N-Acetylglutamic acid

Hydrogenation of the amino compound 95a led to methyl 4-acet-amido-2,3,4-trideoxy-D-g(uco-octonate (121), its structure being established by degradation67 to N-acetylglutamic acid (122). Hydrogenation... 

N-Acetylglutamic acid 3.4 A mixture of dicobalt octacartoonyl (5.1 g, 15 mmol), acetamide 2 (53 g, 0.898 mol), ethyl acrylate 1 (75 g, 0.75 mol) and p-dioxane (150 g) was pressurized in an autoclave with a mixture of CO H2 to 500 psi. The system was heated to 130-153°C, repressurized to 2000 psi and maintained in this condition for 2 h. The mixture was basified with K2CO3 to pH=10, the by-product extracted with EtOAc and the aqueous solution acidified with 85% H3PO4 and extracted with EtOAc. There are obtained 126 g of 3 (77.4%). 

T-Labeled water added to acetic anhydride, allowed to reach equilibrium of labeled acetic acid and acetic anhydride, N-acetylglutamic acid added, and allowed to react 10 min. at lOO DL-glutamic acid-2-3H. Y 55%. Also deuterio analog s. M. C. Hodireiter and K. A. Schellenberg, J. Labelled Compds. 5, 270 (1969). 

Synonyms L-N-Acetylglutamic acid N-Acetylglutamic acid N-Acetyl-L-glutamic acid L-Glutamic acid, N-acetyl- Glutamic acid, N-acetyl-, L-... 

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,...

N-Acetylglutamate NAGS deficiency NAGS 17q21.31 Liver Citrulline i Orotic acid i... 

Branched-chain amino acids apparently stimulate the urea cycle. Carbamoylphosphate synthetase, which channels ammonia into the urea cycle, is induced by ornithine and N-acetylglutamate as a cofactor of urea synthesis. Here, BCAA follow two modes of action (i.) they stimulate the synthesis of N-acetylglutamate via synthetase formed from glutamate and acetyl CoA, and (2.) they inhibit omithine-keto acid transferase, which is the enzyme responsible for ornithine degradation, leading to an increase in ornithine concentration. Ammonia detoxication is thus stimuiated by two regu-iatory mechanisms, (s. fig. 40.2)... 

Two solutions are required to form the substrate mixture. Solution A contains 0.03 ATP and 0.03 M MgS04 7H20, adjusted to pH 6.7 with solid KHCO3. Solution B contains 0.04 M L-omithine hydrochloride and 0.04 ilf A -acetylglutamic acid and is adjusted to pH 6.0 with approximately 1 N KOH solution, made up to 0.4 M with the calculated amount of solid ammonium bicarbonate and adjusted to pH 7.5 with solid KHCO3. The substrate is prepared by mixing 2 parts of solution A with 1 part of solution B pH about 7. It is gassed with CO2 just before use until the pH is about 6.8 at 37°. 

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... 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

Note that NH, because it is a strong base, normally exists as NH4 in aqueous solution. However, carbamoyl phosphate synthetase uses only NH3 as a substrate. The reaction begins with the phosphorylation of HCO3 to form carboxyphosphate, which then reacts with NH3 to form carbamic acid. Finally, a second molecule of ATP phosphofylates carbamic acid to form carbamoyl phosphate. The structure and mechanism of the enzyme that catalyzes these reactions will be presented in Chapter 25. The consumption of two molecules of ATP makes this synthesis of carbamoyl phosphate essentially irreversible. The mammalian enzyme requires N-acetylglutamate for activity, as will be described shortly. 

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