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CH2210
Amino Acid Metabolism
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Fate of Dietary ProteinDietary protein
Denatured and partially hydrolyzed protein (large polypeptides)
Stomach: HCl, pepsin
Amino acids and dipeptides
small intestine: proteases
Amino acids in bloodstream
intestinal lining: proteases
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Overview of Amino Acid Catabolism
H3N C C
H
RO
OThe catabolism of amino acids takes
place in three stages:
1) Removal of the amino group, leaving the carbon
skeleton of the amino acid.
2) Breakdown of the carbon skeletons to a glycolytic
intermediate, citric acid cycle intermediate, or acetyl-S-CoA.
3) Oxidation of these intermediates to CO2 and H2O
with the production of ATP.
small pieces
CO2 H2O
ATP
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aspartate oxaloacetateNH3
C C
H
O
O
CH2C
O
OO
C CO
O
CH2C
O
O
NH4+
glutamine
α-ketoglutarateNH3
C C
H
O
OCH2C
O
H2NCH2
O
C CO
OCH2C
O
OCH2
2 NH4+
alanine pyruvateNH3
C C
H
H3CO
O
O
C CH3CO
ONH4+
Representative Pathways of Amino Acid Catabolism
phenylalanine
fumarate
acetoacetate
NH3
C C
H
CH2O
OC
CCCC C
CH2 CCO
OH3C
O
CH CCHO
OC
O
O
HH
H
H H
NH4+CO2
+
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citrateoxaloacetate
fumarate
succinate
succinyl-CoA
malate isocitrate
aconitate
α-ketoglutarate
oxalosuccinate
pyruvate acetyl-CoA
alanine
aspartate
glutamine
phenylalanine
phenylalanine
acetoacetyl-CoA
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citrateoxaloacetate
fumarate
succinate
succinyl-CoA
malate isocitrate
aconitate
α-ketoglutarate
oxalosuccinate
pyruvate acetyl-CoA acetoacetyl-CoA
ketonesglucosegluconeogenesis ketogenesis
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The α-keto acids derived from catabolism of many amino acids are intermediates in glycolysis and the citric acid cycle.
The α-keto acids derived from catabolism of some amino acids are broken down to acetyl-CoA or acetoacetyl-CoA and are
oxidized by the citric acid cycle or converted to ketone bodies.
Amino acids that can be converted into pyruvate, α-ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate can be converted into glucose by gluconeogenesis and are said to be glucogenic.
These α-keto acids may, therefore, replenish citric acid cycle intermediates.
These amino acids are said to be ketogenic.
Glucogenic and Ketogenic Amino Acids
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citrate
fumarate
succinate
succinyl-CoA
malate isocitrate
aconitate
α-ketoglutarate
oxalosuccinate
pyruvate acetyl-CoA acetoacetyl-CoA ketones
gluconeogenesis
alanine glycine threonine cysteine serine
aspartate asparagine
glutamate glutamine arginine histidine
proline isoleucine methionine
valine threonine
aspartate phenylalanine
tyrosine
leucine lysine phenylalanine tyrosine
tryptophan
leucine isoleucine tryptophan threonine
Glucogenic and Ketogenic Amino Acids
oxaloacetate
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Overview of Amino Acid Catabolism
H3N C C
H
RO
OThe catabolism of amino acids takes
place in three stages:
1) Removal of the amino group, leaving the carbon
skeleton of the amino acid.
2) Breakdown of the carbon skeletons to a glycolytic
intermediate, citric acid cycle intermediate, or acetyl-S-CoA.
3) Oxidation of these intermediates to CO2 and H2O
with the production of ATP.
small pieces
CO2 H2O
ATP
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The Fate of the Amino Group of Amino Acids
The extraction of the amino group from amino acids must be done in such a way so as not to increase
blood ammonium ion levels above normal values.
NH4+
The normal concentration of NH4+ ion in the blood is 3.0 x 10-5 to 6.0 x 10-5 M.
Nitrogen is present in the bloodstream in the form of ammonium ions:
Above these concentrations (hyperammonemia) coma may result.
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NH4+ NH3
R-NH2R-NH3+
Because they are weak bases, amines in high concentrations cannot be used to transport nitrogen
atoms in the bloodstream.
