AMINO ACIDS CATABOLISM AMINO ACIDS CATABOLISM

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Amino acid degaradation
The nitrogenous compound degradation in mammals generally
follows a particular mechanism.
1. the nitrogen in amino acids is removed by deamination reaction
and converted to ammonia-which is toxic, therefore need to be
detoxified and excreted as soon as possible.
Ammonotelic organism (e.g fish) excreted ammonia directly into
surrounding in the form of dissolved ammonia.
Mammals generally have to conserve water, therefore cannot
excrete as dissolved ammonia- but convert it to urea a.k.a
ureotelic organism.
Uricotelic organism (bird, certain reptiles and insect) have more
stringent water conservation problem, therefore convert ammonia to
uric acid.
In human and birds- uric acid is also the nitrogenous product of
purine metabolism.
The nitrogenous compound degradation in mammals generally
follows a particular mechanism.
1. the nitrogen in amino acids is removed by deamination reaction
and converted to ammonia-which is toxic, therefore need to be
detoxified and excreted as soon as possible.
Ammonotelic organism (e.g fish) excreted ammonia directly into
surrounding in the form of dissolved ammonia.
Mammals generally have to conserve water, therefore cannot
excrete as dissolved ammonia- but convert it to urea a.k.a
ureotelic organism.
Uricotelic organism (bird, certain reptiles and insect) have more
stringent water conservation problem, therefore convert ammonia to
uric acid.
In human and birds- uric acid is also the nitrogenous product of
purine metabolism.
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Amino acids catabolism usually begins by the removal of the
amino group through:-
-Transamination
- oxidative deamination
Amino group is then dispose as urea.
Carbon skeleton produced from standard amino acids are
then degraded to form seven metabolic product :-
- acetyl-CoA
- acetoacetyl-CoA
- pyruvate
- -ketoglutarate
- succinyl CoA
- fumarate
- oxaloacetate
Amino acids catabolism usually begins by the removal of the
amino group through:-
-Transamination
- oxidative deamination
Amino group is then dispose as urea.
Carbon skeleton produced from standard amino acids are
then degraded to form seven metabolic product :-
- acetyl-CoA
- acetoacetyl-CoA
- pyruvate
- -ketoglutarate
- succinyl CoA
- fumarate
- oxaloacetate
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Those amino acids that can be converted to acetyl-CoA and
acetoacetyl-CoA are referred to as KETOGENIC because
they can be converted to either fatty acids or ketone
bodies.
Those aa than can be degraded to pyruvate, -ketoglutarate,
succinyl-CoA , fumarate and oxaloacetate, are referred to
as GLUCOGENIC they can be used in gluconeogenesis.
All amino acids except lysine and leucine are at least partly
glucogenic. Lys and leu are purely ketogenic.
Amino acid that yield acetyl-CoA can be divided into 2
groups:-
i) Those that yield pyruvate as intermediate
ii) Those not involves pyruvate as intermediate
Group (i) includes Ala, Cys, Gly, Ser, and Thr. (ACGST)
Group (ii) includes Phe, Lys, Leu, Trp, and Tyr. (FKLWY)
Those amino acids that can be converted to acetyl-CoA and
acetoacetyl-CoA are referred to as KETOGENIC because
they can be converted to either fatty acids or ketone
bodies.
Those aa than can be degraded to pyruvate, -ketoglutarate,
succinyl-CoA , fumarate and oxaloacetate, are referred to
as GLUCOGENIC they can be used in gluconeogenesis.
All amino acids except lysine and leucine are at least partly
glucogenic. Lys and leu are purely ketogenic.
Amino acid that yield acetyl-CoA can be divided into 2
groups:-
i) Those that yield pyruvate as intermediate
ii) Those not involves pyruvate as intermediate
Group (i) includes Ala, Cys, Gly, Ser, and Thr. (ACGST)
Group (ii) includes Phe, Lys, Leu, Trp, and Tyr. (FKLWY)
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In muscle, excess amino groups are transferred to -ketoglutarate
to form glutamate.
