In'sha'Allah it ll be more Informative & Conceptual for the F.Sc Pre-Medical Students, even it ll be valuable for MDCAT

1. UREA CYCLE
FAZAIA (PAF) COLLEGE LAHORE
Presented By
EJAZ KHICHI
M.Sc ; B.Ed : M.Sc (Env. Sc.) Micro-Biology
Former Visiting Faculty PGCES , CIMR (PU)
Ex Vice Principal Fazaia (PAF) College Lahore
Head of Biology Deptt. Fazaia (PAF) College Lahore
BIOLOGY HSSC – II LBISE Chap. 15 PTB

2. UREA
An Organic Compound with the Chemical Formula
CO(NH2)2, which is generated by the metabolism of the
Nitrogen containing Compounds (Proteins) by the
animals, as colourless and odorless Solid which is highly
soluble in Water
- Urea is practically a Non-Toxic Substance with two
(–NH2) Amino Groups joined together by a Carbonyl
(C=O) Functional Group
- Also named as Carbamide
BIOLOGY HSSC – II LBISE Chap. 15 PTB

3. UREA
Urea is the major Disposal Form of Amino Groups, derived
from the Amino Acids Pool
- Is 90% of the Nitrogen containing component of the Urine
- Urea formation takes place in the Liver under a Cyclic
Process ☼ Urea Cycle ☼ (Exogenous Urea)
- Some reactions occur in the Mitochondria of the Liver Cells
as Reaction (1,2) while the Reactions (3,4,5) occur in the
Cytosol of the Liver Cells (Endgenous Urea)
- The Synthesis of a molecule of Urea needs
• 3 ATP molecules
• 1 molecule of Ammonium Ion
• 1 molecule of α-amino nitrogen of Aspartate
• 5 distinct Enzymes that catalyze these numbered reactions
BIOLOGY HSSC – II LBISE Chap. 15 PTB

4. UREA CYCLE
The First Metabolic Pathway, studied by Sir Henseleit Kreb
- Also named as Krebs Henseleit Cycle
- Five years before the study of the TCA Cycle (Krebs Cycle)
- Starts in the Liver and ends (completes) in the Kidneys
Ammonia as a Metabolite is extremely Toxic, if accumulates in
our body, it would be fatal (It’s the Nature’s Solution)
- Liver contains a system of the Carrier Molecules &
Enzymes, which converts Ammonia to Urea
BIOLOGY HSSC – II LBISE Chap. 15 PTB
Sir Hans Adolf Krebs (25 August 1900 – 22 November 1981)
was a German-born British who earned Nobel Prize in 1953 .
He studied Cellular Respiration. He is best known for his
discoveries of two important sequences of chemical reactions
that take place in the cells of Humans and many other
organisms, namely the Citric Acid Cycle and the Urea Cycle.
With Hans Kornberge, he also discovered the Glyoxylate
Cycle, which is a slight variation of the Citric Acid Cycle found in
Plants, Bacteria, Protists and Fungi.

5. Homeostasis & Control System
Control System
- Works for a variety of Homeostatic Regulations
- Works on the Principle of Physical Control System
- Components of the Control System
– Receptors – Control Centre – Effectors
For Example:- Temperature Control System
- Endothermic Animals & Hetrothermic Animals
- Skin ( Receptor) for External Temperature Changes
- Thermometer as Sensor to detect the Temperature Changes
- Thermostat region in Hypothalamus (Brain) as Control Centre
- Cooling Effectors (response to Warmth sensing in External Environment)
- Warmth Effectors (response to Cool sensing in External Environment)
- Feed Back Mechanism
- Positive as well as Negative Feed Back Mechanism
- Vasoconvection – Vasodilation – Vasoconstriction
BIOLOGY HSSC – II LBISE Chap. 15 PTB

