1. Amino acids are catabolized through various pathways to produce intermediates that feed into central metabolic pathways like the Krebs cycle or gluconeogenesis.
2. Glucogenic amino acids are degraded into pyruvate or Krebs cycle intermediates that can be used for gluconeogenesis when glucose levels are low.
3. Ketogenic amino acids are degraded into acetyl-CoA or acetoacetate and can be used for energy production but not glucose synthesis.
3. Deaminated Amino acids yield α-keto acids that, directly or via
additional reactions, feed into major metabolic pathways (e.g., Krebs
Cycle).
Carbon skeletons of glucogenic amino acids are degraded to:
- pyruvate, or
- a 4-C or 5-C intermediate of Krebs Cycle.
These precursors are major carbon source for gluconeogenesis
when glucose levels are low.
They can also be catabolized for energy, or converted to glycogen or fatty
acids for energy storage.
Carbon skeletons of ketogenic amino acids are degraded to:
-acetyl-CoA, or
-acetoacetate.
can be catabolized for energy in Krebs Cycle, or converted to ketone bodies
or fatty acids.
They cannot be converted to glucose.
Glucogenic amino acids
The 3-C α-keto acid pyruvate is produced from alanine,
serine, glycine, cysteine, & threonine.
Alanine deamination via Transaminase directly yields pyruvate.
alanine -ketoglutarate pyruvate glutamate
Aminotransferase (Transaminase)
COO
CH2
CH2
C
COO
O
CH3
HC
COO
NH3
+
COO
CH2
CH2
HC
COO
NH3
+
CH3
C
COO
O+ +
5. Serine is deaminated to pyruvate via Serine Dehydratase.
Serine can be also catabolized (in reverse of its biosynthesis but different
enzymes) into 3-phosphoglycerate .
HO CH2
H
C COO
NH3
+
C COO
OH2O NH4
+
C COO
NH3
+
H2C H3C
H2O
serine aminoacrylate pyruvate
Serine Dehydratase
6.
7. Threonine is catabolized ,through β-ketobutyrate by threonine
dehydrogenase, into pyruvate .
Threonine is catabolized -but to less extent- by Ser/Thr dehydratase into
α-ketobutyrate to be converted to propionyl CoA then to succinyl CoA.
In addition to ketogenic catabolism into acetyl CoA and glycine.
Formation of Serine
OHH
CH2OPO3
-2
C
CO2
-
CH2OPO3
-2
CO 2
-
C=O
NH3
+H
CH2OPO3
-2
C
CO2
-
NH3
+H
CH2OH
CO2
-
C
Glucose
Glycolysis
3-Phospho-
glycerate
3-Phospho-
hydroxypyruvate
3-PhosphoserineSerine (Ser)
Pyruvate
Dehydrogenase
NAD+
NADH +
H+
Glutamate
α Ketoglutarate
Transaminase
Phosphatase
3 Steps
Inhibits
8. Glycine is also a product of threonine catabolism through
α-amino-β-ketobutyrate (as just shown).
It is interconverted to serine by a reversible reaction involving
tetrahydrofolate producing N5,N10-THF (determined by demands for
serine or glycine or availability of N5,N10-THF).
9. Glycine can also be degraded to CO2 and NH3 by a glycine cleavage
complex whose deficiency leads to the mental disorder Nonketotic
hyperglycinemia.
Glyoxalate produced by glycine can be transaminated back to glycine or
oxidized to oxalate which at high level could lead to kidney stones.
Cysteine is synthesized from methionine.
Methionine adenosyltransferase catalyzes the formation of S-
adenosylmethionine which loses a methyl and adenosyl group by
methyltransferase and adenosylhomocysteinase ,respectvely, to form
homocysteine. However, only sulfur atom of homocysteine will transfer
to a serine to form cysteine after formation of the adduct cystathionine
and its cleavage by cystathionase into cysteine and α-ketobutyrate .
