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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