N-Acetylglutamic acid
N-Acetylglutamic acid is biosynthesized from glutamate and acetylornithine by ornithine acetyltransferase, and from glutamic acid and acetyl-CoA by the enzyme N-acetylglutamate synthase. The reverse reaction, hydrolysis of the acetyl group, is catalyzed by a specific hydrolase. It is the first intermediate involved in the biosynthesis of arginine in prokaryotes and simple eukaryotes and a regulator in the process known as the urea cycle that converts toxic ammonia to urea for excretion from the body in vertebrates.
Discovery
N-Acetylglutamic acid is an extracellular metabolite isolated from the prokaryote Rhizobium leguminosarum that was characterized using many structure determination techniques such as proton nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, and gas chromatography-mass spectrometry.In Rhizobium, extracellular build-up of N-acetylglutamic acid is due to metabolism involving nod factor genes on a symbiotic plasmid. When the nod factors are mutated, less N-acetylglutamic acid is produced.
Biosynthesis
Prokaryotes and simple eukaryotes
In prokaryotes and simple eukaryotes, N-acetylglutamic acid can be produced by N-acetylglutamate synthase or ornithine acetyltransferase.Ornithine acetyltransferase (OAT) synthesis
OAT synthesizes N-acetylglutamic acid from glutamate and acetylornithine and is the method of choice for production in prokaryotes that have the ability to synthesize the compound ornithine.''N''-Acetylglutamate synthase (NAGS) synthesis
N-Acetylglutamate synthase is an enzyme that serves as a replenisher of N-acetylglutamic acid to supplement any N-acetylglutamic acid lost by the cell through mitosis or degradation. NAGS synthesizes N-acetylglutamic acid by catalyzing the addition of an acetyl group from acetyl-coenzyme A to glutamate. In prokaryotes with non-cyclic ornithine production, NAGS is the sole method of N-acetylglutamic acid synthesis and is inhibited by arginine. Acetylation of glutamate is thought to prevent glutamate from being used by proline biosynthesis.Vertebrates
In contrast to prokaryotes, NAGS in mammals is enhanced by arginine, along with protamines. It is inhibited by N-acetylglutamic acid and its analogues.The brain also contains N-acetylglutamic acid at trace amounts, however no expression of NAGS is found. This suggests that N-acetylglutamic acid is produced by another enzyme in the brain that is yet to be determined.
Biological roles
Vertebrates and mammals
In vertebrae and mammals, N-acetylglutamic acid is the allosteric activator molecule to mitochondrial carbamyl phosphate synthetase I which is the first enzyme in the urea cycle. It triggers the production of the first urea cycle intermediate, carbamyl phosphate. CPSI is inactive when N-acetylglutamic acid is not present. In the liver and small intestines, N-acetylglutamic acid-dependent CPSI produces citrulline, the second intermediate in the urea cycle. Liver cell distribution of N-acetylglutamic acid is highest in the mitochondria at 56% of total N-acetylglutamic acid availability, 24% in the nucleus, and the remaining 20% in the cytosol. Aminoacylase I in liver and kidney cells degrades N-acetylglutamic acid to glutamate and acetate. In contrast, N-acetylglutamic acid is not the allosteric cofactor to carbamyl phosphate synthetase found in the cytoplasm, which is involved in pyrimidine synthesis.N-acetylglutamic acid concentrations increase when protein consumption increases due to the accumulation of ammonia that must be secreted through the urea cycle, which supports the role of N-acetylglutamic acid as the cofactor for CPSI. Furthermore, N-acetylglutamic acid can be found in many commonly consumed foods such as soy, corn, and coffee, with cocoa powder containing a notably high concentration.
Deficiency in N-acetylglutamic acid in humans is an autosomal recessive disorder that results in blockage of urea production which ultimately increases the concentration of ammonia in the blood. Deficiency can be caused by defects in the NAGS coding gene or by deficiencies in the precursors essential for synthesis.