11. Cystathioninuria
Deficiency in cystathionase (lyase)
No clinical symptoms (↑cystathionine in blood & urine)
Homocysteinuria
• Rare; deficiency of cystathionine β-synthase
• Dislocated optical lenses
• Mental retardation
• Osteoporosis
• Cardiovascular disease death
High blood levels of homocysteine associated with
cardiovascular disease
• May be related to dietary folate deficiency
• Folate enhances conversion of
homocysteine to methionine
Cysteine catabolism yields pyruvate.
12. The 4-C Krebs Cycle intermediate oxaloacetate is produced
from aspartate & asparagine.
Aspartate transamination yields oxaloacetate.
Aspartate is also converted to fumarate in Urea Cycle. Fumarate is
converted to oxaloacetate in Krebs cycle.
aspartate -ketoglutarate oxaloacetate glutamate
Aminotransferase (Transaminase)
COO
CH2
CH2
C
COO
O
COO
CH2
HC
COO
NH3
+
COO
CH2
CH2
HC
COO
NH3
+
COO
CH2
C
COO
O+ +
13. Glutamate -Ketoglutarate
+ +
Oxaloacetate Aspartate
Glutamate-Oxaloacetate
Aminotransferase
(Aspartate Transferase AST)
synthesis
Asparagine loses the amino group from its R-group by hydrolysis
catalyzed by Asparaginase.
This yields aspartate, which can be converted to oxaloacetate, e.g., by
transamination.
C
CH2
HC
COO
NH3
+
OH2N
COO
CH2
HC
COO
NH3
+
H2O NH4
+
asparagine aspartate
Asparaginase
14. ATP-dependent amidation of Asp
ASP + ATP + GLN ASN + AMP + PPi + GLU
By the enzyme Asparagine synthetase.
Low in some cell tumor types. ( Asparaginase treatment ) .
The 4-C Krebs Cycle intermediate succinyl-CoA is produced
from isoleucine, valine, & methionine.
Transulfuration reactions of methionine ,that synthesize cysteine
from homocysteine and serine, produce α-ketobutyrate which is
converted to propionyl CoA, which is metabolized into succinyl-CoA
through unusual reactions one of which is vitamin B12 dependent .
Valine and isoleucine in addition to leucine are branched-chain
amino acids (BCAAs). Their metabolism is an excellent source of
energy (NADH). Initial steps :
BCAA transferases α-keto counterparts α-keto acid dehydrogenases
CoA compounds dehydrogenases double bond compounds
Valine and isoleucine form hydroxylated intermediate.
The isoleucine intermediate is oxidized by NAD into succinyl CoA
and acetyl CoA .
The valine intermediate is oxidized by NAD in another step into
succinyl CoA.
15. The 5-C Krebs Cycle intermediate a-ketoglutarate is produced
from glutamate, glutamine, arginine, proline , & histidine.
O
-
O2CCH2CH2CCO 2
-
NH3
+
-
O2CCH2CH2CHCO 2
-
NH3
+O
H2NCCH2CH2CHCO 2
-
Transamination or
Glutamate
dehydrogenase
-Keto-
glutarate
Glutamate
Glutamine
Glutamine
synthetase
N
H H
CO2
-
+
Proline
NH3
+
+
H3NCH2CH2CH2CHCO 2
-
Ornithine
5 Steps
Intest.
mucusa
Arginine
Urea Cycle (or through citrulline
in kidney)
NH3
+NH2
H2N=C-HNCH2CH2CH2CHCO 2
-
+
Amino Acids Formed From α-Ketoglutarate
4 Steps via glutamic
semialdehyde
Glutamate deamination via
transaminase directly yields
a-ketoglutarate.
Glutamate deamination by
Glutamate Dehydrogenase also
directly yields α-ketoglutarate.
