Formation & clinical significance of urea

A comprehensive presentation on formation Urea & its clinical significance for MBBS, BDS, B. Pharm & Biotechnology students to facilitate self-study.

1. Formation & Clinical significance of Urea
Dr. RohiniC Sane

2. Urea
Urea : End of protein metabolism
Amino group of amino acids
↓
Ammonia
↓
Urea
↓
Excretion through urine

3. Disposal of Ammonia
1)Ammonitelic : ammonia excreted in water eg aquatic animals
2)Uricotelic : ammonia excreted as uric acid eg reptiles & birds
3)Ureotelic :ammonia excreted as urea (non toxic ,water soluble )eg mammals
AMMONIA URIC ACID
UREA

4. Formation of Urea
•Carbomoyl phosphate synthtase -CPS I of urea cycle &
Glutamate dehydrogenase of Transaminase
1.Mitochondrial
2.Coordinate formation of NH3 & Urea synthesis
3.Enzymes activity (4 enzymes )increase with substrate concentration
4.Urea synthesis –Liver
5.Urea transport –blood
6.Urea excretion -kidney
7.Urea synthesis in intestine
Small intestine (E coli contain urease which splits Urea into Ammonia &
CO2 -Ammonia enters into blood , excreted in urine

5. Urea synthesis
Characteristics of Urea synthesis : Urea -End of protein metabolism
1.Site of synthesis –Liver
2.80-90 % N2 excreted through in urine
3.Kreb’s Henseleitcycle= Urea cycle
4.2 Amino groups from Ammonia & Aspartate ( one each )
5.5 enzymes involved ( 2 mitochondrial +2 cytosolic –Liver Cells )
6.Irreversible
7.4 ATP utilized ( 2 ATP for synthesis of Carbamoyl phosphate & 2ATP as ATP 
AMP + PPi
8.NH4⁺ + CO2 + Aspartate + 3ATP Urea + Fumarate +2 ATP +2 Pi +AMP + PPi
9.Regulation of CPS I (rate limiting steps ,↑ by Acetyl Glutamate )
10.Protein consumption↑ NAG ↑ Urea ↑

6. Sources of Atoms of Urea molecule

7. Sources and fate of
Blood Urea Nitrogen
(BUN )

8. Sites of synthesis of
Intermediates of
Urea cycle

9. Synthesis of CarbamoylPhosphate in Urea cycle
1.NH2 +CO2 CarbomoylPhosphate ( enzyme: CarbomoylPhosphate
Synthtase-CPS I )
2.2 ATP required
3.Irreversible
4.Rate limiting
CPS I CPS II
Site Of Action ( Mitochondrial ) ( Cytosolic )
Allosteric Modulator (NAG ) increase activity by N Acetyl
Glutamate (NAG )
not influenced by NAG
Activity ↑ Urea formation ↑ Pyrimidine synthesis

10. Synthesis of
Carbomoyl
phosphate
in Urea cycle by
CPS I

11. Synthesis of Citrullinein Urea cycle
Carbamoyl ℗ +Ornithine Citrulline ( Ornithine trans carbamylase )
•Ornithine regenerated
Ornithine & Citrulline
1.Basic amino acids
2.No codons
3.Not found in protein structure
4.Transporter (mitochondria cytosol)

12. Synthesis of Arginosuccinatein Urea cycle
•Citrulline +Aspartate Arginosuccinate
•EnzymeArginosuccinateSynthtase
•NH2 group of Aspartate contributes ( second amino group of Urea )
•ATP AMP + Ppi( Inorganic phosphate Ppi)

13. Cleavage ofArginosuccinatein Urea cycle
•4. ArginosuccinateArginine+ Formate*
•Enzyme -Arginosuccinase
•Fumarate*TCA Gluconeogenesis
•ArginineOrnithine
•Arginine –next precursor for Urea cycle

14. Formation of Urea from Arginine in Urea cycle
5.ArginineUrea + Ornithine (enzyme –Arginase)
cytosol
Ornithine
mitochondrial
Arginase –mostly in liver
Other 4 enzymes of Urea cycle found in other tissues
Arginine synthesis occurs in other tissues
Urea synthesis occurs only in Liver cells(Arginasepresent only in
Liver )

15. Metabolism of urea in Renal failure
Renal failure Uremia
1.More urea transported to intestine
2.↑ urea Urease (bacteria) ↑ NH3 (HYPERAMMONEMIA )
3.Treatment : oral administration of antibiotics (Neomycin ) kills
intestinal bacteria

16. Aspartate & Fumaratelink Urea cycle & TCA cycle

17. FOUR LINKING POINTS BETWEEN
TCA & UREA CYCLE
1.CO2FROM DECARBOXYLATION OF
TCA USED FOR UREA CYCLE
2. 12 ATP FROM TCA CYCLE-4 ATP
USED IN UREA CYCLE
3. OAA ASP FROM TCA CYCLE USED
FOR ARGINOSUCCINATE SYNTHESIS
4. ARGINOSUCCINATE -FUMARATE
–USED IN TCA CYCLE

18. FOUR LINKING POINTS BETWEEN TCA & UREA
CYCLE
1.CO2FROM DECARBOXYLATION OF TCA USED
FOR UREA CYCLE
2. 12 ATP FROM TCA CYCLE-4 ATP USED IN
UREA CYCLE
3. OAA ASP FROM TCA CYCLE USED FOR
ARGINOSUCCINATE SYNTHESIS
4. ARGINOSUCCINATE -FUMARATE–USED IN
TCA CYCLE

19. Metabolic disorders of Urea cycle-Hyperammonemia
Type of Hyperammonemmia Defective Enzyme
HYPER AMMONEMMIA I CPS I
HYPER AMMONEMMIA II Ornithine Transcarbomylase
HYPER AMMONEMMIA III
Citullinemia
Arginosuccinate synthtase
HYPER AMMONEMMIA IV
Arginosuccinicaciduria
Arginosuccinase
HYPER AMMONEMMIA V
Hyperargininemia
Arginase

20. Symptoms of Hyperammoninemia
Symptoms of Hyperammoninemia
•Increase in Ammonia
•Vomitting
•Lethargy
•Irritability
•Atexia
•Mentalretardation

21. Clinical significance ofBlood Urea estimation
RENALUREMIA
•Acute glomerulonephritis
•Chronic nephritis
•Nephrosclerosis
•Polycystic kidney
POST RENALUREMIA(OBSTRUCTION TO URINARY TRACT )
1.Tumor
2.Stones Reabsorption of Urea
3.Prostrate enlargement

22. Clinical significance ofBlood Urea
Non protein nitrogen (NPN )
•Urea
•Uric acid
•Creatinine
•Creatine 20-40mg/dl
•Peptides
•Amino acids
•BLOOD UREA NITROGEN ( BUN )=14/60 XUREA = 2.14X BLOOD UREA

23. Formation & degradation of N-Acetyl Glut
N-Acetyl Glutamate

24. Key enzymes & ATP
utilization of Urea cycle

25. Chemical Reactions
of Urea cycle