Course: Nutrition and Metabolism - National University acid catabolism.pdf · Fate of amino acids...
Transcript of Course: Nutrition and Metabolism - National University acid catabolism.pdf · Fate of amino acids...
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Course: Nutrition and Metabolism
Part (3): Amino Acids & Protein Metabolism
Lecture (2): Amino Acids Catabolism
Dr. Nuha AminMobile: +249910050800
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CatabolismUrea +
carbon
skeleton
Amino Acid Pool
Dietary amino
acids
Biosynthesis of
nitrogen compounds
fates of amino acids
Protein synthesis
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Fate of amino acids in the body
1. Amino acids are used for protein synthesis
2. Amino acids are used for formation of nitrogen-
containing compounds
3. Amino acids in excess are degraded (used for energy)
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Major dietary source of nitrogen is protein.
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NITROGEN BALANCE
Nitrogen balance = nitrogen ingested - nitrogen excreted
(primarily as protein) (primarily as urea)
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NITROGEN BALANCE
Nitrogen balance = nitrogen ingested - nitrogen excreted
(primarily as protein) (primarily as urea)
Nitrogen balance = 0
Positive nitrogen balance
Negative nitrogen balance.
Nitrogen in = nitrogen out300 g 300 g
Nitrogen in < nitrogen out250 g 300 g
Nitrogen in > nitrogen out
310 g 300 g
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Normal nitrogen balance:
Normal, well fed adults
Positive N balance:
Growing or recovering animals
Negative N balance:
In starvation, trauma and cancer
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AMINO ACID CATABOLISM
• Amino acids cannot be stored in the body.
• If there is an excess of amino acids, the
body will use them for energy production.
Amino acid degradation requires the
removal of the amino group as ammonia.
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Amino Acid Catabolism
NH3Carbon Skeleton
Urea
Urea
Cycle
H2N C
O
NH2
Amino acid H3+N C
H
R
C
O
O-
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Amino Acids Catabolism
excess amino acids are broken down into:
(1) urea excreted from body
(2) Carbon skeletons used as energy
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Removal of NH3 group
Takes place in four steps
1.Transamination
2.Oxidative deamination
3.NH3 transport
4.Urea synthesis
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TRANSAMINATION
• Is the transfer of amino group from a-amino acidto an a-keto acid
• A new amino acid and a new a-keto acid are formed
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• Enzyme is called
transaminase
• Coenzyme is PLP
( vitamin B6)
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Transamination reactions are
reversible reactions
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Transamination Reactions
• Used in amino acid catabolism
• Used in amino acid biosynthesis
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Product of transamination
• The removal of the amino groups of most amino
acids begins with the transfer of amino groups to
just one amino acid - glutamic acid .
• This is catalyzed by transaminase enzymes
which transfer the amino group from amino
acids to a compound called alpha-
ketoglutarate.
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Alanine
Transaminase (ALT)
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Aspartate
Transaminase (AST)
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ALT And AST
alanine + a-ketoglutarate pyruvate + glutamate
aspartate + a-ketoglutarate oxaloacetate + glutamate
alanine
transaminase
aspartate
transaminase
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Clinically Important Transaminases
(if high in blood, they indicate tissue damage)
1) Alanine transaminase (ALT) indicates liver damage
2) Aspartate transaminase (AST) indicates liver damage and myocardial infarction
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2. Oxidative Deamination
• Oxidative deamination occurs on
glutamate because glutamate was the end
product of many transamination reactions.
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• Oxidative deamination: Removes the
amino group from glutamate as ammonia
• This takes place in mitochondrial
matrix of cells.
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•The enzyme is called glutamate dehydrogenase.
Glutamate dehydrogenase requires NAD+ or
NADP+ as cofactor.
Reversible reaction.
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: Excess ammonia is toxic to animal
tissues. Other than amino acid
catabolism in tissues ammonia is also
produced as a result of nucleic acid
degradation.
Glutamine synthase catalyses the
synthesis of glutamine by adding the
ammonia to glutamate at the expense
of ATP hydrolysis.
Glutamine is a non-toxic carrier of
ammonia. It is transported to liver or
kidney via blood.
