A-Acetylglutamate

The activity of carbamoyl phosphate synthase I is determined by A -acetylglutamate, whose steady-state level is dictated by its rate of synthesis from acetyl-CoA and glutamate and its rate of hydrolysis to acetate and glutamate. These reactions are catalyzed by A -acetylglu-tamate synthase and A -acetylglutamate hydrolase, respectively. Major changes in diet can increase the concentrations of individual urea cycle enzymes 10-fold to 20-fold. Starvation, for example, elevates enzyme levels, presumably to cope with the increased production... 

Changes in enzyme levels and allosteric regulation of carbamoyl phosphate synthase by A -acetylglutamate regulate urea biosynthesis. 

This enzyme [EC 1.2.1.38], also known as A-acetylgluta-mate semialdehyde dehydrogenase and NAGSA dehydrogenase, catalyzes the reaction of A-acetylglutamate 5-semialdehyde with NADP+ and phosphate to generate A-acetyl-5-glutamyl phosphate and NADPH. 

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]. 

In the conversion of the /V-acetyl-y-glutamyl phosphate to A-acetylglutamic-y-semialdehyde (fig. 22.2), two processes occur An elimination of a phosphate and a reduction. Which step occurs first Also can you propose a reason for the use of the phosphate group in the first place ... 

Propionyl CoA inhibits A(-acetylglutamate synthetase competitively with respect to acetyl CoA, forming A(-propionylglutamate and reducing the synthesis of A(-acetylglutamate. This is an obligatory activator of carbamyl phosphate synthetase, the first enzyme of urea synthesis. Vitamin B12 deficiency may result in some degree of protein intolerance and hyperammonemia. 

Dejd vu. A-Acetylglutamate is required as a cofactor in the synthesis of carbamoyl phosphate. How might N-acetylglutamate be synthesized from glutamate ... 

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. 

Amidocarbonylation of functionalized olefins provides routes to a number of interesting and valuable amido acids. A-Acetylglutamic acid ester, a precursor for monosodium glutamate, can be synthesized from acrylate, acetamide, and syn gas in 85 % yield (eq. (7)) [14], This in-situ hydrofoimylation/amidocarbonyl-ation route affords the linear amido acids as the major product. By comparison. 

The first step in the formation of urea from ammonia is its combination with bicarbonate to form carbamyl phosphate (Fig. 1). This contributes only one nitrogen atom to urea, the other being donated by aspartic acid in the third step of the pathway. A -Acetylglutamate is required as cofactor, and the presence of Mg is essential, ATP being converted to ADP in the process. The reaction is catalyzed by carbamyl phosphate synthetase (carbamate kinase EC 2.7.2.2). It has been shown that there are probably two forms of this enzyme, at least in rat liver. One is ammonia dependent, is primarily associated with mitochondria, and may be the enzyme responsible for the formation of carbamyl phosphate in the synthesis of urea. The other, which is glutamine dependent, is probably mainly extramitochondrial and may supply the carbamyl phosphate used... 

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°. 

CPSI is activated by A-acetylglutamate as a required allosteric effector. 

Other therapies are more specific to a particular enzyme deficiency. Deficiency of A -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 A -acetylglutamate that is effective in activating carbamoyl phosphate synthetase 1. 

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

It is controlled by a special effector molecule, A -acetylglutamate, which is itself controlled by levels of arginine. 

Acetyl-CoA + glutamic acid A/-acetylglutamic acid + CoA iV -acetyl-L-omithine L-glutamate iV-acetyltransferase (E.C. 2.3.1.35)... 

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

AGAb A(-Acetylglutamic acid, a stimulatory allosteric effector of carbamoyl phosphate synthetase. 

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