C
CO O
H3N H
CH2CH2C
O O
C
CO O
H3N H
CH2CH2C
O NH2L-glutamate
C
CO O
H3N H
CH2CH2C
O NH2
L-glutamine
C
CO O
CH3
H3N H
L-alanine
“Neutral” forms of nitrogen atoms are used for
transport in the bloodstream and across
membranes.
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The pathway for the extraction of amino groups from amino acids consists of three phases:
1) Conversion of amino groups from all amino acids into a single product, glutamate, by transamination.
2) Conversion of glutamate into α-ketoglutarate by oxidative deamination, releasing NH4+ .
3) Conversion of NH4+ into urea, which is extracted from the blood by the kidneys and excreted.
The Fate of the Amino Group of Amino Acids
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CHC
O
O
CHC
O
O
CHC
O
O
CH2C
O
O NH3
aspartate
fumarate
α-amino acid α-keto acid
α-keto glutarate glutamate
NAD+, (NADP)+,
H2O
NADH, (NADPH),
NH4+ CO2
Urea cycleH2N
CNH2
O
Urea
transamination
oxidative deamination
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Transamination
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alpha amino acid alpha keto acid
HC
CO O
R1
NH3 C
CO O
R2
O C
CO O
R1
O HC
CO O
R2
NH3++HC
CO O
R1
NH3 C
CO O
R2
O C
CO O
R1
O HC
CO O
R2
NH3++
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The first step in amino acid metabolism is the removal of the amino group by transamination followed by oxidative deamination.
A transamination reaction can be represented as:
Transamination
Amino acid1 + α-ketoacid2 ⇔ α-ketoacid1 + amino acid 2
HC
CO O
R1
NH3 C
CO O
R2
O C
CO O
R1
O HC
CO O
R2
NH3++
Transamination reactions occur in all cells.
The enzymes responsible for transaminations are called transaminases or amino transferases.
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Most transaminases are specific for α-ketoglutarate but are less specific for the amino acid.
This means that the amino groups of almost all amino acids end up on glutamic acid (i.e., L-glutamate).
L-amino acid + α-ketoglutarate ⇔ α-ketoacid + L-glutamate
C
CO O
R
H3N C
CO O
CH2
O C
CO O
R
O C
CO O
CH2
H3N++H
CH2
CO O
CH2
CO O
H
Transamination
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One exception to this rule is in skeletal muscle, where transaminases use pyruvate as the amino acceptor, producing alanine as the product.
L-amino acid + pyruvate ⇔ α-ketoacid + L-alanine
C
CO O
R
H3N C
CO O
CH3
O C
CO O
R
O C
CO O
CH3
H3N++H H
Another example of a specific transaminase reaction is aspartate transaminase:
L-aspartate + α-ketoglutarate ⇔ oxaloacetate + L-glutamate
C
CO O
CH2
H3N C
CO O
CH2
O C
CO O
O C
CO O
H3N++H H
CO O
CH2
CO O
CH2
CH2
CO O
CH2
CO O
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Transamination in Diagnostic Laboratory Medicine
The presence of alanine transaminase (glutamate:pyruvate transaminase or GPT) and aspartate transaminase
(glutamate:oxaloacetate transaminase, or GOT) in the bloodstream, above a certain base level, may indicate liver damage.
Serum GPT and GOT (SGPT and SGOT) tests measure the
severity and stage of liver damage.
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Vitamin B-6 as a Coenzyme
All transaminases require the coenzyme pyridoxal phosphate (derived from pyridoxine, vitamin B-6):
N
C
HO
H3C
CH2
O H
H
O P
O
O
O
pyridoxal phosphate
Vitamin preparations may contain the precursor to pyridoxal phosphate in different forms:
N
C
HO
H3C
CH2OH
O H
HN
CH2NH2
HO
H3C
CH2OH
H
N
CH2OH
HO
H3C
CH2OH
H
pyridoxalpyridoxamine
pyridoxine
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The Transaminase Mechanism
N
C
HO
H3C
CH2
N H
H
O PO32-
CHCO
O
R
CC
O O
RH3N H
H2O
CC
O O
RO
H2O
pyridoxamine phosphate
N
C
HO
H3C
CH2
N H
H
O PO32-
CCOO
R
H
N
CHO
H3C
CH2
O H
H
O PO32-
N
CHO
H3C
CH2
H3N
H
O PO32-
H
H
pyridoxal phosphate
alpha amino acid
alpha keto acid
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The Fate of the Amino Group of Amino Acids
NH4+
Nitrogen is present in the bloodstream in the form of ammonium ions:
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The pathway for the extraction of amino groups from amino acids consists of three phases:
1) Conversion of amino groups from all amino acids into a single product, glutamate, by transamination.
