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AMINO ACID METABOLISM
Jana Novotná
Department of the Medical Chemistry and Biochemistry
The 2nd Faculty of Medicine, Charles Univ.
Amino acid structure
The 20 common amino acids of proteins
AMINO ACID METABOLISM
BODY PROTEINS
Proteosynthesis
NONPROTEIN
DERIVATIVES
GLYCOLYSIS
KREBS CYCLE
UREA
Conversion
(Carbon skeleton)
AMINO ACIDS
DIETARY
PROTEINS
GLUCOSE
Degradation
250 – 300
g/day
ACETYL CoA
NH3
CO2
Porphyrins
Purines
Pyrimidines
Neurotransmitters
Hormones
Komplex lipids
Aminosugars
KETONBODIES
ENZYMES CLEAVING THE PEPTIDE
CHAIN
Endopeptidases – hydrolyse the peptide bond inside a chain
Pepsin, trypsin, chymotrypsin
Exopeptidases – split the peptide bond at the end of a protein
molecule
Aminopeptidase, carboxypeptidases
Dipeptidases
Pepsin (pH 1.5 – 2.5) – peptide bond derived fromTyr, Phe,
bonds between Leu and Glu
Trypsin (pH 7.5 – 8.5) – bonds between Lys a Arg
Chymotrypsin (pH 7.5 – 8.5) – bonds between Phe a Tyr
Essential Amino Acids in Humans
Required in diet
Humans incapable of forming requisite
carbon skeleton
Arginine*
Histidine*
Isoleucine
Leucine
Valine
Lysine
Methionine
Threonine
Phenylalanine
Tryptophan
*Required to some degree in young growing period and/or sometimes during illness.
Non-essential and nonessential
amino acids in humans
Not required in diet
Can be formed from a-keto acids by transamination and
subsequent reactions
Alanine
Asparagine
Aspartate
Glutamate
Glutamine
Glycine
Proline
Serine
Cysteine (from Met*)
Tyrosine (from Phe*)
* Essential amino acids
General reactions of amino acids are
transamination and deamination of a-amino group
Oxidative
deamination
NH2
R
CH
a-keto acid
Transaminatoin
a-keto acid
+ amino acid
COOH
Oxidative
decarboxylation
amin
Transamination – the transfer of the amino group to a suitable keto acid acceptor.
Oxidative deamination - the amino acid is converted into the corresponding keto acid by the
removal of the amine functional group as ammonia and the amine functional group is replaced by the
ketone group. The ammonia eventually goes into the urea cycle.
Oxidative decarboxylation – the formation of biogenic amines.
Transamination reaction
The first step in the catabolism of most amino acids is removal
of a-amino groups by enzymes aminotransferases or
transaminases
All aminotransferases have the same prostethic group and the same
reaction mechanism.
The prostethic group is pyridoxal phosphate (PPL), the coenzyme form of
pyridoxine (vitamin B6)
Biosynthesis of amino acids:
transamination reactions
amino acid1 +a-keto acid2
amino acid2 +a-keto acid1
NH3 +
-
O 2 CCH 2 CH 2 CHCO 2
-
Glutamate
O
R-CCO 2 -
+
Keto-acid
Pyridoxal phosphate (PLP)dependent aminotransferase
O
O 2 CCH 2 CH2 CCO 2 -
a-Ketoglutarate
+
NH2
R-CHCO 2 -
Amino acid
Active metabolic form of vitamin B6
Mechanism of transamination reaction: PPL complex with enzyme accept an amino group to form
pyridoxamine phosphate, which can donate its amio group to an a-keto acid
(Aldimine)
(Ketimine)
Pyridoxal
phosphate
Schiff
base
Pyridoxamine phosphate
(Aldimin)
(Ketimin)
Aminotransferases are differ in their specificity for Lamino acids.
The enzymes are named for the amino group donor
Clinicaly important transaminases
Alanine-a-ketoglutarate transferase ALT
(also called glutamate-pyruvate transaminase – GPT)
Aspartate-a-ketoglutarate transferase AST
(also called glutamate-oxalacetate transferase – GOT)
Important in the diagnosis of heart and liver damage caused by
heart attack, drug toxicity, or infection.
Glucose-alanine cycle
Alanine plays a special role in transporting
amino groups to liver.
Ala is the carrier of ammonia and of the carbon
skeleton of pyruvate from muscle to liver.
The ammonia is excreted and the pyruvate is used
to produce glucose, which is returned to the muscle.
According to D. L. Nelson, M. M. Cox :LEHNINGER. PRINCIPLES OF BIOCHEMISTRY Fifth edition
Glutamate releases its amino group
as ammonia in the liver
The amino groups from many of the a-amino acids are collected in the liver in
the form of the amino group of L-glutamate molecules.
•
•
•
•
Glutamate undergoes oxidative deamination catalyzed by L-glutamate
dehydrogenase.
Enzyme is present in mitochondrial matrix.
It is the only enzyme that can use either NAD+ or NADP+ as the acceptor of reducing equivalents.
Combine action of an aminotransferase and glutamate dehydrogenase referred to as
transdeamination.
Ammonia transport in the form of glutamine
Excess ammonia is added to
glutamate to form glutamine.
Glutamine
synthetase
Glutamine enters the liver and NH4+ is
liberated in mitochondria by the
enzyme glutaminase.
Ammonia is remove by urea synthesis.