In muscle cell
-ketoglutarate + amino acid glutamate + a-keto acid.
Amino group in glutamate is transported to liver by the alanine cycle.
In blood
Glutamate + pyruvate alanine + -ketoglutarate.
In the liver, glutamate is formed as the rxn catalysed by alanine
transaminase is reversed followed by oxidative deamination of
glutamate to produce -ketoglutarate and free
+
NH
4
i) Alanine + -ketoglutarate glutamate + pyruvate
ii) Glutamate + NAD
+
+ H
2
O -ketoglutarate + NADH + H
+
+
+
NH
4
NH
3
NH
3
NH
3
NH
3
In muscle cell
-ketoglutarate + amino acid glutamate + a-keto acid.
Amino group in glutamate is transported to liver by the alanine cycle.
In blood
Glutamate + pyruvate alanine + -ketoglutarate.
In the liver, glutamate is formed as the rxn catalysed by alanine
transaminase is reversed followed by oxidative deamination of
glutamate to produce -ketoglutarate and free
+
NH
4
i) Alanine + -ketoglutarate glutamate + pyruvate
ii) Glutamate + NAD
+
+ H
2
O -ketoglutarate + NADH + H
+
+
+
NH
4
NH
3
NH
3
NH
3
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In the matrix of mitochondria of hepatocytes
HCO
3
-
+
+
NH
4
NH
2
-C O - P O
-
II II
I
O O
O
-
carbamoyl phosphate 2ATP
2ADP + Pi
+ 3H
+
carbamoyl phosphate
synthase
1.
UREA CYCLE
Bicarbonate react with ammonium ion to form carbamoyl
phosphate. 2ATP are used- one to activate the
bicarbonate, another to phosphorylate the carbamate,
The reaction is irreversible.
NH
2
C - H
II
O
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NH
2
C O -P O
-
II
O O
II
I
O
-
C
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
N
I
O
H
I
citrulline
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
ornithine
Pi
Ornithine
transcarbamyolase
C O
I
NH
2
CH
2
I
+
NH
3
ornithine
Carbamoyl phosphate react with ornithine to form
citrulline. Citrulline is then transported to the
cytoplasm.
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In the cytosol
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
N H
citrulline H
3
N
+
C C O
-
I
I II
H O
CH
2
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
N H
CH
2
COO
-
I
AMP + PPi
ATP
argininosuccinate synthase
C
I
N
I
O
H
I
NH
2
I
CH
2
I
C=O
I
O
-
C
N
I
+
NH - CH
H
I
NH
2
argininosuccinate
I
I
CH
2
COO
-
aspartate
Citrulline react with aspartate to form argininosuccinate
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C
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
N
I
NH - CH
H
I
I
I
CH
2
COO
-
I
C
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
N
I
+
NH
2
H
I
Arginine
I
II
CH
COO
-
I
COO
-
CH
argininosuccinate lyase
C NH - CH
I
NH
2
argininosuccinate
I
COO
-
C
+
NH
2
I
NH
2
COO
-
fumarate
Argininosuccinate lyase cleaves argininosuccinate to
release arginine and fumarate
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H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
+
NH
3
ornithine
C
H
3
N
+
C C O
-
I
I II
H O
CH
2
I
CH
2
I
CH
2
I
N
I
+
NH
2
H
Arginine C = O
NH
2
NH
2
H
2
O
arginase
C
I
+
NH
2
I
NH
2
Arginase catalysed the hydrolysis of arginine to form ornithine
and urea.