OOC
H2
C
H2
C C COO
O
+ NH4
+
NAD(P)+
NAD(P)H
OOC
H2
C
H2
C C COO
NH3
+
H
glutamate
-ketoglutarate
Glutamate Dehydrogenase
aspartate -ketoglutarate oxaloacetate glutamate
Aminotransferase (Transaminase)
COO
CH2
CH2
C
COO
O
COO
CH2
HC
COO
NH3
+
COO
CH2
CH2
HC
COO
NH3
+
COO
CH2
C
COO
O+ +
16. GABA Formation
NH3
+
-
O2CCH2CH2CHCO 2
-
NH3
+
-
O2CCH2CH2CH2
Glutamate Gamma-aminobutyrate
(GABA)
GABA is an important inhibitory neurotransmitter
in the brain
Drugs (e.g., benzodiazepines) that enhance the effects
of GABA are useful in treating epilepsy
Glutamate
decarboxylase
CO2
Glutamine is catabolized into glutamate by glutaminase.
Creatine and Creatinine
Arginine
Phosphocreatine
N
N
H
CH3
HN
O
Creatinine
(Urine) Non-enzymatic
(Muscle)
NH2
CH3
H2N=C-NCH2CO2
-
+
Creatine kinase
(Muscle)
ATP
Creatine ADP
+ Pi
17. Proline and Arginine are catabolized into α-ketoglutarate
but in slightly different pathway than their synthesis.
Histidine is converted to glutamate.
The first step is catalyzed by histadinase.
The last step in this pathway involves the cofactor tetrahydrofolate.
Histidinemia is caused by histidinase deficiency. Mental retardation (not
always)(↑histidine in blood) (& urine).
Histidine Metabolism: Histamine Formation
N
N
H
CH2CHCO2
-
NH3
+
N
N
H
CH2CH2NH2
Histidine Histamine
Histidine
decarboxylase
CO2
HC C CH2
H
C COO
NH3
+N NH
C
H
OOC
H
C CH2 CH2 COO
HN NH
C
H
OOC
H
C CH2 CH2 COO
NH3
+
THF
N 5
-formimino-THF
NH4
+
H2O
H2O
histidine
N-formimino-
glutamate
glutamate
18. Aromatic Amino Acids
Aromatic amino acids phenylalanine & tyrosine are catabolized to
fumarate and acetoacetate.
Hydroxylation of phenylalanine to form tyrosine involves the reductant
tetrahydrobiopterin.
Some tyrosine is used to synthesize catecholamines : DOPA
(dihydroxyphenylalanine) and Dopamine (related to Parkinson’s
disease) in brain , Norepinephrine and Epinephrine in adrenal medulla,
in synthetic order :-
CH2 CH COO
NH3
+
CH2 CH COO
NH3
+
HO
phenylalanine
tyrosine
O2 + tetrahydrobiopterin
H2O + dihydrobiopterin
Phenylalanine
Hydroxylase
19. CH2CHCO2
-
NH3
+
HO
CH2CHCO2
-
NH3
+
HO
HO
CH2CH2NH2
HO
HO
CHCH2NH2
HO
HO
OH
CHCH2NHCH3
HO
HO
OH
Tyr hydroxylase
O2
Tyrosine Dihydroxyphenylalanine
(DOPA)
Dopamine
DOPA
decarboxylase CO2
Dopamine
hydroxylase
Norepinephrine
Catechol
Epinephrine
(Adrenaline)
SAM
S-Adenosyl-
homocysteine
Methyl
transferase
Genetic deficiency of Phenylalanine
Hydroxylase leads to the disease
Phenylketonuria (PKU).
Phenylalanine & phenylpyruvate
(the product of phenylalanine
deamination via transaminase)
accumulate in blood & urine.
Mental retardation results unless
treatment begins immediately after
birth. Treatment consists of limiting
phenylalanine intake to levels barely
adequate to support growth. Tyrosine,
an essential nutrient for individuals
with phenylketonuria, must be
supplied in the diet.
• Occurs in 1:16,000 live births in U.S.
