Acetylglutamate synthase

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

This enzyme [EC 2.3.1.35], also known as ornithine ace-tyltransferase, and ornithine transacetylase, catalyzes the reversible reaction of A -acetyl-L-ornithine with L-gluta-mate to produce L-ornithine and A-acetyl-L-glutamate. This protein also exhibits a low hydrolysis activity (about 1% of that of the transferase activity) of iV -acetyl-L-ornithine to yield acetate and L-ornithine. This enzyme is not identical with A-acetylglutamate synthase [EC 2.3.1.1]. 

ACETYL-CoA ACYLTRANSFERASE ACETYL-CoAACP TRANSACYLASE ACETYL-CoA CARBOXYLASE ACETYL-CoA SYNTHETASE N-ACETYLGLUTAMATE SYNTHASE... 

Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M. Restoration of ure-agenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr 2004 145(4) 552-4. 

N-Acetylglutamate synthase deficiency p Glut, Cit, Argt, Lysj... 

Table 2.1.9 Changes of blood amino acids in various primary inherited defects and as a result of secondary changes. ASA Argininosuccinic acid, CPS carbamoyl phosphate synthase, LPI Lysinuric protein intolerance, MAD multiple acyl-CoA dehydrogenation, MSUD maple syrup urine disease, NAGS N-acetylglutamate synthase, NKH nonketotic hyperglycinemia, NTBC 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione, OCT Ornithine carbamoyltransferase,...

ATP -I- N-acetyl-L-glutamate = ADP -I- N-acetyl-L-glutamate 5-phosphate (<2> random bi-bi mechanism [8] <3> mechanism [9] <6> enzyme has to interact stoichiometrically with acetylglutamate synthase in order to be active [10,12])... 

Abadjieva, A. Pauwels, K. Hilven, P. Crabeel, M. A new yeast metabolon involving at least the two first enzymes of arginine biosynthesis acetylglutamate synthase activity requires complex formation with acetylglutamate kinase. J. Biol. Chem., 276, 42869-42880 (2001)... 

Pauwels, K. Abadjieva, A. Hilven, P. Stankiewicz, A. Crabeel, M. The N-acetylglutamate synthase/N-acetylglutamate kinase metabolon of Saccharo-myces cerevisiae allows co-ordinated feedback regulation of the first two steps in arginine biosynthesis. Eur. J. Biochem., 270, 1014-1024 (2003)... 

Other therapies are more specific to a particular enzyme deficiency. Deficiency of Ai-acetylglutamate synthase results in the absence of the normal activator of carbamoyl phosphate synthetase I (Fig. 18-13). This condition can be treated by administering carbamoyl glutamate, an analog of Af-acetylglutamate that is effective in activating carbamoyl phosphate synthetase I. 

Integrates the latest on regulation of reactions throughout the chapter, with new material on genetic defects in urea cycle enzymes, and updated information on the regulatory function of N-acetylglutamate synthase. 

A-Acetylglutamate is synthesized from acetyl CoA and glutamate. Once again, acetyl CoA serves as an activated acetyl donor. This reaction is catalyzed by A-acetylglutamate synthase. 

Formation of urea in hepatocytes. NAGS = N-acetylglutamate synthase CPSI = carbamoylphosphate synthase I OCT = ornithine carbamoyltransferase C-OT = citrulline-omithine translocase AS = argininosuccinate synthase AL = argininosuccinate lyase A = arginase. — -> indicates the absolute requirement of N-acetylglutamate for CPSI activity. 

Carbamoyl phosphate synthesis requires amino acid acetyltransferase (N-acetylglutamate synthase, mitochondrial) and carbamoyl-phosphate synthase I (CPSI). N-Acetylglutamate (NAG) is an obligatory positive effector of CPSI. NAG synthase is under positive allosteric modulation by arginine and product inhibition by NAG. Depletion of CoA-SH decreases NAG synthesis and ureage-nesis. This situation can occur in organic acidemias (e.g., propionic acidemia Chapter 18), in which organic acids produced in excess compete for CoA-SH for formation... 

The urea cycle enzymes are controlled in the short term by the concentrations of their substrates. Carbamoyl phosphate synthetase I is also allosterically activated by N-acetylglutamate. This latter molecule is a sensitive indicator of the cell s glutamate concentration. (Recall that a significant amount of NH4 is derived from glutamate.) N-acetylglutamate is produced from glutamate and acetyl-CoA in a reaction catalyzed by N-acetylglutamate synthase. 

Recall What is the logic behind high levels of arginine positively regulating A -acetylglutamate synthase ... 

Propionyl CoA and methylmalonyl CoA both inhibit N-acetylglutamate synthase activity in slices of liver tissue. What clinical symptom would you expect to see in patients suffering from methylmalonic aciduria as a result of this inhibition ... 

A novel type of N-acetylglutamate synthase is involved in the first step of arginine biosynthesis in Corynebacterium glutamicum. BMC Genomics,... 

Haberle J. Role of caiglumic add in the treatment of acute hyperammonemia due to N-acetylglutamate synthase defidency. Ther Qin Risk Manag. 2011 7 327-32. 

Urea cycle disorders A-acetylglutamate iV-acetylglutamate synthase (NAGS) synthase deficiency... 

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