2) Conversion of glutamate into α-ketoglutarate by oxidative deamination, releasing NH4+ .
3) Conversion of NH4+ into urea, which is extracted from the blood by the kidneys and excreted.
The Fate of the Amino Group of Amino Acids
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CHC
O
O
CHC
O
O
CHC
O
O
CH2C
O
O NH3
aspartate
fumarate
α-amino acid α-keto acid
α-keto glutarate glutamate
CO2
Urea cycleH2N
CNH2
O
Urea
transamination
oxidative deamination
NAD+, (NADP)+,
H2O
NADH, (NADPH),
NH4+
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C
CO O
CH2
O
CH2C
O O
C
CO O
H3N H
CH2CH2C
O O
NH4++
NADH (NADPH)NAD+ (NADP+) H2O
glutamate dehydrogenase
Oxidative Deamination
This reaction is reversible and provides a mechanism for
1) generating ammonium ion for excretion as urea
2) generating a-ketoglutarate
3) assimilating ammonium ion for use in other metabolic pathways in the liver and kidneys
glutamate α-ketoglutarate
DOES NOT ENTER THE
BLOODSTREAM
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Amino Group and Ammonia Transport
Amino groups collected in extrahepatic tissues in the form of glutamate must be packaged in a non-toxic form for
transport through the blood to the liver.
Glutamate, itself, cannot pass through the cell membranes.
Two different transport forms are used:
1) Production of glutamine in most cell types
2) Production of alanine in muscle cells.
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Glutamine Production
+ NH4+ + ATP + H+ + ADP +Pi
C
CO O
H3N H
CH2CH2C
O O
C
CO O
H3N H
CH2CH2C
O NH2
glutamine synthetase
In almost all cell types, glutamine synthetase catalyzes the formation of glutamine from glutamate:
The glutamine, thus formed, is electrically neutral, nontoxic, and can pass through the cell membranes into the blood. The concentration of glutamine in the blood is higher than any other amino acid.
L-glutamate L-glutamine
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Amino Group and Ammonia Transport
Once in the liver, the reverse reaction takes place and glutamine is deaminated to ammonium ion and glutamate.
C
CO O
H3N H
CH2CH2C
O NH2
C
CO O
H3N H
CH2CH2C
O O
+ H2O + NH4+
Glutamate can then be oxidatively deaminated to ammonium ion and α-ketoglutarate.
L-glutamate L-glutamine
C
CO O
H3N H
CH2CH2C
O O
L-glutamate
C
CO O
CH2
O
CH2C
O O
α-ketoglutarate
+ NAD+ + H2O + NADH + NH4+
glutamate dehydrogenase
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L-glutamate
C
CO O
H3N H
CH2CH2C
O O
C
CO O
CH2
O
CH2C
O O
α-ketoglutarate
+ NADP+ + H2O+ NADPH + NH4+
glutamate dehydrogenase
In active muscle cells, large quantities of ammonium ion are produced. After two reactions, alanine is formed. Like glutamine, alanine is
electrically neutral:
C
CO O
CH2
OC
CO O
H3N H
CH2C
O O
CH2CH2C
O O
C
CO O
CH3
O C
CO O
CH3
H3N++ H
α-ketoglutarateL-glutamate
pyruvate alanine
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C
CO O
CH3
H3N H
C
CO O
H3N H
CH2CH2C
O NH2
Like glutamine, alanine is electrically neutral and readily traverses membranes and enters the blood stream.
alanine
L-glutamine
In the liver, the combination of transamination and oxidative deamination reaction releases ammonium ions.