6. Homeostatic Controlling System
Lower Fluctuation in Internal Environments
BIOLOGY HSSC – II LBISE Chap. 15 PTB

7. BIOLOGY HSSC – II LBISE Chap. 15 PTB

8. NEGATIVE FEED BACK MECHANISM
BIOLOGY HSSC – II LBISE Chap. 15 PTB

9. NAGETIVE
FEED BACK MECHANISM

10. METABOLIC PATHWAYS IN
UREA CYCLE
Step – 1 Formation of Carbamoyl Phosphate
- Reaction of Bicarbonate with ATP forms the Carbonyl Phosphate and ADP
- Ammonia then displaces ADP, forming Carbamate and Orthophosphate
- Phosphorylation of Carbamate by the second ATP then forms Carbamoyl
Phosphate
Step – 2 Formation of Citrulline
- The Carbamoyl Group of Carbamoyl Phosphate is transferred to
Ornithine, forming Citrulline and Ortho Phosphate
- The reaction is catalyzed by Ornithine transcarbamoylase
- Subsequent metabolism of Citrulline take
place in the Cytosol
- Entry of Ornithine into the Mitochondria and exit of Citrulline from the
Mitochondria involves Mitochondrial Inner Membrane transport Systems
- The remainder steps of the Urea Cycle take place in the Cytosol
- This requires the continuous export of Citrulline and the uptake of
Ornithine across the Inner Mitochondrial Membrane
BIOLOGY HSSC – II LBISE Chap. 15 PTB

11. METABOLIC PATHWAYS IN
UREA CYCLE
Step – 3 Formation Of Arginosuccinate
- Production of Arginino-Succinate is an energetically expensive process,
since the ATP is split to AMP and Pyrophosphate
- The Pyrophosphate is then cleaved to inorganic Phosphate using the
Pyrophosphatase , so the overall reaction costs two equivalents of high
energy Phosphates per mole
- This reaction requires ATP and involves intermediate formation of CitruIlyl-
AMP. The subsequent displacement of AMP by Aspartate then forms
Argininosuccinate
Step – 4 Cleavage Of Arginosuccinate
- The Cleavage of Argininosuccinate catalyzed by Argininosuccinate Lyase
(ASL), proceeds with retention of Nitrogen into Arginine and releases, the
Aspartate skeleton as Fumarate
- Addition of Water to Fumarate forms L-malate and subsequent NAD+
dependent Oxidation of Malate forms Oxaloacetate
BIOLOGY HSSC – II LBISE Chap. 15 PTB

12. METABOLIC PATHWAYS IN
UREA CYCLE
- Trans-amination of the Oxaloacetate by the Glutamate Aminotransferase
then reforms Aspartate
- Carbon skeleton of Aspartate-Fumarate, acts as a carrier of the Nitrogen
of Glutamate into a Precursor of Urea
- In each case fumarate is formed as a By-product
- Fumarate is not transported by the Mitochondria, so this requires the
presence of Cytosolic Fumarase to form the Malate
Step – 5 Cleavage of Arginine
- The Hydrolytic cleavage of the Guanidino Group of the Arginine, catalyzed by the
Liver Arginase (ARGl) releases Urea, the other product, Ornithine, re-enters the
Liver’s Mitochondria for additional rounds of the Urea Synthesis
- Ornithine and Lysine a repotent Inhibitors of the Arginase, competitive with the
Arginine
- Arginase is activated by Co2+ & Mn2+
- Ornithine & Lysine compete with the Arginine (Competitive Inhibition)
BIOLOGY HSSC – II LBISE Chap. 15 PTB

13. Link Between
Citric Acid Cycle & Urea Cycle
- The Fumarate, produced in the Urea Cycle, is an
intermediate compound in the Citric Acid Cycle
- Aspartate formed in the Mitochondria by the Trans-amination
between the Oxaloacetate and Glutamate which is
transported to the Cytosol, where it serves as the Nitrogen
Donor in the Urea Cycle
- These reactions, making up of the Aspartate-Arginosuccinate
shunt, provide the Metabolic Link between the Urea Cycle and
Citric Acid Cycle
BIOLOGY HSSC – II LBISE Chap. 15 PTB

