For Medical & Non Medical Students

1. DISPOSAL
OF
AMMONIA
By
N.Santhosh Kumar
Asst.Professor
Department of Biochemistry
SIMS & RH, Tumkur

2. Formation of Glutamate
Formation of Glutamine
Ultimately to form urea
Three principal route for its metabolic disposal of
ammonia is

4. UREA CYCLE
“Krebs Henseleit Cycle”

5. Ammonia
Aspartate
CO2
Structure Of Urea

6. “Krebs Henseleit Cycle”
[Hans Krebs & Kurt Henseleit -1932]
Site of synthesis: Liver
Location of enzymes: It is partly mitochondrial and partly
cytosolic.
Energetics: The overall process in each turn of cycle requires 4
molecules of ATP. But one cycle generates 1.5 ATPs

8. Eukaryotes have two forms of CPS:
• Mitochondrial CPS-I uses ammonia as its nitrogen donor and
participates in urea biosynthesis.
• Cytosolic CPS - II uses glutamine as its nitrogen donor and is
involved in pyrimidine biosynthesis.
The differences between the two enzymes are as follows:

9. Regulation of the Urea cycle
Regulated by substrate availability
Higher the rate of ammonia form
higher the urea
Stimulation of urea cycle enzymes
occur in response to high protein diet (or) prolonged
fasting when gluconeogenesis from a.a’s high

10. Allosteric regulation
Acetyl CoA + Glutamate
N- Acetyl glutamate
N- Acetyl glutamate synthase
high protein diet,
Arg & starvation
CO2 + NH4
+
Carbamoyl Phosphate
Synthetase-I
Carbamoyl phosphate
+
+

11. Significance Of Urea Cycle
• Converts toxic ammonia into non toxic urea
• Forms semi essential amino acid –Arginine & non essenial amino
acid -proline
• It disposes off two waste products, ammonia & bicarbonate
• Ornithine formed in urea cycle is a precursor for the formation of
polyamines like putrescine, spermidine & spermine
• It involved in metabolic integration of nitrogen metabolism
• Fumarate synthesized by urea cycle, links the transamination
reactions, through urea cycle –citric acid cycle

13. Disposal of Urea
Broken down to CO2 and NH3 by the bacterial enzyme
Urease (in intestine)
Urea produced in the liver freely diffuses and is transported
in blood to kidneys and excreted.

14. INHIRITED DISORDERS
OF
UREA CYCLE
.

15. Deficiency of any of the urea cycle enzymes would result in hyper
ammonemia.

16. Inherited disorders Clinical features
Hyper ammonemia
type-I
 Carbamyl phosphate synthetase -1 (CRP-1)
enzyme defect
 Ammonia toxicity is occurs.
Ornithinemia (or)
Hyper ammonemia
type-II
 Ornithine transcarbamylase enzyme defect
 Increased levels of glutamine, NH3 &
ornithine seen in blood.
Citrullinemia
 Arginino succinate synthetase enzyme defect
 Mental retardation
 Increased levels of NH3& citrulline are seen
in blood.

17. Inherited disorders Clinical features
Argininosuccinic
acidurias
 It is inherited disorder in fatal (before 2yrs of
age)
 Arginino succinase enzyme defect.
 Mental retardation.
 Increased levels of Arginino-succinate are seen
in blood & urine.
Hyper argininemia  Arginase enzyme defect.
 Hyper ammonemia is occurs.
 Increased excretion of lysine, cystine, ornithine
& arginine in urine.

18. Urea cycle disorders due to transporter defect
HHH syndrome (hyper ornithinemia, hyper ammonemia,
homocitrullinuria syndrome)
• Results from mutation of the ORNT-1 gene that encodes the
mitochandrial membrane ornithine permase
• Failure of transport cytosolic ornitine into mitochondria makes the
urea cycle inoperable- leads to hyperammonemia and
hyperornithineamia
• Absence of ornithine mitochondrial CP, carbomoylates lysine to
homocitrulline –in homocitrulinuria

19. Orotic aciduria in hyperammonemia type-II
• X –chromosome linked deficiency – hyperammonemia
type-II due to defect in ornithine transcarbamolyase
• CP accumulates in the mitochondria which reaches the
cytoplasm and used for synthesis of pyrimidine bases
• Orotic acid an intermediate in the pyrimidine synthesis
accumulates which leads to orotic aciduria

20. Thank you
Have a nice day to all