Ammonia is produced from amino acid catabolism and transported to the liver for urea synthesis. The urea cycle converts ammonia to urea using enzymes in the liver mitochondria and cytosol. Defects in the urea cycle can cause toxic hyperammonemia. Treatment focuses on limiting ammonia intake and increasing excretion through drugs and diet modification. High blood urea levels can occur from prerenal causes like dehydration or heart failure reducing kidney function, or renal failure impairing excretion.

23. Sources and fate of Ammonia (NH3)
 Sources of Ammonia
 Ammonia is produced in the body from:
 1-Deamination of Amino Acids 2
- Bacterial Action in intestine
 3- Catabolism of Amines 4
-Catabolism of Purines and Pyrimidines

24. Fate of ammonia
 Ammonia is used in the body to form :
 1-Urea by urea cycle in the liver
 2-Non-essential amino acids by transamination
 3-Amino sugars byTransamidation 4
-Purines and pyrimidines

25. Transport of ammonia from tissues
to the liver
 Ammonia transports between tissues and the liver mos
tly in the form of glutamine and alanine (non-toxic
transport) and not as free ammonia.
 1-Transport ammonia by glutamine
 This mechanism is used by most tissues in which ammon
ia binds with glutamic acids in presence of glutamine sy
nthetase and ATP to form glutamine , then glutamine is
transported in the blood to the liver where it is cleaved
to produce glutamic acid and free ammonia by glutami
nase

26. Transport of ammonia from tissues t
o the liver
 2-Transport ammonia by alanine
 This mechanism is used mainly by muscles by tra
nsamination of pyruvate to
 form alanine by alanine transaminase (ALT,GPT), t
hen alanine is transported by the blood to the live
r, where it is converted to pyruvate, by transamina
tion.

27. Urea cycle
 Also known as the ornithine cycle or Krebs-He
nseleit cycle,it is a cycle of biochemical reactions
occurring in liver, which produces urea (non-toxic)
from ammonia (toxic).The urea cycle consists of fiv
e reactions: two mitochondrial and three cytos
olic.The cycle converts two amino groups, one fro
m NH4
+ and one from Aspartic acid, and a carbon at
om from HCO3
−, to produce urea at the cost of fou
r ATP.

28. Steps of Urea cycle
 1-Formation of carbamoyl phosphate by cond
ensation of CO2, ammonia, and ATP by mitochondri
al carbamoyl phosphate synthetase I.The enzy
me requires N-acetyl glutamate as allosteric activat
or.

30. Urea cycle
 2- Carbamoyl phosphate and ornithine are combin
ed together to form citrulline by ornithine transc
arbamoylase.This enzyme is present in mitochond
ria.

32. Urea cycle
 3-This reaction and the other reactions of urea cy
cle occurs in cytosol, citrulline formed in mitochond
ria enters cytosol through specific transporter pres
ent in inner mitochondrial membrane. Arginino su
ccinate synthetase present in cytosol catalyzes c
ondensation of citrulline and aspartate to for
m argininosuccinate in prescence of ATP.

34. Urea cycle
 4-Argininosuccinate is cleaved by Argininosuccina
se to arginine and fumarate.

36. Urea cycle
 5- Arginine is converted to urea and ornithine by
arginase.The ornithine which formed enters mitoc
hondria through transporter present in inner mitoc
hondrial membrane to start reactions of urea cycle
again.

39. Regulation of urea formation
 Formation of urea is regulated by activity of carba
moyl phosphate synthetase I, N-acetylglutamate
(an allosteric activator) regulates the activity of this
enzyme.
 High protein intake leads to form more N-acetylglut
amate. So high protein diet affects urea formation. In
starvation also urea synthesis is increased due to in
creased protein breakdown.

40. Metabolic disorders of urea cycle
 Urea formation is impaired in several inherited dise
ases.They are due to deficiency of enzymes of urea
cycle.All defects in urea synthesis result in ammonia
intoxication. Urea cycle disorders are characterized
by hyperammonemia, encephalopathy,vomiting,letha
rgy, and mental retardation.All metabolic disorders
of urea cycle are autosomal recessive disorders exc
ept hyperammonemia type II is X-linked disorders.

