The document discusses the urea cycle, which involves a cyclic set of chemical reactions that occur in the liver to convert ammonia into urea for excretion. It details the 5 enzyme-catalyzed reactions, participating amino acids and cofactors. One molecule of urea requires 3 ATP and utilizes ammonia, bicarbonate, and aspartate. The cycle is regulated by N-acetyl glutamate and compartmentalized between mitochondria and cytosol. Disorders cause hyperammonemia due to deficient enzymes, with earlier blocks causing more severe symptoms like vomiting and lethargy.

2. LEARNING OBJECTIVES
 At the end of the lecture the students should be
able to
 Explain about UREA CYCLE in detail
 Know the ENERGETICS of urea cycle
 Understand the REGULATIONS of urea cycle
 The DISORDERS of urea cycle

3. INTRODUCTION
 Urea is the major disposal form of amino groups derived
from amino acids pool and 90% of nitrogen-containing
component of urine
 Urea cycle is cyclic process
 Some reaction occur in mitochondria (1,2) and some in
cytosol (3,4,5)
 Synthesis of 1 molecule of urea need:
 3 molecule of ATP
 1 molecule of ammonium ion
 1 molecule of α-amino nitrogen of aspartate

4. 5 Enzyme catalyzed the numbered reaction
6 Participating amino acids
 Mostly serves as carriers of atoms that become urea
(Ornithine, Citrulline, Aspartate, Arginosuccinate, Arginine)
 SOLELY ACT AS ENZYME ACTIVATOR IS
N-ACETYL GLUTAMATE (NAG)
 Consumed ornithine at reaction 2 are regenerated at
reaction 5
 No net loss or gain of Ornithine, Citrulline, Arginosuccinate,
Arginine
 Ammonia, carbon dioxide, and ATP and aspartate are consumed

6. 1st REACTION
 In mitochondria
 2 ATP USED
 Rate limiting step
 Irreversible and allosterically
regulated
ENZYME : carbamoyl phosphate
synthetase-1 (CPS-1)
ACTIONS: condense 1 molecule of
ammonia with carbon dioxide
PRODUCE: carbamoyl phosphate

7. DIFFERENCES BETWEEN
CPS-I AND CPS-II

8. 2nd REACTION
 In mitochondria
ENZYME : ornithine transcarbamoylase
ACTIONS: transfere carbamoyl group to amino group of
Ornithine
PRODUCE: citrulline

9. 3rd REACTION
 In cytoplasm
 Use 1 ATP
 Pyrophosphate inhibit the reaction
ENZYME : arginosuccinate synthetase
ACTIONS: add 1 molecule of aspartic acids to citrulline,
providing 2nd nitrogen atom of urea
PRODUCE: arginosuccinate

11. 4th REACTION
 In cytoplasm
 Fumarate inhibit the reaction (avoided by enzyme
localization)
 Urea cycle linked to krebs cycle
ENZYME: arginosuccinate lyase
ACTIONS: cleaves arginosuccinate to arginine and fumarate
PRODUCE: arginine , fumarate (funneled to krebs cycle in
mitochondria to be converted to aspartic acid)

13. 5th REACTION
 In cytoplasm
 Final reaction of the cycle
 Ornithine as catalyst
ENZYME: arginase
ACTIONS: hydrolyse arginine
PRODUCE: UREA and ornithine

15. OVERALL REACTION

17. UREA CYCLE ENERGETICS
 4 ATP used in urea cycle
 Formation of fumarate
to malate to
oxaloacetate produce 1
NADH (2.5 ATP)
 Net energy expenditure
only 1.5 energy
phosphate
 “UREA BICYCLE”

18. REGULATIONS OF UREA CYCLE
 Coarse regulation
 Enzyme level changes with protein content of diet
 Starvation, urea cycle elevated to meet increase rate of
protein catabolism
 Fine regulation (allosterically)
 Majorly via CPS-1, through positive effector is N-acetyl
glutamate (NAG)
 Arginine activate NAG synthase

19.  Compartmentalization
 First 2 enzyme on mitochondria
 Minimised the inhibitory effect of fumarate on its own
formation

20. DISORDER OF UREA CYCLE
 Deficient of any urea cycle’s enzyme
 Result in HYPERAMMONEMIA
 When block is one step earlier the ammonia itself
accumulated, much severe
 Deficiency of later enzyme, result in less severe and
symptoms
 Generally disorder of urea cycle described as
hyperammonemia, encelopathy, respiratory
alkalosis
 Symptoms include vomitting, irritability, lethargy,
severe mental retard

21. UREA CYCLE DISORDER
 The accumulation of ammonia in blood (normally
below 40mg/dL) and body fluids can cause toxic
symptoms.

23. ENZYME INVOLVED DISEASES
Carbamoyl Phosphate Synthetase-1
(CPS-1)
Hyperammonemia Type I
Ornithine Transcarbamoylase Hyperammonemia Type II
Orotic aciduria
Ornithine Transporter Deficiency Hyperornithinemia,
Hyperammonemia,
Homocitrulinuria
(HHH Syndrome)
Arginosuccinate Synthetase Citrullinemia,
Citrullinuria
Arginosuccinate Lyase Arginosuccinate aciduria
Arginase Hyperargeninemia,
Argininuria

24. LEARNING OBJECTIVES
 At the end of the lecture the students should be able to
 Explain about urea cycle in details
 Know the energetics of urea cycle
 Understand the regulation of urea cycle
 The disorder of urea cycle

25. References
 DM, Vasudevan, Textbook Of BIOCHEMISTRY For
Medical Students
 Lippincott’s Illustrated Reviews,biochemistry
 Harper’s Illustrated Biochemistry