Note: Three ATPs is consumed in the synthesis of one
molecule of urea.
urea
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argininosuccinate
aspartate fumarate
oxaloacetate
malate
Aspartate-arginino
succinate cycle
amino acid
-keto acid
X
citrate
Aspartate
argininosuccinate
cycle temporarily
shut down the
citric acid cycle to
allow the
conversion of
oxaloacetate to
aspartate
arginine
ornithine
urea
citrulline
Urea cycle
Carbamoyl
phosphate
Aspartate
argininosuccinate
cycle temporarily
shut down the
citric acid cycle to
allow the
conversion of
oxaloacetate to
aspartate
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glycine
serine
N
5
, N
10
methylene THF
THF
Ser. dehydratase
cysteine
cysteine sulfate
transamination
Acetyl CoA
Threonine
CoASH
NADH
+ H
+
NAD
+
Thr. dehydrogenase
-amino-b-ketobutyrate lyase
-amino- -ketobutyrate
(Primary pathway)
+
NH
4
H
2
O
NAD
+
CoASH
-amino- -ketobutyrate
The catabolic pathway of Thr, Gly, Ser, Ala, and Cys to
acetyl-CoA with pyruvate as intermediate
Acetyl-CoA
CO
2
pyruvate
+
NH
4
CoASH
NAD
+
NADH
+ H
+
Alanine
Glu-ala
transaminase
AMINO ACIDS FORMING ACETYL-CoA
desulfuration
NADH
+ H
+
CO
2
Propionyl-CoA
(Pathway in primate)
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13
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Tryptophan
-ketoadipate
alanine
formate
Lysine
Acetoacetate
fumarate
Tyrosine
Phenylalanine
Leucine
I
CH2
I
+
NH
3
-CH-COO
-
+
NH
3
-CH-COO
-
I
CH
2
I
CH
2
I
CH
2
I
CH
2
I
+
NH
3
-ketoadipate
Acetoacetyl-CoA Acetyl-CoA
Acetoacetate
Catabolic pathway of Trp, Phe, Tyr, Leu, and Lys to acetyl-CoA
(pyruvate is not an intermediate)
AMINO ACIDS FORMING ACETYL-CoA
I
CH
2
I
CH
2
I
CH
2
I
CH
2
I
+
NH
3
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The conversion of Phe to Tyr
Catalysed by phenylalanine-4-monooxygenase and irreversible.
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Glutamate- -semialdehyde
Arginine
Proline
AMINO ACIDS FORMING -KETOGLUTARATE
Catabolic pathway of Arg, Pro, His, Gln, and Glu to -ketoglutarate
Histidine
glutamine Glutamate
-ketoglutarate
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Propionyl-CoA
Isoleucine
Methionine
Valine
AMINO ACIDS FORMING SUCCINYL-CoA
Propionyl-CoA
Methylmalonyl-CoA
Succinyl-CoA
Catabolic pathway of Met, Ile, and Val to succinyl-CoA
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Asparagine
Aspartate
AMINO ACIDS FORMING OXALAOACETATE
Oxalaoacetate
Catabolic pathway of Asparagine and Aspartate to oxaloacetate
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oxaloacetate
citrate
Acetyl-CoA
Asp
Glutamate
- -semialdehyde
Arg
Pro
Pyruvate
Cys
Thr
Ala Trp
Ser Gly
Leu
Acetoacetyl-CoA
acetoacetate
Tyr
Phe
Trp
-ketoadipate
Lys
oxaloacetate
succinyl-CoA
citrate
isocitrate
succinate
fumarate
malate
CO
2
CO
2
Krebs
cycle
Asp
Asn
-ketoglutarate glu
gln His
Glutamate
- -semialdehyde
Propionyl CoA
Ile
Met
Methymalonyl
semialdehyde
Val
To acetyl CoA
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Degradation of selected neurotransmitters
To maintain precise information transfer,
neurotransmitter must be quickly degraded or removed
from the synaptic cleft.
Acetylcholine (muscle contraction initiator) action is
terminated by the enzyme acetylcholinesterase.
(acetylcholine must be destroyed rapidly so that muscle
can relax before the next contraction).
Acetylcholineesterase is a serine esterase that
hydrolyses acetycholine to acetate and choline.
This enzyme is irreversibly inhibited by DFP
(diisoprophylfluorophospahate), which caused muscle
paralysis.
