Last edited: 1/8/2022

22. UREA CYCLE

Metabolism | Urea Cycle Medical Editor: Uta Hüning

OUTLINE II) AMMONIA (NH3)

I) RECAPITULATION ● Ammonia (NH3) produced during oxidative deamination of
II) AMMONIA (NH3) glutamate
● NH3 reacts with H+
III) DEFECTS IN UREA CYCLE
→ Becomes Ammonium (NH4)
IV) SUMMARY → Enters bloodstream
V) APPENDIX
(A) FATES OF AMMONIUM (NH4)
VI) REVIEW QUESTIONS
(1) Brain
I) RECAPITULATION ● Generate glycine
● Generate glutamine
(1) Transamination o Where:
● Reversible reaction  Astrocytes (glial cells in brain)
● Where? o Glutamate → glutamine by incorporating NH4
o Muscle and other tissues o By: glutamine synthetase
● Reaction: amino acid + keto-acid o Dangerous because glutamine is osmotically active!
o Alanine + α-KG → Pyruvate + Glutamate  ↑ NH4 → ↑ Glutamine
o Aspartate + α-KG → OAA + Glutamate → ↑ water in brain
→ brain swelling / cerebral edema
● By:  Consequences: high Intra cranial pressure (ICP)
o ALT (alanine amino transferase) can lead to brain herniation, coma
o AST (aspartate amino transferase)

www.AfraTafreeh.com
Figure 1: Transamination of Alanine by ALT

(2) Oxidative deamination

● Where?
o Liver
● Many AA generate glutamate during their catabolism
● Glutamate + NADP+ + H2O → α-KG + NH3 + NADPH
● By: Glutamate DH
● Side products:

o NH3 Figure 3: Osmotically active glutamate and glycine pull water

into the brain causing edema
Remember: (2) Liver
● Ammonia (NH3) = toxic!
● Urea cycle
o Convert ammonium (NH4) into urea
o Urea is less toxic

Figure 2: Oxidative deamination of glutamate

Urea Cycle METABOLISM: Note #22. 1 of 4

 (B) UREA CYCLE
(i) 1. step
(iv) 4. Step
● NH4 enters mitochondria
● Reacts with bicarbonate, needs 2 ATPs
● Arginosuccinate → arginine + fumarate
● NH3 + HCO3- + 2 ATP
● By: argininosuccinase
→ carbamoyl-phosphate + 2 ADP + Pi
● By: carbamoyl phosphate synthetase type 1 (CPS-1)

Figure 7: Argininosuccinase splits argininosuccinate into

arginine and fumarate
Figure 4: Ammonium combines with bicarbonate and forms
carbamoyl phosphate by CPS-1 (v) 5. step:
(ii) 2. step ● In the cytosol
● Arginine + H2O → Ornithine + Urea
● Ornithine (amino acid) enters mitochondria
● Ornithine + carbamoyl phosphate → citrulline + Pi
● By: ornithine transcarbamylase, zinc, biotin

Figure 5: Ornithine transcarbamylase fuses ornithine and Figure 8: Arginase splits arginine into ornithine and urea
carbamoyl phosphate to generate citrulline
● Ornithine re-enters cycle to form Citrulline
(iii) 3. Step ● Urea enters bloodstream
→ To kidneys
● In the cytosol
→ To urine
● Citrulline + aspartate + ATP
→ ↓ Ammonia levels
→ argininosuccinate + AMP + PPi
● By: argininosuccinate synthetase III) DEFECTS IN UREA CYCLE
● Note: Aspartate exited mitochondria through Malate-
aspartate shuttle
● Why?
o ↑ ammonium → ↑ glutamine and glycine level
→ ↑ ICP, brain edema
● Treatment:
o Benzoate

● Effect:
o Alleviate symptoms by binding glutamine and glycine
→ excreted in urine → decrease toxicity in body

Figure 6: Argininosuccinate synthetase fuses citrulline and

Aspartate to generate argininosuccinate

Figure 9: Drugs can help to excrete ammonium

2 of 4 METABOLISM: Note #22. Urea Cycle

 IV) SUMMARY
● Ammonia (NH3) generated in oxidative deamination of glutamate
● Problem: Ammonia (NH3) = toxic! (2) Defects in Urea Cycle
o Leads to accumulation of glutamine, glycine in brain ● Very dangerous
o ↑ ICP, brain edema ● Because lead to accumulation of
● Solution: ammonia (toxic) or build up of
o Remove/excrete NH3 osmotically active substances
(glutamine, glycine) that can lead
● How? to brain edema
o Urea cycle ● Treatment:
o NH3 incorporated into urea molecule o Benzoate
o Urea excreted by kidney in urine o Phenyl butyrate
(1) Urea cycle ● Effect:
o Alleviate symptoms by binding
Step Reactants Products Catalyzed Location
by glutamine and glycine
→ excreted in urine
1 NH3 + HCO3- + carbamoyl CPS1 mitochondria
→ decrease toxicity in body
2ATP phosphate + 2ADP
+ Pi
2 carbamoyl citrulline + Pi OTC, mitochondria
phosphate + zinc,
ornithine biotin
3 citrulline + argininosuccinate ASS cytosol
aspartate + ATP + AMP + PPi
4 argininosuccinate arginine + ASL cytosol
fumarate
5 arginine + H2O ornithine + urea ARG1, cytosol
manganese
● Urea enters bloodstream → kidneys → urine

www.AfraTafreeh.com

Figure 10: Urea cycle overview

Urea Cycle METABOLISM: Note #22. 3 of 4

 V) APPENDIX

Figure 11: Overview - Urea Cycle and paths of ammonium

VI) REVIEW QUESTIONS

1) Why is ammonia problematic for the body? 5) Which product enters the urea cycle by combining
a) It is osmotically active with ornithine? How is it formed?
b) It is toxic a) Carbamoyl phosphate, formed by carbamoyl
c) It leads to dehydration phosphate synthetase type 1
d) A build-up interferes with protein metabolism b) Carbamoyl phosphate, formed by carbamoyl
2) How can the body decrease ammonia? phosphate synthetase type 2
a) Cori cycle c) Carbamoyl phosphate, formed by carbamoyl
b) Krebs cycle phosphate synthetase type 3
c) Urea cycle d) Carbamoyl phosphate, formed by carbamoyl
d) Glycolysis phosphate synthetase type 4

3) Why does the urea cycle turn ammonia into urea? 6) What is the role of aspartate in the urea cycle?
a) Urea is as toxic but can be directly excreted in urine a) It combines with fumarate to form ornithine
b) Urea is less toxic and can be directly excreted in b) It combines with asparagine to form citrulline
urine c) It combines with citrulline to form argininosuccinate
c) Urea is less toxic and excreted via sweating d) It takes up ammonia and can be excreted
d) Urea is as toxic but can be used for
gluconeogenesis CHECK YOUR ANSWERS
4) Why is a build-up of glutamine or glycine in the brain
a problem?
a) They lead to dehydration
b) Their charge interferes with neural communication
c) They lead to a shortage of amino acids in the rest of
the body
d) They are osmotically active and can lead to brain
edema

4 of 4 METABOLISM: Note #22. Urea Cycle