Biochemistry Notes for Class 12 Topic “Proteins- Urea Cycle” Complete Notes for Class 12

Urea Cycle

Urea is the major end product of nitrogen catabolism in humans. Urea synthesis is a cyclic process. Synthesis of 1 mol of urea requires 3 mol of ATP plus 1 mol each of ammonium ion and of the a-amino nitrogen of aspartate. Five enzymes catalyze the numbered reactions of Figure 3.8. Of the six participating amino acids, N-acetylglutamate functions solely as an enzyme activator. The others serve as carriers of the atoms that ultimately become urea. The major metabolic role of ornithine, citrulline, and argininosuccinate in mammals is urea synthesis. Since the ornithine consumed in reaction 2 is regenerated in reaction 5, there is no net loss or gain of ornithine, citrulline, argininosuccinate, or arginine. Ammonium ion, CO2, ATP, and aspartate are, however, consumed. Some reactions of urea synthesis occur in the matrix of the mitochondrion, other reactions in the cytosol.

Carbamoyl phosphate synthase I initiates Urea biosynthesis
Condensation of CO2, ammonia, and ATP to form carbamoyl phosphate is catalyzed by mitochondrial carbamoyl phosphate synthase I. Carbamoyl phosphate synthase I, the rate-limiting enzyme of the urea cycle, is active only in the presence of its allosteric activator N-acetylglutamate, which enhances the affinity of the synthase for ATP.

Carbamoyl phosphate plus Ornithine forms Citrulline
L-Ornithine transcarbamoylase catalyzes transfer of the carbamoyl group of carbamoyl phosphate to ornithine, forming citrulline and orthophosphate. While the reaction occurs in the mitochondrial matrix, both the formation of ornithine and the subsequent metabolism of citrulline take place in the cytosol.

Citrulline plus Aspartate forms Argininosuccinate
Argininosuccinate synthase links aspartate and citrulline via the amino group of aspartate and provides the second nitrogen of urea. The reaction requires ATP and involves intermediate formation of citrullyl-AMP. Subsequent displacement
of AMP by aspartate then forms citrulline.

Cleavage of Argininosuccinate forms Arginine and Fumarate
Cleavage of argininosuccinate, catalyzed by argininosuccinase, proceeds with retention of nitrogen in arginine and release of the aspartate skeleton as fumarate.

Cleavage of Arginine releases Urea and re-forms Ornithine
Hydrolytic cleavage of the guanidino group of arginine, catalyzed by liver arginase, releases urea. The other product, ornithine, reenters liver mitochondria for additional rounds of urea synthesis.

Carbamoyl phosphate synthase I is the pacemaker enzyme of the Urea cycle
The activity of carbamoyl phosphate synthase I is determined by Nacetylglutamate, 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 N-acetylglutamate synthase and Nacetylglutamate 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 of ammonia that accompanies enhanced protein degradation.

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