With each nerve impulse , more acetylcholine molecules
enter the neuromuscular synaptic cleft, accumulates and
overstimulating the muscle and led to paralysis.
Affected individuals suffocate because of paralysed
respiratory muscle.
To maintain precise information transfer,
neurotransmitter must be quickly degraded or removed
from the synaptic cleft.
Acetylcholine (muscle contraction initiator) action is
terminated by the enzyme acetylcholinesterase.
(acetylcholine must be destroyed rapidly so that muscle
can relax before the next contraction).
Acetylcholineesterase is a serine esterase that
hydrolyses acetycholine to acetate and choline.
This enzyme is irreversibly inhibited by DFP
(diisoprophylfluorophospahate), which caused muscle
paralysis.
With each nerve impulse , more acetylcholine molecules
enter the neuromuscular synaptic cleft, accumulates and
overstimulating the muscle and led to paralysis.
Affected individuals suffocate because of paralysed
respiratory muscle. 5/8/2013 23
Degradation of selected neurotransmitters
Catecholamines epinephrine, norepinephrine and
dopamine are inactivated by oxidation reactions
catalysed by monoamine oxidase (MAO).
The catecholamine have to be transported out of the
synaptic cleft before inactivation because the MAO is
found within the nerve endings.
Epinephrine, released as a hormone from the adrenal
gland, is carried in the blood and is catabolised in
nonneural tissue (perhaps the kidney).
Catecholamine also inactivated in methylation reactions
catalsed by catechol-O-metyltransferase (COMT).
Serotonin is degraded in two step pathway. First
serotonin is oxidised by MAO. The product, 5-
hydroxyindole-3-acetaldehyde, is then further oxidised
by aldehyde dehydrogenase to form 5-hydroxyindole-3-
acetate.
Catecholamines epinephrine, norepinephrine and
dopamine are inactivated by oxidation reactions
catalysed by monoamine oxidase (MAO).
The catecholamine have to be transported out of the
synaptic cleft before inactivation because the MAO is
found within the nerve endings.
Epinephrine, released as a hormone from the adrenal
gland, is carried in the blood and is catabolised in
nonneural tissue (perhaps the kidney).
Catecholamine also inactivated in methylation reactions
catalsed by catechol-O-metyltransferase (COMT).
Serotonin is degraded in two step pathway. First
serotonin is oxidised by MAO. The product, 5-
hydroxyindole-3-acetaldehyde, is then further oxidised
by aldehyde dehydrogenase to form 5-hydroxyindole-3-
acetate.
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Clinical manifestation/disease related to amino acid
metabolism disorder
1. PKU (phenylketourea)
accumulation of Phe in nervous tissue. Phenyl keto acid in urine.
Caused mental retardation.
2. Tyrosinemia accumulation of tyrosine in the blood. Also cause
mental retardation.
3. Alkaptourea def. of homogentisate oxidase in the metabolism of
tyrosine. Urine turn black due large quantities of homogentisic
acid. Disorder will lead skin getting darker in later years and high
susceptible to athritis.
4. Albinism genetic defect of the tyrosinase enzyme. Skin, eye,
hair contain no alittle pigment (melanin)
5. Hyperhomocytienemia accumulation of homocysteine and
methionine. Suggested to induced atherosclerosis and
thrombosis.
1. PKU (phenylketourea)
accumulation of Phe in nervous tissue. Phenyl keto acid in urine.
Caused mental retardation.
2. Tyrosinemia accumulation of tyrosine in the blood. Also cause
mental retardation.
3. Alkaptourea def. of homogentisate oxidase in the metabolism of
tyrosine. Urine turn black due large quantities of homogentisic
acid. Disorder will lead skin getting darker in later years and high
susceptible to athritis.
4. Albinism genetic defect of the tyrosinase enzyme. Skin, eye,
hair contain no alittle pigment (melanin)
5. Hyperhomocytienemia accumulation of homocysteine and
methionine. Suggested to induced atherosclerosis and
thrombosis.
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