• Seizures, mental retardation, brain damage
• Treatment: limit phenylalanine intake
• Screening of all newborns mandated in all states
Transaminase
Phenylalanine Phenylpyruvate
(Phenylketone)
Phenylalanine Deficient in
Hydroxylase Phenylketonuria
Tyrosine Melanins
Multiple
Reactions
Fumarate + Acetoacetate
20. High [phenylalanine] inhibits Tyrosine Hydroxylase (tyrosinase), on the
pathway for synthesis of the pigment melanin from tyrosine. Therefore,
individuals with phenylketonuria have light skin & hair color.
Conversion of tyrosine to melanin requires tyrosinase or tyrosine
hydroxylase in melanocytes whose defect or absence leads to Albinism .
Transaminase
Phenylalanine Phenylpyruvate
(Phenylketone)
Phenylalanine Deficient in
Hydroxylase Phenylketonuria
Tyrosine Melanins
Multiple
Reactions
Fumarate + Acetoacetate
21. Homogentisic Acid Formation
CH2CHCO2
-
NH3
+
HO
OH
OH
CH2CO2
-
Transamination
Tyrosine
Homogentisate
O2
CO2
CH2CCO2
-
O
HO
Homogentisate
dioxygenase
O2
Cleavage of
aromatic ring
Fumarate + acetoacetate
Deficient in
alkaptonuria
Tyrosinemia
Deficiency of tyrosine transaminase leads to diffferent diseases including:
Eye, skin and mental retardation
liver failure, renal dysfunction, rickets, and neuropathy
Alkaptonuria (first metabolic inborn error identified)
• Deficiency of homogentisate dioxygenase
• Urine turns dark on standing
• Oxidation of homogentisic acid
• Asymptomatic in childhood
• Tendency toward arthritis in adulthood (Cartilage deposition)
22. Tryptophan
Tryptophan has complex pathways for degradation. kynurenine is
formed and can be further metabolized into glutarate then acetoacetyl
CoA.
Kynurenine can give rise to neurotransmitters.
Typtophan hydroxylation then decarboxylation end up with the brain
neurotransmitter serotonin. The sleep-inducing molecule Melatonin is
synthesized from tryptophan.
Ingestion of tryptophan rich food leads to sleepiness due to melatonin
sleeping effect.
ketogenic amino acids
The only two entirely ketogenic amino acids are Leucine and
Lysine
As explained earlier for the other branched-chain amino acids (BCAAs)
valine and isoleucine they share with leucine initial steps of catabolism
that form a double bond CoA compound.
However, leucine gives an intermediate which is cleaved to acetoacetate
and acetyl CoA.
Diseases of metabolism of BCAAs
Enzyme deficiency is not common. Rare hypervalinemia and
hyperleucinemia-isoleucinemia.
Deficiency in ketoacid dehydrogenases leads to maple syrup urine
disease, mental retardation, ketoacidosis, and short life span.
Enzyme deficiency of later reactions gives sweaty feet urine smell, and
cat urine smell.
23. Lysine has ( as tryptophan) a complex pathways for degradation into
acetoacetyl CoA.
Hyperlysinemia is benign . More serious is familial lysinuric protein
intolerance due to failure in intestinal transport that leads to decrease in
plasma lysine, arginine and ornithine down to 1/3 normal, with after meal
hyperammonemia related to urea cycle.
Other glucogenic amino acids that are have ketogenic fate include:
The aromatic amino acids phenylalanine and tyrosine that generate
acetoacetate, and tryptophan which produces acetoacetyl CoA (as we
saw earlier).
That is in addition to the BCAA isoleucine shown to form acetyl
CoA . And finally threonine which forms acetyl CoA and glycine
through α-amino-β-ketobutyrate mentioned earlier.
END
Metabolic Defects in Amino Acid Metabolism
1. Hereditary deficiency of any of the Urea Cycle enzymes leads to
hyperammonemia
2. Nonketotic hyperglycinemia
3. Oxalate kidney stones
4. Cystathioninuria
5. Homocysteinuria
6. Histidinemia
7. Hyperphenylalaninemias- Phenlketoneuria (PKU)
8. Albinism
9. Tyrosinemia
10. Alcaptouria
11. BCAA metabolic diseases
12. Lysine metabolic diseases