2. INTRODUCTION
Nitrogen is the fourth most important contributor (after carbon, hydrogen and oxygen) to
the mass of living cells
Atmospheric nitrogen is abundant but too inert to be in use to many biochemical reactions
Only few organisms have the ability to convert them to biologically useful forms
Some of the ammonia generated is recycled to be used in biosynthetic pathways, the excess
is either excreted directly or converted to urea and uric acid to be excreted
The amino nitrogen is excreted in three different forms in various life forms: as ammonia
in most aquatic vertebrates, bony fishes and amphibian larvae (ammonotelic organisms), as
urea in many terrestrial vertebrates, also sharks and adult amphibian, called ureotelic
organisms and as uric acid in reptiles and birds (uricotelic organisms)
Plants however, recycle virtually all amino groups and nitrogen excretion occurs only under
unusual circumstances. There is no general pathway for nitrogen excretion in plants
3. UREA CYCLE
In ureotelic organisms, the ammonia in the mitochondria of liver cells is converted to
urea via urea cycle
This pathway was discovered by Hans Adolf Kreb and a medical student associate,
Kurt Henseleit in 1932
Urea cycle was the first cyclic metabolic pathway to be discovered
Ornithine plays a role similar as oxaloacetate in citric acid cycle and this cycle is also
called as ornithine cycle
The urea is passed via bloodstream to the kidneys and excreted by urine
4.
5. STEPS INVOLVED IN UREA CYCLE
Ammonium ion generated in liver mitochondria together with bicarbonate produced by
mitochondrial respiration are utilized to form carbamoyl phosphate in the mitochondrial
matrix. This is a ATP dependent reaction catalyzed by carbamoyl phosphate synthetase-I, a
regulatory enzyme present in liver mitochondria of ureotelic organisms
In bacteria, glutamine rather than ammonia serves as the substrate for carbamoyl
phosphate synthesis
Carbamoyl phosphate now enters urea cycle, which itself consists of 4 enzymatic steps:
STEP 1: Synthesis of citrulline
STEP 2: Synthesis of arginosuccinate
STEP 3: Cleavage of arginosuccinate to arginine and fumarate
STEP 4: Cleavage of arginine to urea and ornithine
6. KREB’S BICYCLE
Fumarate produced in the cytosol is also an intermediate in the citric acid cycle
Fumarate enters TCA in the mitochondrion where it is first hydrated to malate by
fumarase, in turn oxidized to oxaloacetate by malate dehydrogenase
The oxaloacetate accepts an amino group from glutamate by transamination and the
aspartate thus formed leaves mitochondria and donates its amino group to urea cycle
The other product of transamination is ἀ -ketoglutarate, another intermediate of TCA
Since both cycles are intertwined, also called as Kreb’s bicycle
9. REGULATION
N-acetylglutamic acid
Synthesis of carbamoyl phosphate is dependent on NAcGlu.
NAcGlu allosterically activates CPS I
Obligate activator of carbamoyl phosphate synthetase
Glu is not only substrate for NAG’s but also an activator of urea cycle
Substrate concentration
Inherited deficiencies in cycle enzymes other than ARG1 do not result in significant
decreases in urea production (if any cycle enzyme is entirely missing, death occurs shortly
after birth)
Rather, the deficient enzyme's substrate builds up, increasing the rate of the deficient
reaction to normal.
10. The substrate concentrations become elevated all the way back up the cycle to
NH4+resulting in hyperammonemia
Although the root cause of NH4+ toxicity is not completely understood, a high
NH4+puts an enormous strain on the NH+4- clearing system, especially in
the brain (symptoms of urea cycle enzyme deficiencies include intellectual
disability and lethargy). This clearing system involves GLUD1 and GLUL, which
decrease the 2-oxoglutarate (2OG) and Glu pools. The brain is most sensitive to the
depletion of these pools. Depletion of 2OG decreases the rate of TCAC, whereas Glu is
both a neurotransmitter and a precursor to GABA, another neurotransmitter.
11. GENETIC DEFECTS IN UREA CYCLE
oBlockage of carbamoyl phosphate synthesis has serious consequences, as there is no
alternative pathway for urea cycle
oThey all lead to elevated level of NH4+, in the blood (hyperammonemia)
oSome of the symptoms are visible a day or two after birth, when afflicted infant
becomes lethargic and vomits periodically
oComa and irreversible brain damage may ensue
oThe high level of NH4+ are toxic, probably due to elevated levels of glutamine, lead
directly to brain damage
12. CONCLUSION
•Urea cycle is a cycle of biochemical reactions that produces urea from ammonia
•Ammonia is excreted as urea in ureotelic animals
•The urea cycle occurs primarily in liver and to a lesser extent in the kidneys also
•This cycle occurs in five main steps
•Ammonia is converted to carbamoyl phosphate, to enter the cycle
•There are four enzymatic reactions: one mitochondrial and 3 cytosolic and makes use of
6 enzymes
•Regulation is carried by N-acetylglutamic acid and substrate concentrations
•Urea cycle disorders may lead to brain damage and coma in infants
13. REFERENCES
Nelson. L. David and Cox. M. Michael. Lehninger- Principles of Biochemistry. W. H.
freeman and company, sixth edition (2006), New York
Nitin & Sanjay Jain. Fundamentals of Biochemistry, J. L. Jain. S. Chand & Company
Ltd, New Delhi, sixth edition, 2005
