The urea cycle is a metabolic pathway that occurs in the liver to convert excess nitrogen from amino acid catabolism into urea for excretion. It involves five enzymes and five steps to synthesize urea from ammonia and carbon dioxide. Defects in the urea cycle can cause hyperammonemia, where high ammonia levels impair the citric acid cycle and ATP production in the brain.

1. M.Mahalingam
2nd year
Biomedical science
Bdu trichy
Urea Cycle

2. UREA BIOSYNTHESIS OCCURS IN FOUR STAGES:
(1) TRANSAMINA-TION,
(2) OXIDATIVE DEAMINATION OF GLUTAMATE,
(3) AM-MONIA TRANSPORT, AND
(4) REACTIONS OF THE UREA CYCLE

3. INTRODUCTION
• The continuous degradation and synthesis of cellular proteins
occurs in all life forms
• Each day, humans turnover 1-2% of their protein , principally
muscle protein
• Of the liberated amino acid , approximately 75% are reutilized
• Since excess amino acid are not stored , those not
immediately incorporated into new protein are rapidly
degraded to ambhibolic intermediates
• The excess nitrogen forms urea

4. UREA CYCLE

5. • The urea cycle is the first metabolic pathway to be elucidated
• The cycle is known as Krebs–Henseleit or Ornithine cycle
• Urea is synthesized in liver & transported to kidneys for excretion in
urea
• The two nitrogen atoms of urea are derived from two different
sources,
 one from ammonia & the other directly from the a- amino group of
aspartic acid.
• Urea is the end product of protein metabolism (amino acid metabolism).
• Urea accounts for 80-90% of the nitrogen containing components of urine

7. • Urea synthesis is a five-step cyclic process, with five distinct enzymes.
The first two enzymes are present in mitochondria while the rest are
localized in cytosol
Involed enzymes
Enzymes in mitochondria:
1.Carbamoyl phosphate synthase I
2.OrnithineTrans-carbamylase
Enzymes in cytosol:
3. Arginino Succinats Synthase
4. Arginino succinase
5. Arginase.

8. Cytosol

9. Step: 1 Formation of carbamoyl phosphate
Carbamoyl phosphate synthetase-I
Carbamoyl phosphate synthase I (CPS I) of mitochondria catalyses' the condensation of NH4
+
ions with CO2 to form carbamoyl phosphate.
This step consumes two ATP & is irreversible.
It is a rate-limiting enzymes of cps I

10.  Carbamoyl phosphate synthase II (CPS II) -involved in pyrimidine
synthesis & it is present in cytosol.
 It accepts amino group from glutamine & does not require N-
acetylglutamate for its activity.
Carbamoyl Phosphate Synthetases


11. Step 2: Formation of Citrulline
Ornithine Transcarbomylase
Ornithine + Carbamoyl phosphate Citrulline + Pi
Citrulline is synthesized from carbamoyl phosphate & ornithine by ornithine transcarbamoylase
Citrulline is transported to cytosol by a transporter system
.

12. Step 3: Formation of Arginosuccinate
• Citrulline condenses with aspartate to form arginosuccinate by the
enzyme Arginosuccinate synthetase.
• Second amino group of urea is incorporated.
• It requires ATP, it is cleaved to AMP & PPi
• 2 High energy bonds are required.
• Immediately broken down to inorganic phosphate (Pi).

13. Step:4 Formation of Arginine or cleavage of Arginosuccinate
• The enzyme Argininosuccinase or argininosuccinate lyase cleaves arginosuccinate
to arginine & fumarate (an intermediate in TCA cycle)
• Fumarate provides connecting link with TCA cycle or gluconeogenesis
• The fumarate is converted to oxaloacetate
via fumarase & MDH & transaminated to aspartate.
• aspartate is regenerated in this reaction

14. STEP 5: FORMATION OF UREA
• Arginase is the 5th and final enzyme that cleaves arginine to yield urea &
ornithine.
• Ornithine is regenerated, enters mitochondria for its reuse in the urea
cycle.
• Arginase is activated by Co2+ & Mn2
• Arginase is mostly found in the liver

15. ENERGETICS OF UREA CYCLE
• The overall reaction may be summarized as:
NH3 + CO2 + Aspartate +3 ATP → Urea + fumarate +2 ATP +AMP+4 Pi

16. REGULATION OF UREA CYCLE
• Carbamoyl phosphate synthase (CPS-I) is rate limiting enzyme in
urea cycle.
• CPS-I is allosterically activated by N-acetylglutamate (NAG). .
• The rate of urea synthesis in liver is correlated with the
concentration of N-acetylglutamate.
• Carbamoyl phosphate synthase I and glutamate dehydrogenase are located
in mitochondria. They coordinate each other in the formation of NH3, and its
utilization for the synthesis of carbamoyl phosphate

17. FORMATION & DEGRADATION OF N-
ACETYLGLUTAMATE

18. INTERACTION OF UREA CYCLE AND CITRIC ACID CYCLE
VIA ASPARTATE-ARGININOSUCCINATE SHUNT

19. Disorders of the Urea Cycle
• The main function of Urea cycle is to remove toxic ammonia from blood
as urea.
• Defects in the metabolism of conversion of ammonia to urea, i.e., Urea
cycle leads to Hyperammonaemia or NH3 intoxication

21.  Increased levels of ammonia causes the formation of glutamate.
 More utilization of α-ketoglutarate.
 Decreased levels of α- Ketoglutarate in Brain.
 αlpha-KG is a key intermediate in TCA cycle.
 Decreased levels impairs TCA cycle.
 Decreased ATP production.

NADPH + H+ NADP+
α- Ketoglutarate + NH3 Glutamate
GDH