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8/8/2019 15530542 Ammonia Metabolism Urea Cycle
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AMMONIA METABOLISM
UREA CYCLE
Compiled by:-
PRATEEK CHOPRA
BT/BIO/05/310022
AMITY INSTITUTE OF BIOTECHNOLOGY
NOIDA
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OBJECTIVES
1. Define protein balance, nitrogen balance and essential amino acid.
2. Describe the transaminase, and glutamate dehydrogenase reactions
and discuss their roles in the removal of nitrogen waste in the body.
3. Identify the direct sources of nitrogen for the urea cycle.
4. Define hyperammonemia and discuss why a defect in either carbamoyl
phosphate synthetase I or ornithine transcarbamoylase leads to
hyperammonemia
5. Distinguish between ketogenic and gluconeogenic (glycogenic)
amino acids.
6. Describe the phenylalanine hydroxylase reaction and explain its
relationship to phenylketonuria;
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PHYSIOLOGICAL PREMISE
Have you ever carefully read a packet of EqualTM? If so,
you may have noticed a warning to phenylketonurics.
The chemical sweetener in equal is a dipeptide
containing phenylalanine and aspartate. Some
individuals are born with one of the more commonamino acid disorders, phenylketonuria. They are unable
to metabolize phenylalanine to tyrosine. Consequently
vast amounts of phenylalanine will accumulate in the
blood if too much of this amino acid is consumed in the
diet. Constant excess of phenylalanine in the blood can
cause severe mental retardation. Hence this is one ofseveral diseases tested for in newborns in all states.
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CatabolismUrea + CO
2AminoAcid Pool
Carbon compounds
+ nitrogen
De novo
synthesis
Dietary aminoacids
Porphyrins, creatine, carnitine,
hormones, nucleotides
Biosynthesis ofnitrogen compounds
Fates of amino acidsAmino acid sources
Figure 1. Sources and fates of amino acids
BODY PROTEIN
Proteolysis Protein synthesis
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PROTEIN BALANCE
positive: synthesis > degradation (e.g., growth, body building)
negative: synthesis < degradation (e.g., starvation, trauma, cancer cachexia)
BODY PROTEIN
Proteolysis Protein synthesis
Amino Acid Pool
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E-Amino acid
E-Keto acid
NH2
HOOC-CH-CH2CH
2COOH
O
HOOC-C-R
NH2
HOOC-CH-R
O
HOOC-C-CH2CH2COOH
E-Ketoglutarate
Glutamate
Cofactor = pyridoxal phosphate
Figure 2. Depiction of a general transamination
(aminotransferase) reaction. The E-amino acid otherthan glutamate can be a wide variety
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+ E-ketoglutarate+
glutamate
Aspartate aminotransferase
(glutamate-oxaloacetate transaminase)
NH2 Aspartate
HOOC-CH-CH2COOH
O Oxaloacetate
HOOC-C-CH2COOH
Alanine aminotransferase
(glutamate-pyruvate transaminase)
+ E-ketoglutarate+
glutamate
NH2 Alanine
HOOC-CH-CH3
O Pyruvate
HOOC-C-CH3
Figure 3. The reactions catalyzed by aspartate aminotransferase
and alanine aminotransferase.
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NADH NAD+
E-Ketoglutarate+ NH4
+
Glutamate
Glutamate
dehydrogenase
Glutamine
Glutamine
synthetase
NH3 + ATP
ADP + Pi
Figure 3. In non-hepatic tissues the linked reactions of glutamate
dehydrogenase and glutamine synthetase remove two ammonia
molecules from the tissues as a way of ridding the tissues of nitrogen
waste. The glutamine deposits the ammonia in the kidney for
excretion.
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Glutaminase
Glutamate
Glutamine
NH4+
Glutamate dehydrogenase
E-Ketoglutarate+ NH4
+
NAD+ NADH
Figure 5. Kidney production of ammonia for excretion following
successive removal of amino groups from glutamine via glutaminase
and glutamate dehydrogenase
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Figure 6. In liver, nitrogen waste from amino acids ends up in urea.Amino acids are derived either from the breakdown of protein in
various tissues or from what is synthesized in those tissues
E-Amino acid
E-Keto acid
E-Ketoglutarate
Glutamate
Aminotransferase
NAD+ + H2O
Glu
dehydrogenase
E-Ketoglutarate
Glutamate
NADH + NH4+NH4+
UREA
Ureacycle
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CYTOPLASM MITOCHONDRIA
Figure 7. Carbamoyl phosphate synthetase reaction and the urea cycle.
Overall: 3ATP+HCO3-
+NH4+
+asp 2ADP+AMP+2Pi+PPi+fumarate+urea
Ornithine
Citrulline
argininosuccinate synthetase argininosuccinase arginase
AMP+PPi
-Aspartate
Argininosuccinate
ATP
Arginine
Fumarate
(returns
to TCA
cycle)
Pi
Ornithine
Citrulline
Ornithine
transcarbamoylase
Carbamoyl phosphate
2ATP + HCO3- +NH4
+
2ADP + Pi
Carbamoylphosphate
synthetase
UREAO
H2N-C- NH2
Ornithine
-OOC-CH-NH3+
CH
2COO-
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UREA CYCLE FACTS
Found primarily in liver and lesser extent in kidney
Nitrogen added to the urea cycle via carbamoyl phosphate
and aspartate
Carbamoyl phosphate synthetase is allosterically
activated by N-acetylglutamate
(acetyl CoA + glutamatep N-acetylglutamate)
Arginine stimulates the formation of N-acetylglutamate
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Fatty liver can lead to cirrhosis
HYPERAMMONEMIASAcquired = Liver disease leads to portal-systemic shunting
Inherited = Urea cycle enzyme defects of CPS I or ornithine
transcarbamoylase lead to severe hyperammonemia
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O2
Tyrosine
H2O
Dihydrobiopterin
Phenylalanine
hydroxylase
Phenylalanine
NADP+ NADPH
Tetrahydrobiopterin
Figure 8. Unusual compounds produced from phenylalanine in
phenylketonuria. The phenylalanine hydroxylase reaction (or
regeneration of the tetrahydrobiopterin cofactor) are defective in
phenylketonuria.
primary defect in
phenylketonuria
Phenylpyruvate
Phenylacetate
Phenyllactate
X