Amino Acid Metabolism

Overview of Urea Cycle
Practice Exercise 1:	The carbon atom in urea is derived from which of the following compounds? No response Aspartate Glycine NH4+ CO2
Practice Exercise 2:	The formation of carbamoyl phosphate occurs in the cytosol of the cell. No Response True False
Practice Exercise 3:	In humans, the -amino group removed during the degradation of amino acids is secreted in the form of No response Ammonia Urea Carbamoyl phosphate Aspartate
Practice Exercise 4:	Urea is formed by the urea cycle by the hydrolysis of arginosuccinate. No Response True False

The details of the Urea Cycle, classified by the enzyme names, are shown below.

• Carbamoyl phosphate synthetase (in mitochondria)

  • CO₂ + NH₄⁺ + 2ATP + H₂O
    

    + 2ADP + P_i + 3 H⁺

  • Note that 2 high energy phosphate bonds are required for the formation of carbamoyl phosphate making this an essentially irreversible reaction.

  ---

• Ornithine Transcarbamoylase (in mitochondria)

  • +

  ---

• Arginosuccinate Synthetase (in cytosol)

  • + + ATP + AMP + PP_i

  • Note the unusual hydrolysis of ATP to form AMP and pyrophosphate ( PP_i). The PP_i is hydrolyzed to give 2 P_i. Therefore, this step requires 2 high energy phosphate bonds.

  ---

• Arginosuccinase (in cytosol)

  • + H₂O +

  ---

• Arginase (in cytosol)

  • + H₂O +

  • Urea is formed by the hydrolysis of arginine regenerating ornithine.

The stoichiometry of the synthesis of urea is:

CO₂ + NH₄⁺ + 3 ATP + aspartate + 2 H₂O urea + 2 ADP + 2 P_i + AMP + PP_i + fumarate

Note that three (3) ATP molecules, but 4 high energy phosphate bonds (due to hydrolysis of PP_i) are required for the synthesis of urea from CO₂ and NH₄⁺.

Lesson 10.2 Urea Cycle

10.2D The Urea Cycle-Citric Acid Cycle Connection

As has been discussed in previous lessons, metabolic pathways do not exist in isolation in the cell. One of the products of the urea cycle, fumarate, links this cycle to the citric acid cycle. Remember that fumarate is formed by the arginosuccinase reaction when arginosuccinate is hydrolyzed to arginine and fumarate. The fumarate formed in this reaction can be converted by the fumarase reaction of the citric acid cycle to malate. The malate produced is converted to oxaloacetate which can be transaminated to form aspartate. See lesson 10.1 for the details of the transamination reaction. Therefore, the fumarate produced by the urea cycle is eventually converted to another necessary compound aspartate for the urea cycle to continue. The following diagram illustrates the relationship between the urea and the citric acid cycles.

10.2E Defects in ammonia metabolism

The liver is the major organ involved in removing NH₄⁺ from the circulation. In humans, high levels of NH₄⁺ are toxic. Partial deficiencies in all 4 enzymes involved in the urea cycle have been identified. These defects result in hyperammonemia. The consequences of these genetic effects are evident within 1-2 days of birth. A low protein diet is given to lessen the amount of ammonia in the blood. One possible mechanism for the effects of high NH₄⁺ levels on brain function involves the synthesis of glutamate and GABA. High NH₄⁺ may inhibit the production of GABA. This could contribute to the lethargy seen in patients with hepatic disease leading to elevated NH₄⁺ levels.

10.2D Summary

After completing this lesson you should understand that

1. Urea is the major route of NH₄⁺ excretion in mammals
2. The urea cycle is responsible for the formation of urea
3. Reactions of the urea cycle takes place in the mitochondria and cytoplasm
4. The atoms in urea come from NH₄⁺, aspartate, and CO₂
5. The formation of carbamoyl phosphate from NH₄⁺ and CO₂ is essentially irreversible
6. Fumarate links the urea cycle with the citric acid cycle
7. Genetic defects in the enzymes of the urea cycle lead to hyperammonemia