In liver or kidney mitochondria, the
glutamine is converted to glutamate
and ammonia. Ammonia is
incorporated in urea cycle in liver to
be excreted.
3.Transport of excess ammonia
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Glucose-Alanine cycle:
Amino group from excess
glutamate produced in muscle as
a result of amino acid catabolism,
is transferred to pyruvate
resulting in the formation of
alanine.
Alanine is another safe way to
transport ammonia from muscle to
liver via blood.
In liver alanine aminotransferase
transfers the amino gp to glutarate
and pyruvate regenerated is used
in gluconeogenesis.
Glucose produced by
gluconeogenesis is transported to
muscle where it enters the
glycolysis.
Thus the excess puruvate and
ammonia generated in muscle are
safely transported to liver.
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4.UREA CYCLE
– NH3 is produced from amino acid catabolism is
toxic and must be eliminated.
– NH3 is eliminated through the urea cycle
that occurs in the liver.
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• Urea cycle is a five-step pathway carried out by
liver cells.
The urea cycle
Occurs in the liver.
Results in the formation of urea.
Urea is eliminated by excretion (urine).
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L-arginino-
succinate
L-ornithine
fumarate
L-arginine
urea
H2O
argininosuccinate
lyase
arginase
NH4+ + CO2
carbamoyl
phosphate
L-citrulline
L- aspartate
ATP
AMP + PPi
Pi
2 ATP
2 ADP + Pi
ornithine
transcarbamoylase
argininosuccinate
synthase
carbamoyl-phosphate
synthase I
mitochondrial
matrix
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Step 1First step combines CO2 and NH4
+ to form
carbamoyl phosphate
– Reaction requires ATP and H2O
– Takes place in the mitochondria
– Catalyzed by carbamoyl phosphate
synthetase
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Step 2Carbamoyl phosphate condenses with the
amino acid ornithine to produce the amino acid
citrulline
– Occurs in the mitochondria
– Catalyzed by ornithine transcarbamoylase
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Step 3Citrulline is transported to the cytoplasm
– Condenses with aspartate to produce
argininosuccinate
– Catalyzed by argininosuccinate
synthetase
– Requires energy released by ATP
hydrolysis
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Step 4• Argininosuccinate cleaved to
produce the amino acid arginine and
fumarate of the citric acid cycle
• Reaction catalyzed by
argininosuccinate lyase
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Step 5• Final reaction hydrolyzes arginine to
generate urea – the reaction product that is
excreted
• Reaction also regenerates ornithine, the
original reactant in the cycle
• Reaction is catalyzed by arginase
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Metabolic disorders of urea
cycle
•All defects in urea synthesis
result in ammonia intoxication
•The defect is more serious in
the initial steps of urea
synthesis due to accumulation
of free ammonia
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•Major clinical manifestations
are; vomiting, avoidance of high
protein diets, intermittent
ataxia, irritability, lethargy, and
mental retardation
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•Disorder:
•1- hyperammonemia type I
•2- hyperammonemia typeII
•3- citrullinemia
•4- argininosuccinicaciduria
•5- hyperargininemia
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•1- Hyperammonemia typeI:
•It is familial condition due to
defect in carbamoyl phosphate
synthetase deficiency
•All manifestation of
accumulation of ammonia…
•
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•2- Hyperammonemia Type II:
•Due to deficiency of ornithine
transcarbamoylase
•It is an X linked defect.
Manifestations similar to type I.
There is elevated level of
glutamine in the blood,
cerebrospinal fluid and urine.
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•3- Citrullinemia:
•Rare recessive inherited
disorder due to deficiency in
argininosuccinate synthase.
•1-2 grams of citrulline are
excreted in urine daily.
•Feeding arginine increase
excretion of citrulline and
feeding benzoate diverts
ammonia to hippurate.
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•4- Argininosuccinicaciduria:
•Rare recessive inherited disorder due
to deficiency in argininosuccinase.
•There is elevated level of
argininosuccinate in the blood, CSF,
and urine.
•It can be of early or late onset.
•It is fatal early in life
•It is treated by arginine supplements
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•5- hyperargininemia:
•Due to deficiency in arginase.
•It is characterized by elevated
arginine in the blood and CSF.
•Treated by low protein in the
diet
•Gene therapy…….