A mouse model of argininosuccinic aciduria: biochemical characterization.

Abstract

Argininosuccinate lyase (AL) has several roles in intermediary metabolism. It is an essential component of the urea cycle, providing a pathway for the disposal of excess nitrogen in mammals. AL links the urea cycle to the tricarboxylic acid (TCA) cycle by generating fumarate. Finally, AL is required for the endogenous production of arginine. In this latter role it may function outside ureagenic organs to provide arginine as a substrate for nitric oxide synthases (NOS). Increasing evidence suggests that argininosuccinate synthetase (AS) and AL are more globally expressed, and the coordinate regulation of AS and AL gene expression with that of the inducible form of NOS (iNOS) provides evidence that this may facilitate the regulation of NOS activity. Deficiency of AL leads to the human urea cycle disorder argininosuccinic aciduria. We produced an AL deficient mouse by gene targeting in order to investigate the role of AL in endogenous arginine production. This mouse also provides a model of the human disorder to explore the pathogenesis of the disorder and possible new treatments. Metabolic studies of these mice demonstrated that they have the same biochemical phenotype as humans, with hyperammonemia, elevated plasma argininosuccinic acid and low plasma arginine. Plasma nitrites, derived from NO, were not reduced in AL deficient mice and there was no significant difference is the level of cyclic GMP, the second messenger induced by NO.

• Authors: V Reid Sutton, Yanzhen Pan, Erica C Davis, William J Craigen
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 78 Issue 1 Pg. 11-6 (Jan 2003) ISSN: 1096-7192 [Print] United States
• PMID: 12559843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Argininosuccinic Acid
• Nitric Oxide
• Urea
• Arginine
• Ornithine Carbamoyltransferase
• Arginase
• Argininosuccinate Lyase
• Carbamoyl-Phosphate Synthase (Ammonia)
• Cyclic GMP

Topics

• Amino Acid Metabolism, Inborn Errors (enzymology, genetics, urine)
• Animals
• Arginase (metabolism)
• Arginine (blood)
• Argininosuccinate Lyase (genetics, metabolism)
• Argininosuccinic Acid (blood, urine)
• Argininosuccinic Aciduria
• Carbamoyl-Phosphate Synthase (Ammonia) (metabolism)
• Cyclic GMP (urine)
• Disease Models, Animal
• Female
• Genotype
• Humans
• Hyperammonemia (blood)
• Male
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• Nitric Oxide (metabolism)
• Ornithine Carbamoyltransferase (metabolism)
• Urea (metabolism)