In ureotelic organisms, the ammonia deposited in the mitochondria of hepatocytes is converted to urea in the urea cycle. This pathway was discovered in 1932 by Hans Krebs (who later also discovered the citric acid cycle) and a medical student associate, Kurt Henseleit. Urea production occurs almost exclusively in the liver and is the fate of most of the ammonia channeled there. The urea passes into the bloodstream and thus to the kidneys and is excreted into the urine. The production of urea now becomes the focus of our discussion.

2.  Nitrogen excretion
 Urea cycle
 Disposal of urea
 Link between citric acid cycle and urea cycle
 Regulation of the cycle
 Energetics
 Metabolic disorders

3.  If not used for synthesis of new amino acids or other nitrogenous
products, amino groups are channeled into a single excretory end
product.
 Depending upon the end product animals are classified as
1. Ammonotelic : excrete ammonia; ammonia is highly toxic and
requires more water for dilution. Eg:bonyfishes.
2.Ureotellic: excrete urea; less toxic than ammonia and require less
water for dilution. Eg:terrestrial animals.
3.Uricotellic:excrete uric acid eg: birds and reptiles.

4.  In ureotellic organisms , the ammonia diposited in the mitochondria
of hepatocytes is converted to urea in the urea cycle.
 This pathway was discovered in 1932 by Hans Krebs.

6. Diagramatic representation of Urea cycle

7.  Urea formed freely diffuses and is transported in the blood to the
kidneys and is excreated.
 Small amount enters into the intestine where it is broken down to
CO2 and NH3 by the bacterial enzyme urease.

8.  The fumarate produced in the urea cycle is an intermediate in citric
acid cycle.
 Aspartate formed in mitochondria by transamination between
oxaloacetate and glutamate which is transported to the cytosol,
where it serves as nitrogen donor in the urea cycle.
 These reactions ,making up the ASPARTATE-
ARGININOSUCCINATE SHUNT , provide metabolic link between
these two separate pathways.

9. LINK BETWEEN CITRIC ACID CYCLE AND UREA CYCLE

10.  The first reaction of the cycle catalysed by carbamoyl phosphate
synthase is allosterically activated by N-acetylglutamate .
 Steady state levels of n-acetylglutamate are determined by
concentration of glutamate and acetyl –CoA (substrate for
synthesis of the enzyme) and arginine (an activator of the enzyme
and thus an activator of the urea cycle).
 The remaining enzymes of the cycle are mostly controlled by the
concentration of their respective substrates.

11.  Two ATP are generated in the formation of carbamoyl phosphate.

12.  One ATP is required to make argininosuccinate ; this ATP
undergoes pyrophosphate cleavage to AMP and PPi which is
hydrolysed to 2 Pi.
 Thus four high energy phosphate groups are utilized.

13.  Defect in the function of any of the enzymes involved in the cycle
leads to build up of ammonia which may prove toxic.
 Depending on which enzymes fails to function different
intermediates of the cycle may accumulate.
 Clinical symptoms associated with with defect in urea cycle
enzymes include
1. vomiting
2.lathargy
3.irritability
4.ataxia
5.mental retardation.

14.  In healthy people the normal blood urea concentration is 10-40
mg/dL.
 Higher protien intake marginally increases blood urea level.
 About 15-30 g of urea is excreted in the urine per day.

15.  Lehninger Principles of Biochemistry ;5th edition 2008 ;David L.
Nelson, Michael M. Cox. Page no:682-686.
 Biochemistry ; 2nd edition 2002 ;U.Satyanarayan.