AMINO%20ACID%20METABOLISM

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AMINO ACID METABOLISM

• Jana Novotná
• Department of the Medical Chemistry and
  Biochemistry
• The 2nd Faculty of Medicine, Charles Univ.

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Amino acid structure
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The 20 common amino acids of proteins
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Metabolic relationship of amino acids
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Enzymes cleaving the peptide bond
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 from
Tyr, 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
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Essential amino acids in humans
Lysine Methionine Threonine Phenylalanine
Tryptophan
Arginine Histidine Isoleucine Leucine
Valine
Required to some degree in young growing period
and/or sometimes during illness.
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Non-essential and nonessential amino acids in
humans
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
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General reactions of amino acid catabolism
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The fate of the amino group during amino acid
catabolism
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Transamination reaction
The first step in the catabolism of most amino
acids is removal of a-amino groups by enzymes
transaminases or aminotransferases
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)
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Biosynthesis of amino acid transamination
reactions
amino acid1 a-keto acid2 amino acid2
a-keto acid1
Keto-acid

Glutamate
Pyridoxal phosphate (PLP)- dependent
aminotransferase
Amino acid

a-Ketoglutarate
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Active metabolic form of vitamin B6
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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.
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All amino acids except threonine, lysine, and
proline can be transaminated Transaminases are
differ in their specificity for L-amino acids.
The enzymes are named for the amino group donor.
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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.
ALT
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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
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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.

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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.
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Relationship between glutamate, glutamine and
a-ketoglutarate
NH3
NH3
E
E
a-ketoglutarate
glutamate
glutamine
NH3
NH3
E
A. Glutamate dehydrogenase
E




H2O
glutamate
a-ketoglutarate
NH3
NADH
NAD
To urea cycle
From transamination reactions
B. Glutamine synthetase (liver)
ADP
ATP
E

glutamine
glutamate
NH3
C. Glutaminase (kidney)
E


glutamine
H2O
glutamate
NH3
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Oxidative deamination

• L-amino acid oxidase produces 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.

Is possible only for hydroxy amino acids
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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

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Glucogenic Amino Acids

• formed a-ketoglutarate, pyruvate, oxaloacetate,
  fumarate, or succinyl-CoA

Alanine Serine Cysteine Glycine Threonine
Tryptophan
Methionine Valine Glutamine Glutamate
Proline Histidine
Aspartate Asparagine Arginine Phenylalanine
Tyrosine Isoleucine
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Ketogenic Amino Acids

• formed acetyl CoA or acetoacetate

Lysine Leucine
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Both glucogenic and ketogenic amino acids
formed a-ketoglutarate, pyruvate, oxaloacetate,
fumarate, or succinyl-CoA in addition to acetyl
CoA or acetoacetate
Isoleucine Threonine Tryptophan Phenylalanine Tyro
sine
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The C3 family alanine, serine, cysteine and
threonine are converted to pyruvate
Pyruvate
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The C4 family aspartate and asparagine are
converted into oxalacetate
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The C5 family several amino acids are converted
into a-ketoglutarate through glutamate
Glutamine
a-ketoglutarate
Proline
Arginine
Histidine
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Interconversion of amino acids and intermediates
of carbohydrate metabolism and Krebs cycle
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Metabolism of some selected amino acids
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Serine biosynthesis from glycolytic intermediate
3-phosphoglycerate
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mino-acid-metabolism.html
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Glycine biosynthesis from serine
Reaction involves the transfer of the
hydroxymethyl group from serine to the cofactor
tetrahydrofolate (THF), producing glycine and
N5,N10-methylene-THF.
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mino-acid-metabolism.html
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Glycine oxidation to CO2
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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mino-acid-metabolism.html
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Cysteine and methionine are metabolically related
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).
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Cysteine synthesis

Conversion of homocysteine back to Met.
N5-methyl-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.

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mino-acid-metabolism.html
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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.
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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-re
lated cofactor tetrahydrobiopterin, which is
maintained in the reduced state by the
NADH-dependent enzyme dihydropteridine reductase
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Phenylketonuria
Hyperphenylalaninemia - complete deficiency of
phenylalanine hydroxylase (plasma level of Phe
raises from normal 0.5 to 2 mg/dL to more than 20
mg/dL). 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
a-ketoglutarate. Absence of a-ketoglutarate in
the brain shuts down the TCA cycle and the
associated production of aerobic energy, which is
essential to normal brain development. Newborns
are routinelly tested for blood concentration of
Phe. The diet with low-phenylalanine diet.
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Catabolism of branched amino acids
valine
isoleucine
leucine
a-ketoglutarate glutamate (transamination)
a-ketoisovalerate
a-keto-b-methylbutyrate
a-ketoisokaproate
NAD
oxidative decarboxylation Dehydrogenase of a-keto
acids
CO2
NADH H
isovaleryl CoA
a-methylbutyryl CoA
isobutyryl CoA
Dehydrogenation etc., similar to fatty acid
b-oxidation
acetyl CoA
acetyl CoA
propionyl CoA


acetoacetate
propionyl CoA
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Branched-chain aminoaciduria
Disease also called Maple Syrup Urine Disease
(MSUD) (because of the characteristic odor of the
urine in affected individuals). Deficiency in an
enzyme, branched-chain a-keto acid dehydrogenase
leads to an accumulation of three branched-chain
amino acids and their corresponding
branched-chain a-keto acids which are excreted in
the urine. There is only one dehydrogenase
enzyme for all three amino acids. Mental
retardation in these cases is extensive.
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Histidine Metabolism Histamine Formation
Histidine decarboxylase
Histidine
Histamine
CO2
Histamine Synthesized in and released by mast
cells Mediator of allergic response
vasodilation, bronchoconstriction
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Tryptophan catabolism

• Tryptophan has complex catabolic pathway
• the indol ring is ketogenic
• the side chain forms the glucogenic products
• Kynurenate and xanthurenate are excrete in the
  urine.

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Enzymes which metabolised amino acides containe
vitamines as cofactors 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) Me
ny enzymes of amino acid metabolism
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