14. Link Between
Citric Acid Cycle & Urea Cycle
BIOLOGY HSSC – II LBISE Chap. 15 PTB

15. Regulations of the Urea Cycle
COARSE REGULATION
• Enzyme level changes with Protein content of the Diet
• During Starvation, the Urea Cycle, is elevated to meet the
increase rate of Protein Catabolism
FINE REGULATION (ALLOSTERICALLY)
• Majorly via CPS-1, through the Positive effector is N-acetyl
Glutamate (NAG)
• Arginine Activate NAG Synthase

16. Energetics of Urea Cycle
NH3 + CO2 + Aspartate → Urea + Fumarate
- 2 ATP are used in 1st Reaction
- Another ATP is converted to AMP + PPi in the 3rd step which is equivalent
to two ATPs
- The Urea Cycle consumes 4 high energy Phosphate Bonds
- Fumarate formed in the 4th step may be converted to Malate
- Malate when oxidized to Oxalo-Acetate, produces 1 NADH equivalent to
2.5 ATPs
• So the Net Energy Expenditure is only 1.5 high Energy Phosphates
The Urea Cycle & TCA Cycle are interlinked (Urea Bicycle)
Disorders of Urea Cycle
- The main function of Urea Cycle is to remove the Toxic Ammonia from the
Bloodstream as Urea
- Defects in the metabolism of conversion of Ammonia to Urea i.e.,
Urea Cycle leads to Hyper-Ammonaemia or NH3 Intoxication
BIOLOGY HSSC – II LBISE Chap. 15 PTB

17. HYPERAMMONAEMIA &
AMMONIA TOXICITY
- Inherited Disorders of the Urea Cycle’s Enzymes
(Familial Hyperammonaemia)
- Acquired Disorders – Liver Diseases
severe Renal Diseases – Acquired Hyperammonaemia
Increased levels of Ammonia crosses BBB
- Formation of Glutamate
- More utilization of α-keto-Glutarate
- Decreased Levels of α- Keto-Glutarate in Brain
- α-KG is a key intermediate in TCA Cycle
- Decreased Levels impair TCA Cycle
- Decreased ATP Production
- Decreased Glutamate Production
BIOLOGY HSSC – II LBISE Chap. 15 PTB

18. Hepatic Coma
(Acquired Hyperammonemia)
BIOLOGY HSSC – II LBISE Chap. 15 PTB
- Hepatic Failure is Hepatic Coma which leads to Death
- Hyper- Ammonaemia is the characteristic feature of the Liver
Failure (also called Portal Systemic Encephalopathy)
Normally the ammonia & other toxic compounds produced by
the Intestinal Bacterial Metabolism are transported to the Liver
by the Portal Circulation & are Detoxified by the Liver
But when there is the Portal Systemic Shunting of Blood, the
Toxins bypass the Liver & their Concentration in Systemic
Circulation rises which results in Hyper-Ammonaemia

19. Inherited Disorders of
Urea Cycle
DISORDERS DEFFECTIVE ENZYME / S PRODUCT / S
ACCUMULATED
Hyper Ammonaemia – I Carbamoyl-Phosphate Synthetase I Ammonia
Hyper Ammonaemia - II Ornithine Transcarbomylase Ammonia
Citrullineamia Arginino-Succinate Synthetase Citrulline
Arginosuccinic Aciduria Arginino-Succinate Lyase Argino
Succinate
Argininemia Arginase Arginine

20. BIOLOGY HSSC – II LBISE Chap. 15 PTB
UREA CYCLE
Presented By
EJAZ KHICHI
M.Sc ; B.Ed : M.Sc (Env. Sc.) Micro-Biology
Former Visiting Faculty PGCES , CIMR (PU)
Ex Vice Principal Fazaia (PAF) College Lahore
Head of Biology Deptt. Fazaia (PAF) College Lahore