41. Metabolic disorders of urea cycle
 1- Hyper ammonemiaType I
 It is due to deficiency of carbamoyl phosphate s
ynthetase I. Mental etardation is the main sympto
m of this condition.
 2- Hyper ammonemiaType II
 It is due to deficiency of enzyme ornithine transc
arbamoylase.

42. Metabolic disorders of urea cycle
 3- Citrullinemia
 This condition is due to the deficiency of arginino
succinate synthetase. Citrulline accumulates in bl
ood and excreted in urine.
 4- Argininosuccinicaciduria
 This condition is due to deficiency of Argininosuc
cinase.So, argininosuccinate accumulates in blood a
nd excreted in urine.

43. Metabolic disorders of urea cycle
 5- Hyperargininemia
 This condition is due to deficiency of arginase H
ence, arginine accumulates and excreted in urine.
 6- N-acetyl glutamate synthetase deficiency
 It is a rare disorder, N-acetyl glutamate synthetase i
s needed in formation of N-acetyl glutamate fro
m acetyl-CoA and glutamate. Since carbamoyl gluta
mate is an analog of acetyl glutamate administration
of carbamoyl glutamate can lower symptoms of this
case.

44. Treatment of hyperammonemia
 Treatment centers on limiting intake of ammonia and increa
sing its excretion.
 1-Dietary protein (a source of ammonium) is restricted.
 2- Intravenous sodium phenylacetate and sodium benzoate
are used to treat hyperammonemia in patients with urea c
ycle enzyme deficiencies. Phenylacetate conjugates with glut
amine to form phenylacetylglutamine, which is excreted by
the kidneys. Sodium benzoate conjugating with glycine to f
orm hippuric acid, which is rapidly excreted by the kidneys.

45. Treatment of hyperammonemia
 3- Acidification of the intestinal lumen using lactulos
e can decrease ammonia (NH3 is diffusible) levels by
addition of H+ to ammonia to form ammonium (
NH4 is not diffusible) and trapping it in the stool.Th
is is a treatment for hepatic encephalopathy.

46. Mechanism of ammonia toxicity
 Mechanism of toxic effect of ammonia on brain is not clearl
y understood but ammonia can cause brain toxicity by four
ways:
 1-Elevated levels of glutamine, formed from NH4
+ and gluta
mate , produce osmotic effects that lead directly to brain s
welling.
 2-The entry of ammonia into brain leads to formation of gl
utamate by the reversal of glutamate dehydrogenase reacti
on.This depletes available α-keto glutarate in the brain, whi
ch lead to inhibit citric acid cycle and ATP production dimi
nishes,which leads to brain cell dysfunction.

47. Mechanism of ammonia toxicity
 3-Brain is rich in glutamine synthetase ,and the amm
onia which enters brain is used for glutamine synthe
sis, which leads to depletion of cellular ATP and cell
dysfunction.
 4- Glutamate is considered as neurotransmitter the
toxice effect of ammonia may be due to over stimul
ation of nerve cells by glutamate formed from amm
onia and α-ketoglutarate by the action of glutamate
dehydrogenase.

48. Fate of urea
 Following synthesis in the liver, urea is carried in the blood
to the kidney, where it is readily filtered from the plasma by
the glomerulus. Most of the urea in the glomerular filtrate i
s excreted in the urine, and some urea is reabsorbed by pas
sive diffusion during passage of the filtrate through the rena
l tubules.The concentration of urea in the plasma is determ
ined by renal function and perfusion, the protein content of
the diet, and the rate of protein catabolism.
 The normal range of blood urea is ≤ 50 mg/dl.An elevated
concentration of urea in the blood is called uremia.

49. Increased urea levels occur in the fol
lowing conditions:
 A-Prerenal causes
 1-Congestive heart failure (due to decreased blood flow to
the kidneys, decreased renal excretion, and accumulation i
n circulating blood)
 2-Excessive protein ingestion (due to increased protein me
tabolism)
 3-Gastrointestinal (GI) bleeding (Excessive blood protein in
the GI tract and increased protein metabolism)
 4-Shock (due to decreased blood flow to the kidneys, decr
eased renal excreation)
 5-Dehydration

50. B-Renal causes
 1-Renal failure ( due to decreased renal excretion)
 2-Glomerulonephritis

51. C-Postrenal causes
 1-Urinary tract obstruction