it is about how ammonia is detoxified to urea and its biomedical significance. This PPT can be used by students of MBBS, MD, BDS and general Biochemistry students

1. UREA CYCLE

2.  Pathway for final disposal of
ammonia
 Synonym: Krebs- Henseleit cycle
 Organ: Liver
 Organellar location: Mitochondria&
Cytoplasm

3. Sir Hans Krebs (1932)
1st metabolic cycle to be
discovered
N. P. prize for TCA cycle

4. UREA CYCLE
 Urea- CO (NH2)2
 C- from HCO3
-
 N- one from ammonium ion
- one from Aspartate
 5 steps
 2 in mitochondria
 3 in cytoplasm

6. 1. Formation of Carbamoyl
Phosphate
 Rate –limiting
step of urea
synthesis
 Takes place in
mitochondria
 CPS-I enzyme
 N-acetyl
glutamate
 Irreversible &
allosterically
N-Acetyl glutamate

7. Difference between CPS-I and CPS-II
Characteristics CPS-I CPS-II
Cellular location Mitochondria Cytosol
Pathway involved Urea cycle Pyrimidine
synthesis
Source of nitrogen Ammonia Glutamine
Allosteric activator N-acetylglutamate
(NAG)
Nil

8. 2. Formation of Citrulline
 Also mitochondrial
 Ornithine transcarbamoylase
 Present in milk; but not in tissue proteins or
blood

9. 3. Formation of Argininosuccinate
 2nd atom of
nitrogen of urea
 Argininosuccinate
synthase
 ATP hydrolyses to
AMP
 PPi is an inhibitor
to this step

10. 4. Formation of Arginine
 Argininosuccinate lyase
 Fumarate inhibits the enzyme
 But Fumarate is funneled to TCA
cycle

11. 5. Formation of Urea
 Arginase -
hydrolytic
enzyme
 Ornithine &
Urea formed
 Ornithine-
enters
mitochondria

12. Summary of Urea Cycle

13. Bioenergetics
 4 ATPs consumed
 2 ATPs in 1st step
 Formation of Argininosuccinate
requires 2 high energy bond
ATP→AMP+ PPi

14. Regulation of Urea cycle
1. Feed-forward reaction- Availability of ammonia
2. Induction of urea cycle enzymes- High protein
diet
- Prolonged
starvation
3. Allosteric regulation- CPS-I is allosterically
activated by NAG

15. 4. Compartmentalization- Prevents
inhibition of Argininosuccinate lyase by
Fumarate

16. Krebs Bicycle or Tricycle???

17. 1. Toxic Ammonia→ Less-toxic Urea
2. Bicarbonate also consumed
3. Forms Arginine
4. Integrates with TCA cycle
5. Ornithine → Proline
6. Ornithine → Precursor of polyamines

18. Disorders of Urea Cycle
 UCDs - 6 enzyme deficiencies , 2
transporter defects
 All present with hyperammonaemia
 1 defect is X-linked (OTC) – most
common – the rest are autosomal
recessive
 Age of onset varies from 2 days to
adulthood
 Severity varies from lethal
hyperammonaemic encephalopathy to
asymptomatic

19. Diseases Enzyme deficit Features
Hyperammonemia I CPS-I Mental
retardation,↑↑NH3
Hyperammonemia
II
OTC ↑NH3 , ↑Gln, orotic
aciduria
Hyperornithinemia Defective Ornithine
transporter
↑NH3 & Ornithine
Citrullinaemia Argininosuccinate
synthetase
↑NH3 & Citrulline;
citrullinuria
Argininosuccinic
aciduria
Argininosuccinate
lyase
Argininosuccinate in
blood & urine.
Trichorrhexis nodosa
Hyperargininemia Arginase ↑Arginine in blood & CSF;
Cys & Lys in urine

20.  CNS affected
 Convulsions
 Flapping tremor
 Slurred speech
 Blurred vision
 Nausea, vomiting
 Lethargy
 Coma, death

21. Causes of toxic effect of NH3
 ↓ATP due to diversion of excess of α-
ketoglutarate from TCA cycle
intermediates to form Glu & Gln in
brain - ↓ glucose in brain (major fuel
of brain)
 ↑formation of GABA from Glutamate-
↓neural transmission
 ↑Glutamine- osmotic effect- brain
edema

22. Uraemia
 Normal blood level: 15-45 mg/dl
 75% of the NPN
 > 90% excreted through kidney, rest via GI
tract & skin
 Concentration affected by
- dietary protein,
- rate of protein catabolism
- muscle wasting as in
starvation
- Digestion of blood proteins
after

23. Types Causes
Pre-renal uremia •High Protein diet
•Any causes of ↑catabolism
•Any cause of impaired renal perfusion
Renal Uremia •Any cause that impedes GFR
Post-renal uremia Obstruction to urine outflow
Reduced plasma
urea concentration
•Low protein diet
•Severe liver disease
•Water retention

24. Clinical significance
Measuring GFR- Urea
clearance test
Together with creatinine
estimation to know renal status

25. DO NOT PRETEND – BE
DO NOT THINK- ACT
DO NOT DREAM- REALISE

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Biochemistry
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