Relationship between glutamate,
glutamine and a-ketoglutarate
NH3
NH3
glutamate
a-ketoglutarate
NH3
glutamine
NH3
A. Glutamate dehydrogenase
glutamate
NAD+
+
B. Glutamine synthetase
glutamate
+
ATP
NH3
+
H2O
a-ketoglutarate
ADP
glutamine
C. Glutaminase
glutamine
+
H2O
glutamate
+
NH3
+
NH3
+
NADH
Oxidative deamination
A. Oxidative deamination
Amino acids
+
FMN
•L-amino acid oxidase produces
+
H2O
L-amino acid oxidase
a-keto acids
+ FMNH2 +
NH3
O2
ammonia and a-keto acid directly, using
FMN as cofactor.
•The reduced form of flavin must be
regenerated by O2 molecule.
•This reaction produces H2O2 molecule
which is decompensated by catalase.
catalse
FMN
B. Nonoxidative deamination
H2O2
H2O
+
O2
Is possible only for hydroxy amino acids
serine
threonine
Serin-threonin dehydratase
pyruvate +
NH3
a-ketoglutate
+
NH3
Amino acid metabolism and central
metabolic pathways
20 amino acids are converted to 7
products:
 pyruvate
 acetyl-CoA
 acetoacetate
 a-ketoglutarate
 succynyl-CoA
 oxalacetate
 fumarate
Glucogenic Amino Acids
Yield a-ketoglutarate, pyruvate, oxaloacetate,
fumarate, or succinyl-CoA
Aspartate
Asparagine
Arginine
Phenylalanine
Tyrosine
Isoleucine
Methionine
Valine
Glutamine
Glutamate
Proline
Histidine
Alanine
Serine
Cysteine
Glycine
Threonine
Tryptophan
Ketogenic Amino Acids
Yield acetyl CoA or acetoacetate
Lysine
Leucine
Both glucogenic and ketogenic amino
acids
Yield a-ketoglutarate, pyruvate, oxaloacetate,
fumarate, or succinyl-CoA in addition to acetyl
CoA or acetoacetate
Isoleucine
Threonine
Tryptophan
Phenylalanine
Tyrosine
Metabolism of some amino
acids
Glycine biosynthesis
Glycine produced from serine or from the diet can also be oxidized by glycine
decarboxylase (also referred to as the glycine cleavage complex, GCC) to yield a second
equivalent of N5,N10-methylene-tetrahydrofolate as well as ammonia and CO2.
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Serine biosynthesis from glycine
Reaction involves the transfer of the hydroxymethyl group from serine to the cofactor
tetrahydrofolate (THF), producing glycine and N5,N10-methylene-THF.
Copy from: http://themedicalbiochemistrypage.org/amino-acid-metabolism.html
Cysteine and methionine biosynthesis
The sulfur for cysteine synthesis comes from the essential amino acid methionine.
SAM
Condensation of ATP and methionine yield
S-adenosylmethionine (SAM)
SAM serves as a precurosor for numerous methyl transfer reactions (e.g. the conversion
of norepinephrine to epinenephrine).
Utilization of methionine in the synthesis of
cysteine
Conversion of homocysteine back to Met. N5methyl-THF is donor of methyl group.
*
*folate + vit B12
1.
Conversion of SAM to
homocysteine.
2.
Condensation of homocysteine
with serine to cystathione.
3.
Cystathione is cleavaged to
cysteine.
Copy from: http://themedicalbiochemistrypage.org/amino-acid-metabolism.html
Homocystinuria
Genetic defects for both the synthase and the lyase.
Missing or impaired cystathionine synthase leads to homocystinuria.
High concentration of homocysteine and methionine in the urine.
Homocysteine is highly reactive molecule.
Disease is often associated with mental retardation, multisystemic disorder of
connective tissue, muscle, CNS, and cardiovascular system.
Biosynthesis of Tyrosine from Phenylalanine
Phenylalanine hydroxylase is a mixed-function oxygenase: one atom of oxygen is incorporated into
water and the other into the hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor
tetrahydrobiopterin, which is maintained in the reduced state by the NADH-dependent enzyme
dihydropteridine reductase
Phenylketonuria
Missing or deficient phenylalanine hydroxylase results in
hyperphenylalaninemia.
Phenylketonuria is the most widely recognized
hyperphenylalaninemia (and most severe) It is the genetic
disease.
The mental retardation is caused by the accumulation of
phenylalanine, which becomes a major donor of amino groups in
aminotransferase activity and depletes neural tissue of αketoglutarate.
Absence of α-ketoglutarate in the brain shuts down the TCA
cycle and the associated production of aerobic energy, which is
essential to normal brain development.
Enzymes which metabolised amino acides
containe vitamines as cofactors
Vater soluble vitamins B
THIAMINE B1 (thiamine diphosphate)
oxidative decarboxylation of a-ketoacids
RIBOFLAVIN B2 (flavin mononucleotide FMN, flavin adenine dinucleotide FAD)
oxidses of a-aminoacids
NIACIN B3 – nicotinic acid (nikotinamide adenine dinucleotide NAD+
nikotinamide adenine dinukleotide phosphate NADP+)
dehydrogenases, reductase
PYRIDOXIN B6 (pyridoxalphosphate)
transamination reaction and decarboxylation
FOLIC ACID (tetrahydropholate)
Meny enzymes of amino acid metabolism
Nitrogenous derivatives of amino acids
Glycine
heme, purine, creatine, conjugation of bile acids
Histidine
histamine
Ornithine a arginin
creatine, polyamines (spermidine, spermine)
Tryptophan
serotonine (melatonine)
Tyrosine
Epinephrine, norepinephrine
Glutamic acid
g-aminobutyric acid (GABA)
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