effectively catalysed by the aberrant OCT, in spite of its low affinity for ornithine. As a consequence, blood and tissue ammonia concentrations and orotic acid excretion are reduced near to normal values, and the abnormal amino acid patterns in blood, brain and liver are normalized. Selective inactivation of OAT seems a promising therapeutic approach in some hereditary OCT deficiencies, and a total that may allow us to clarify the role of ammonia and orotic acid in the development of nanism and abnormal behaviour in spf mutant mice.

Arginine and Ornithine Are the Main Precursors for Citrulline Synthesis in Mice3

“…In adults, the catabolic route seems to predominate (45,46). Furthermore, this directionality of OAT has been supported by in vivo studies showing that OAT inhibition in adult mice increased the plasma ornithine concentration (47,48), whereas in suckling piglets, OAT inhibition decreased ornithine levels (49). The inhibition of OAT in transgenic mice results in a paradoxical neonatal hypoornithemia and hyper-ornithemia after weaning, which mimics similar findings reported in humans with gyrate atrophy (50).…”

Sirt3 Promotes the Urea Cycle and Fatty Acid Oxidation during Dietary Restriction

“…Elevated orotic acid ( orotic aciduria ) is a reliable clinical marker of OTC deficiency (Finkelstein et al, 1990). When flux through OTC is decreased during urea cycle dysfunction, a subsequent buildup of carbamyol phosphate is then shunted into the pyrimidine biosynthetic pathway to form orotic acid (Brosnan and Brosnan, 2007; Seiler et al, 1994a). Consistent with the Sirt3-dependent increase in liver OTC activity (Figure 4D), urinary orotic acid was significantly decreased in response to CR (Figure 4E).…”