Kreb’s Henseleit Urea Cycle:–

• The urea is the final metabolic product of protein. It is a non-toxic form of a toxic NH4 generated in tissues.
• Urea is exclusively produced in liver and then transported through the blood to the kidneys for the excretion through urine.
• Urea is formed from the NH4, CO2 and alpha-amino nitrogen of aspartate which requires ATP.
• Enzymes which catalyzes the urea cycle are present in the mitochondria and cytosol of liver cell.
• The first two reactions are catalyzed in mitochondria and other in cytosol.

Reactions of urea cycle

1. Formation of carbamoyl phosphate

The condensations of CO2 + NH4 and ATP to form carbamoyl phosphate. This is catalyzed by carbamoyl phosphate synthase-1(CPS-1). 2 ATP are required in which 1 ATP serve as the source of phosphate and second one is converted to AMP and pyrophosphate (PPi).

2. Formation of citrulline

The carbamoyl phosphate donates its phosphate group to the ornithine to form citrulline. This reaction is catalyzed by mitochondrial ornithine trans-carbamoylase.

3. Formation of arginosuccinate

Transfer of second amino group from aspartate to citrulline forms arginosuccinate. This reaction requires Mg-ATP.

4. Formation of arginine and fumerate

Breakdown of arginosuccinate by arginosuccinase forms free arginine and fumerate. The fumerate formed then enters the TCA cycle.

5. Formation of urea and Ornithine

In the last reaction of urea cycle, the liver hydrolytic enzyme breaks the arginine to form urea and ornithine.

• The regenerated ornithine again enters the liver mitochondria to initiate another urea cycle
• The urea formed Is then excreted through urine.

Energy cost of urea cycle Four ATP are consumed per molecule of urea formation

• Two ATP are required to make carbamoyl phosphate
• 1 ATP is required to make arginosuccinate
• 1 ATP is required to restore AMP to ATP.

Regulation of urea cycle

• Urea cycle is regulated by substrate availability. Higher the concentration of ammonia, higher will be the urea formation and urea cycle will stimulate
• CPS-1 is an allosteric enzyme. This enzyme is activated by N-acetylglutamate (NAG). NAG is synthesized from acetyl-CoA and glutamate. The synthesis of NAG increases after taking protein rich diet, or by arginine, or during starvation.

Significance of urea cycle

1. Toxic ammonia is converted to non-toxic urea
2. It helps to dispose off 2 waste product, ammonia and CO2
3. It also forms arginine amino acid
4. It regulated blood Ph.
5. Ornithine is the precursor for the formation of polyamines such as spermidine spermine etc.

Multiple choice questions (MCQs)

1. Urea is formed from which toxic material?

A. CO2

B. Ammonia

C. Uric acid

D. All of the above

2. Urea cycle provides intermediate for which pathway?

A. Glycolysis

B. HMP-shunt

C. TCA cycle

D. Gluconeogenesis

3. Where do urea cycle occur?

A. Muscle cell

B. Liver cell

C. Kidney

D. Heart

4. From where are the two amino groups of urea derived?

A. both derived from ammonia

B. Both derived from aspartate

C. One from ammonia and 1 from aspartate

D. None of the above

5. Which of the following is the rate limiting step of urea cycle?

A. Synthesis of citrulline

B. Synthesis of carbamoyl phosphate

C. synthesis of arginine

D. Synthesis of ornithine

6. Which of the following is the first reaction of urea cycle?

A. Formation of ornithine

B. Formation of urea

C. Formation of arginosuccinate

D. None of the above

7. How many ATP are required for the formation of carbamoyl phosphate?

A. 2

B. 3

C. 4

D. 1

8. Match the following enzyme and its product-

a. CPS-1                                                    1. fumerate

b. Ornithine trans-carbamoylase       2. urea

c. Arginase                                               3. citrulline

d. Argininosuccinase                             4. Carbamoyl phosphate

9. Carbamoyl phosphate donates its phosphate group to which compound to form catrulline?

A. Arginosuccinate

B. Ornithine

C. Fumerate

D. Urea

10. Which of the following compounds are formed in urea cycle?

A. Arginosuccinate

B. Ornithine

C. Fumerate

D. All of the above

11. How many ATP is/are converted to AMP and PPi to form arginosuccinate?

A. 1

B. 2

C. 4

D. 6

12. Which of the following statement is NOT true?

A. Four ATP molecules arereqired for synthesis of urea

B. Urea dispose CO2, ammonia and biotin

C. CPS-1 is the principal enzyme of urea cycle

D. High concentration of ammonia, stimulates urea cycle.

13. Why ornithine and citrulline not found in the protein structure?

A. They have excess codons

B. They lack codons

C. The secondary structure lacks hydrogen bonding

D. Both A and C

14. Which of the following is the significance of urea cycle?

A. Regulates BP

B. Regulates blood volume

C. Regulate blood flow

D. Regulate blood Ph

15. What enhances urea synthesis?

A. increased level of N-acetyl glutamate (NAG)

B. Decreased level of NAG

C. Protein rich diet

D. Both A and C

ANSWERS:

1. Ammonia

2. TCA cycle

3. Liver

4. One from ammonia and 1 from aspartate

5. Synthesis of carbamoyl phosphate

6. None of the above

7. 2

8. a – 4 b – 3 c – 2 d – 1

9. Ornithine

10. All of the above

11.1

12. Urea dispose CO2, ammonia and biotin

13. They lack codons

14. Regulate blood Ph

15. Both A and C

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REFERENCE:–

1. Pankaja Naik- Biochemistry; 4^th edition; page no:- 271-273

2. U Satyanarayana, U Chakrapani-Biochemistry; 4th edition; Page no:- 337-340