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Glucose
Pyruvate Lactate
2 ATPGlucose
Pyruvate
Alanine
Urea
6 ATP
4 ATP
Alanine
𝛂-amino acid
𝛂-keto acid
Liver Muscle tissue
N
Glucose/Alanine Cycle
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Overall Reaction:
NH4+ + HCO3- + 3 ATP + aspartate (-NH3+)
urea + 2 ADP + AMP + 4 PO43- + fumarate
Urea Cycle
H2NC
NH2
O
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CNH2H2N
O
C
C
O O
HH3N
CH2CH2CH2NH
COH2N
C
C
O O
HH3N
CH2CH2CH2NH3
C
C
O O
HH3N
CH2CH2CH2NH
CNH2H2N
C
C
O O
HH3N
CH2CH2CH2NH
CNH2N C
CO O
H
CH2C
O O
arginine
ornithine
citrulline
arginosuccinate
urea
Urea Cycle
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ornithine
arginine
argininosuccinate
citrulline
citrulline
ornithine
urea
glutamate
glutamate a-ketoglutarate
NH4+
Pi
mitochondria
cytosolaspartate
fumarate
ATP
AMP, 2Pi
Urea Cycle
carbamoyl phosphate
HCO3-2 ATP
2 ADP,Pi
Urea Cycle
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CNH2H2N
O
C
C
O O
HH3N
CH2CH2CH2NH
COH2N
C
C
O O
HH3N
CH2CH2CH2NH3
C
C
O O
HH3N
CH2CH2CH2NH
CNH2H2N
C
C
O O
HH3N
CH2CH2CH2NH
CNH2N C
CO O
H
CH2C
O O
arginine
ornithine
citrulline
arginosuccinate
urea
C
CO O
H
CH2
CO O
H3N
C
C
H
H
C
O
O
C O
O
aspartate
fumarate
COH2N
P O
O
O
O
P O
O
O
NH4+ , HCO3-, 2ATP
2ADP,Pi
carbamoyl phosphate
Urea Cycle
AMP,2Pi ATP
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Overall Reaction:
NH4+ + HCO3- + 3 ATP + aspartate
urea + 2 ADP + AMP + 4 PO43- + fumarate
Urea Cycle
![Page 37: Lecture #25-Amino acid metabolism (2019)-42 copyprofkatz.com/courses/wp-content/uploads/2019/07/...into a single product, glutamate, by transamination. 2) Conversion of glutamate into](https://reader033.vdocument.in/reader033/viewer/2022053001/5f05376e7e708231d411dbbe/html5/thumbnails/37.jpg)
ATP, via TCA
cycle
Glucose
Fatty acids
Ketones
Urea
NH4+
Amino acid pool
Dietary protein pyruvate,
acetyl-CoA, acetoacetate,
TCA cycle intermediates
Liver proteins Plasma proteins
Other nitrogen-containing
compounds
![Page 38: Lecture #25-Amino acid metabolism (2019)-42 copyprofkatz.com/courses/wp-content/uploads/2019/07/...into a single product, glutamate, by transamination. 2) Conversion of glutamate into](https://reader033.vdocument.in/reader033/viewer/2022053001/5f05376e7e708231d411dbbe/html5/thumbnails/38.jpg)
aquatic invertebrates,
bony fishes, crocodiles
mammals, sharks, some bony fishes,
turtles
birds, insects, reptiles, land
gastropodsscorpions,
spiders
NH3H2N
C O
H2N
CHN
CNH
C
C
NH
C
HN
O
O
O
Nitrogen excretion products for various organisms
Water solubility
Energy needed to produce
N→?
CHN
CN
C
C
NH
CH
N
H2N
O
ammonia urea uric acid guanine
Habitat
![Page 39: Lecture #25-Amino acid metabolism (2019)-42 copyprofkatz.com/courses/wp-content/uploads/2019/07/...into a single product, glutamate, by transamination. 2) Conversion of glutamate into](https://reader033.vdocument.in/reader033/viewer/2022053001/5f05376e7e708231d411dbbe/html5/thumbnails/39.jpg)
H2N
C O
H2N
NH3
H2N
C O
H2N
NH3