BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II: GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 18. AMINO ACID DEGRADATION AND THE UREA CYCLE

18.3. Serine and Threonine Can Be Deaminated Directly

The α-amino groups of Serine and Threonine can be converted directly into NН₄ because each of these Amino Acids possesses a hydroxyl group in its side chain. These direct deamination reactions are catalyzed by serine dehydratase and Threonine dehydratase, both of which require PLP as a prosthetic group.

Serine + Pyruvate + NH₄⁺,

Threonine → α-Ketobutyrate + NН₄⁺.

These Enzymes are called dehydratases because the deamination steps they catalyze are preceded by dehydration. Serine loses a hydrogen atom from its α-carbon and a hydroxyl group from its β-carbon to form aminoacrylate. This unstable compound reacts with H₂O to yield pyruvate and NН₄⁺.

18.4. In Most Terrestrial Vertebrates, Excess Nitrogen Is Converted into Urea and Excreted

A portion of the NН₄⁺ generated during amino acid degradation is utilized in The Biosynthesis of nitrogen-containing compounds. In most terrestrial vertebrates, excess NН₄⁺ is converted into urea and excreted in this form. In Birds and terrestrial reptiles, NН₄⁺ is converted into uric acid for excretion, whereas many aquatic animals excrete it directly as ammonia. These three groups of organisms are referred to as ureotelic, uricotelic, and ammonotelic, respectively.

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Fig. 18.4. The Urea Cycle

In terrestrial vertebrates, urea is synthesized via the urea cycle. This pathway of reactions was proposed by Hans Krebs and Kurt Henseleit in 1932—five years before the discovery of The Tricarboxylic Acid Cycle. Indeed, the urea cycle was the first cyclic metabolic pathway ever discovered. One of the nitrogen atoms of urea synthesized in this cycle is derived from ammonia, and the other from aspartate. The carbon atom of urea originates from СO₂. Ornithine serves as the carrier that transports these carbon and nitrogen atoms through the urea cycle.

The immediate precursor of urea is Arginine, which is hydrolyzed by arginase to yield urea and ornithine. The remaining Reactions of the urea cycle accomplish the synthesis of arginine from ornithine. First, a carbamoyl group is transferred to ornithine to form citrulline, a reaction catalyzed by ornithine transcarbamylase. The donor of the carbamoyl group in this reaction is carbamoyl phosphate, which has a high group-transfer potential owing to its anhydride bond.

Argininosuccinate synthetase subsequently catalyzes the Condensation of citrulline and aspartate. This synthesis of argininosuccinate is driven by the Cleavage of ATP to AMP and pyrophosphate, followed by the subsequent Hydrolysis of pyrophosphate.

In the final step, argininosuccinase cleaves argininosuccinate into arginine and fumarate. Notably, through these Reactions Involving the transfer of the amino group of aspartate to form arginine, the carbon Skeleton of aspartate is preserved.

Carbamoyl phosphate is synthesized from NH₄⁺, СO₂, ATP, and H₂O in a complex reaction catalyzed by carbamoyl phosphate synthetase. An unusual property of this enzyme is its absolute requirement for N-acetylglutamate for catalytic activity.

The consumption of two ATP molecules renders the synthesis of carbamoyl phosphate effectively irreversible.

18.5. The Urea Cycle is Linked to the Tricarboxylic Acid Cycle

The stoichiometry of urea synthesis is as follows:

СO₂ + NH₄ ⁺+ ЗАТР + Аспартат + 2Н₂O → Мочевина + 2ADP + 2 Pi + АМР + PP_i + Фумарат.

Pyrophosphate is rapidly hydrolyzed, meaning that four high-energy phosphate bonds are consumed in the synthesis of a single urea molecule. The synthesis of fumarate plays a crucial role in the urea cycle because it interconnects the urea cycle and the tricarboxylic acid cycle (Fig. 18.5). Fumarate is hydrated to malate, which is subsequently oxidized to oxaloacetate. For this key intermediate, several metabolic fates are possible: 1) it can undergo Transamination to yield aspartate; 2) it can be converted into glucose via Gluconeogenesis; 3) it can condense with acetyl-CoA to form citrate.

Fig. 18.5. The urea cycle, the tricarboxylic acid cycle, and the transamination of oxaloacetate are interconnected via fumarate and aspartate

Another remarkable feature is the compartmentalization of the urea cycle and its associated reactions. The production mediated by Glutamate dehydrogenase, its incorporation into carbamoyl phosphate, and the subsequent synthesis of citrulline all take place within the mitochondrial matrix. In contrast, the next Three Reactions of the urea cycle, which lead to The formation of urea, occur in the Cytosol.