Download - 9 Amino Acid Metabolism 2014-2015 Handout
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Amino acid catabolism
- During times of starvation, amino acids are used to replenish TCA cycle intermediates and as precursors for gluconeogenesis
- Organisms with a diet rich in proteins can oxidize excess amino acids as fuels
- Amino acids are not stored
- In animals, amino acids (in the form of polypeptides) are the major source of nitrogen.
- What is the key difference between amino acids and the other 2 types of oxidizable molecules?
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Transamination (in liver):
Universal amino group acceptor
PLP : pyridoxal phosphate
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Deamination (oxidative deamination) - in liver:
Dehydrogenation (oxidation)
deamination
Transamination + Deamination = Transdeamination
urea
Glutamate Dehydrogenase
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How do non-hepatic tissues remove ammonia?
Amino group
Amide group
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Transport of glutamine to liver:
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Removal of excess ammonia from muscle
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The Urea Cycle In liver cells:
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Formation of carbomoyl phosphate
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Argininosuccinate synthase reaction:
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Transamination
Lyase
Arginase
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Links between the urea cycle and the TCA cycle
Cytosolic fumarase
transamination
fumarase
OAA
“Kreb Bicycle”
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Oxidation of the carbon skeletons in amino acids
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Amino acids giving rise to -ketoglutarate: Glutamate, Glutamine, Histidine
Histidine ammonia lyase
Methyl group transfer
(oxidative deamination)
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Amino acids giving rise to -ketoglutarate: Arginine and Proline
α-Ketoglutarate
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Aspartate and Asparagine
(Asp)
(Asn)
aspartate aminotransferase
Amino acids giving rise to oxaloacetate:
asparaginase
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Amino acids giving rise to pyruvate: Cysteine, tryptophan, threonine, serine, glycine and alanine
pyruvate
glutamate α-ketoglutarate
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5, 10-Methylene THF
THF
H2O
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Amino acids giving rise to succinyl-CoA: Methionine, threonine
Succinyl-CoA
Cystathionine
α-Ketobutyrate
dehydrogenase
Propionyl-CoA + CO2
NAD+ NADH
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Branched chain amino acid (BCAA) catabolism: Valine, Isoleucine, Leucine
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Aromatic amino acid metabolism: Phenylalanine and tyrosine
Phenylalanine hydroxylase
O2 H2O
NAD+ NADH + H+
X
Phenylketonuria (1 in 10,000 newborns)
CH2
COO-
Phenylacetate
CH2
CH
COO-
HO
Phenyllactate
CO2
H2O
Phenylpyruvate
CH2
C
COO-
O
Accumulates in phenylketonuria patients
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Aspartame -Artificial sweetener -Dipeptide of phenylalanine methyl ester and aspartate
“phenylketonurics: contains phenylalanine”
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Amino Acid Biosynthesis
The Nitrogen Cycle
Plants, bacteria, fungi
[N2 as electron acceptor]
Bacteria (symbiotic in legume plants)
Nutrifying bacteria
Denitrification
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Nitrogen fixation by the nitrogenase complex:
N2 + 8 H+ + 8 e- + 16 ATP 2NH3 + H2 + 16 ADP + 16 Pi
Nitrogen-fixing bacteria in root nodules of legume plants
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Ammonia Assimilation
- Entry point for ammonia: glutamate (Glu) and glutamine (Gln)
Glutamate
synthase
- Plants and bacteria: an additional pathway
NAD(P)H + H+ NAD(P)+
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Essential and Non-essential Amino Acids (in mammals)
Essential Amino Acids: Histidine, Isoleucine, Leucine, Lysine, Methionine Phenyalanine, Tryptophan, Threonine, Valine
Non-essential amino acids (precursor): Glutamate, glutamine, proline, arginine (-ketoglutarate) Alanine (pyruvate) Aspartate, asparagine (OAA) Serine, glycine (3-Phophoglycerate) *Cysteine (Methionine) *Tyrosine (Phenylalanine) *Conditional essential
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Biosynthesis of Amino Acids
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TRANSAMINATIONS
Example:
Glu-ala aminotransferase
Glu α-KG
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Aspartate and Asparagine Biosynthesis
Purine and pyrimidine biosynthesis
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Asparagine synthetase amide group
amide group
α
β
α
β
α
β
PPi
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Proline Biosynthesis
Glutamate kinase
1 2 3 4 5
α β γ
5
Glutamate Glutamate-5-P
Glutamate 5-P
Dehydrogenase
1-Pyrroline-5-
carboxylate reductase
NAD(P)H + H+ NAD(P)+
Proline Δ1-Pyrroline-5-
carboxylate
ATP ADP
NAD(P)H + H+
NAD(P)+
Pi
Glutamate-5-semialdehyde
Spontaneous
cyclization
C
O
-O
CH2 CH2 CH
NH3+
COO-
C
O
O
CH2 CH2 CH
NH3+
PO
-
-O
O
COO-
C
O
H
CH2 CH2 CH
NH3+
COO-
CH2H2C
HC
N
CH COO-
CH2H2C
H2C
HN
CH COO-
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Arginine Biosynthesis (related to urea cycle)
(Acetyl-CoA) N-acetyl group
Glutamate acetylglutamate synthase
N-Acetylglutamate
N-Acetyl-γ-glutamyl phosphate
N-Acetylglutamate kinase
N-Acetylglutamate dehydrogenase
1 2 3 4 5
α β γ
1 2 3 4 5
α β γ
1 2 3 4 5
α β γ
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1 2 3 4 5
α β γ
1 2 3 4 5
α β γ
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argininosuccinase
Fumarate
N-Acetylornithine
+
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Serine and Glycine Biosynthesis
Glutamate
-Ketoglutarate
Phosphoserine
transaminase
Phosphoserine
phosphatase
H2O Pi
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H2O
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Tyrosine synthesis from phenylalanine
Phenylalanine
Tyrosine
tetrahydrobiopterin Phenyalanine hydroxylase
Mixed function oxidase (mechanism similar to fatty acid desaturase)
(defective in phenylketonurics)
CH2 CH COO-
NH3+
HO
CH2 CH COO-
NH3+
O2
H2O
NADH + H+
NAD+
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Methionine cylce
(SAM)
(SAH)
Cysteine synthesis from methionine [ Plants and bacteria: SO4
2- cysteine ] assimilation
Cysteine synthesis
(from diet)
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(From methionine cycle)
(CBS)
Homocystinuria - Genetic defect in CBS - Homocysteine level in blood stream - Risks of heart diseases
Cysteine Biosynthesis