Urea Cycle | Energetics of Urea Cycle | Regulation of Urea Cycle | Metabolic disorder of Urea Cycle

This PPT contains topics related to Urea Cycle, Energetics of Urea Cycle, Regulation of Urea Cycle, Metabolic disorder of Urea Cycle & Clinical Importance.

Books referred: https://www.amazon.in/Biochemistry-2019-Satyanarayana-Satyanarayana-Author/dp/B07WGHCTKZ/ref=sr_1_1?crid=3FLX88MWT4Y30&dchild=1&keywords=satyanarayan+biochemistry&qid=1591701828&s=books&sprefix=satyanarayan+%2Cstripbooks%2C387&sr=1-1

2. Urea Cycle
•Urea: End product of protein metabolism/amino acid metabolism.
•The nitrogen of amino acids which is converted to ammonia is toxic
to the body. Therefore it is converted to urea and detoxified.
•Urea cycle is also known as Krebs-Henseleitcycle because the
metabolic cycle was elucidated by Hans Krebs and Kurt Henseleitin metabolic cycle was elucidated by Hans Krebs and Kurt Henseleitin
1932.
•Urea synthesis is a five-step cyclic process, with five distinct
enzymes.
•The first two enzymes are present in mitochondriawhile the rest
are localized in cytosol.

3. Outline of Urea Cycle

4. Details: Five-step of Urea CycleDetails: Five-step of Urea Cycle

5. Step 1:
Synthesis of carbamoylphosphate:
•Carbamoylphosphate synthaseI (CPS I) catalyses the
condensation of NH4+ ions with CO2 to form carbamoyl
phosphate. CPS I requires Nacetylglutamatefor its activity.
•This step consumes two ATP, and isirreversible& rate-limiting.•This step consumes two ATP, and isirreversible& rate-limiting.
•Carbamoylphosphate synthaseII (CPS II) isinvolved in
pyrimidinesynthesis (present in cytosol). It accepts amino
group from glutamine and does not require
N-acetylglutamatefor its activity.

6. Step 2:
Formation of citrulline:
•Carbamoylphosphate+OrnithineCitrullineby
“ornithinetranscarbamoylase”
•Citrullineproduced is transported to cytosolby a •Citrullineproduced is transported to cytosolby a
transporter system.
•Ornithineis regenerated and used in urea cycle.

7. Step 3:
Synthesis of arginosuccinate:
•Citrulline+aspartateArginosuccinateby
“Arginosuccinatesynthase”
•The second amino group of urea is incorporated in this
reaction. reaction.
•It requires ATP which is broken down into AMP +
pyrophosphate (PPi).
•The latter is immediately broken down to inorganic
phosphate (Pi).

8. Step 4:
Cleavage of arginosuccinate:
•ArginosuccinateArginine+ Fumarateby
“Arginosuccinase”.
•Arginineis the immediate precursor for urea. •Arginineis the immediate precursor for urea.
•Fumarateliberated here provides a connecting link with
TCA cycle, gluconeogenesisetc.

9. Step 5:
Formation of urea:
•ArginineUrea+ Ornithineby “Arginase”
•Arginaseis activated by Co2+ and Mn2+. •Arginaseis activated by Co2+ and Mn2+.
•Ornithinethen enters mitochondria for reuse.

11. Overall reaction and energetics
•The urea cycle is irreversible and consumes 4 ATP.
•Two ATP:synthesis of carbamoylphosphate.
•One ATP:Converted to AMP and PPito produce •One ATP:Converted to AMP and PPito produce
arginosuccinatewhich equals to 2 ATP.
•Hence 4 ATP are actually consumed.

12. Regulation of urea cycle
•The first reaction catalysedby carbamoylphosphate
synthaseI (CPS I) is rate-limiting reaction.
•CPS I is allostericallyactivated by N-acetylglutamate•CPS I is allostericallyactivated by N-acetylglutamate
(NAG).
•It is synthesized from glutamate and acetyl CoAby
synthaseand degraded by a hydrolase.

13. Metabolic disorders of urea cycle
Defect Enzyme involved
Hyperammonemiatype ICarbamoylphosphate synthaseI
Hyperammonemiatype IIOrnithinetranscarbamoylaseHyperammonemiatype IIOrnithinetranscarbamoylase
Citrullinemia Arginosuccinatesynthase
ArginosuccinicaciduriaArginosuccinase
Hyperargininemia Arginase

14. Metabolic disorders of urea cycle
•All the disorders invariably lead to hyperammonemia, leading
to toxicity.
•The clinical symptoms associated with defect in urea cycle
enzymes include vomiting, lethargy, irritability, ataxia and enzymes include vomiting, lethargy, irritability, ataxia and
mental retardation.

15. Blood urea -clinical importance
•Normal blood urea concentration is 10-40 mg/dl.
•Blood urea estimation is widely used as a screening
test for the evaluation of kidney (renal) function. test for the evaluation of kidney (renal) function.
•It is estimated in the laboratory either by urease
methodor diacetylmonoxime(DAM) procedure..

16. Elevation in blood urea: Classified into
three categories
1. Pre-renal : Because of increased protein breakdown,
leads to a negative nitrogen balance. In leukemia and
bleeding disorders also, blood urea is elevated.
2. Renal : In acute glomerulonephritis, chronic nephritis,
nephrosclerosis, polycystic kidney, blood urea is
2. Renal : In acute glomerulonephritis, chronic nephritis,
nephrosclerosis, polycystic kidney, blood urea is
increased.
3. Post-renal : When obstruction is in the urinary tract
blood urea is elevated. This is due to increased
reabsorptionof urea from the renal tubules.

17. UREMIA: Increased blood urea levels due to
renal failure.
AZOTEMIA:Elevation in blood urea/or other AZOTEMIA:Elevation in blood urea/or other
nitrogen metabolites which may or may not
be associated with renal diseases.