Download Aromatic amino acid metabolism

AROMATIC AMINO ACID
 Aromatic amino acid contains aromatic ring. They are:
 Phenylalanine(Benzene ring or phenyl).
 Tyrosine(phenol).
 Tryptophan(indole).
Phenylalanine and Tryptophan are essential amino acids.
Tyrosine can synthesis from Phenylalanine.
Partially glucogenic and partially ketogenic.
Only plants and microorganisms are able to synthesize
aromatic amino acids.
phenylalanine
tyrosine
tryptophan
Biosynthesis of aromatic amino acids:
 Biosynthesis of aromatic amino acids starts with a common
pathway, the Shikimate pathway.
 The biosynthesis begins with Phosphoenolpyruvate and
Erythrose-4- phosphate to form Shikimate.
 Shikimate then goes on to form the branch point
intermediate Chorismate.
 Chorismate can be converted into anthranilate (L-Trp) or
prephenate (L-Phe and L-Tyr).
Shikimate pathway
: 2-keto-3-deoxy-D-arabinoheptulosonate-7- phosphate synthase.
: dehydroquinate synthase.
: 3-dehydroquinate dehydrogenase, : shikimate dehydrogenase,:
shikimate kinase, : 3-enolpyruvylshikimate-5-phosphate synthase, and
: chorismate synthase.
Tryptophan synthesis
 Tryptophan is synthesized from chorismate in a 5-step
process.
 Chorismate requires an amino group from the side chain of
glutamine and releases pyruvate to form anthranilate.
 Anthranilate then undergoes condensation with
phosphoribosyl pyrophosphate (PRPP), an activated form
of ribose phosphate.
 The C-1 atom of ribose 5-phosphate becomes bonded to the
nitrogen atom of anthranilate in a reaction that is driven by
the hydrolysis of pyrophosphate.
 The ribose moiety of ribosylanthranilate undergoes
rearrangement to yield enol-1-o-carboxylphenylamino-1deoxyribulose-5-phosphate.
This intermediate is dehydrated and then decarboxylated to
indole-3- glycerol phosphate, which reacts with serine to
form tryptophan.
: anthranilate synthase, : anthranilate phosphoribosyl transferase,
: N-(5’-phosphoribosyl)- anthranilate isomerase,
: indole-3-glycerol phosphate synthase, and : tryptophan synthase.
Tyrosine and phenylalanine synthesis
 A mutase converts chorismate into prephenate, the
immediate precursor of the aromatic ring of tyrosine and
phenylalanine.
 Prephenate is oxidatively decarboxylated to phydroxyphenylpyruvate.
 Alternatively, dehydration followed by decarboxylation
yields phenyl pyruvate.
 These α-keto acids are then transaminated, with
glutamate as amino group donor, to form tyrosine and
phenylalanine, respectively.
chorismate mutase
prephenate dehydrogenase
prephenate dehydratase
Tyrosine can also be made by animals directly from
phenylalanine via hydroxylation at C-4 of the phenyl group
by phenyl hydroxylase, which also participates in the
degradation of phenylalanine.
Hydroxylation of phenylalanine to form tyrosine involves
the reductant tetrahydrobiopterin.
Dihydrobiopterin is reduced to tetrahydrobiopterin by
electron transfer from NADH.
Thus NADH is secondarily the e- donor for conversion of
phenylalanine to tyrosine
Degradation of Aromatic Amino Acids
(1) Transaminase.
(2)p-hydroxy-phenylpyruvate
dioxygenase (vitamin Cdependent).
(3)homogentisate dioxygenase .
(4)4-Maleylacetoacetate isomerase .
(5)fumarylacetoacetase.
Tryptophan degradation requires several oxygenases
Formamidase
tryptophan pyrrolase
kynurenine hydroxylase
NADPH +
H+
NADP+
PLP
Kynureninase
Pyruvate
NAD and NADP
Amino Acids as Metabolic Precursors
 Tyrosine is the precursor to several important molecules in
metabolic signaling and neurotransmission, including
epinephrine and dopamine.
 Tyrosine is oxidized by the enzyme tyrosine hydroxylase in a
reaction requiring the enzyme cofactor tetrahydrobiopterin to
form dihydroxyphenylalanine (L-DOPA), a metabolic precursor
to dopamine
Tyrosine is also the precursor
to pigment molecules called
melanins that are produced
from dopaquinone.
 The two primary melanins are
eumelanins, which are dark
pigments having a brown or
black color, and pheomelanins
that have red or yellow color.
 The yellow color of pheomelanin
pigments comes from the sulfur
in cysteine that is combined with
dopaquinone.
Thyroid hormones - Thyroxine (tetraiodothyronine) &
triiodothyronine - are synthesized from the tyrosine residues of the
protein thyroglobulin & activated iodine.
 Iodination of tyrosine ring occurs to produce mono & diiodotyrosine
from which triiodothyronine (T3) & thyroxine (T4) are synthesized.
The protein thyroglobulin undergoes proteolytic breakdown to
release the free hormones - T3 & T4.
Tryptophan, is the
precursor to:
1. Serotonin and
melatonin.
2. Niacin.
INBORN ERRORS OF AMINO ACIDS METABOLISM:
Alcaptonuria - inherited disorder
of the tyrosine metabolism caused
by the absence of homogentisate
oxidase.
homogentisic acid is accumulated
and excreted in the urine
 turns a black color upon exposure
to air
In children:
 urine in diaper may darken
 In adults:
 darkening of the ear
 dark spots on the on the
sclera and cornea
 arthritis
phenylketonuria (PKU)
A genetic defect in the gene encoding phenylalanine hydroxylase is
responsible for the metabolic disease phenylketonuria (PKU).
Defect in myelination of nerves
The brain weight is below normal.
Mental and physical retardations.
The life expectancy is drastically shortened.
Diagnostic criteria:
 phenylalanine level in the blood
 FeCl3 test
 DNA probes (prenatal)
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.
The clinical symptoms of
PKU are caused by the
accumulation of
phenylalanine in the
blood that is 30-50 times
higher than normal.
This high level of
phenylalanine leads to the
production of phenylalanine
metabolites such as
phenylpyruvate,
phenylacetate and
phenyllactate, all of which
are associated with the
observed neurological and
developmental problems
NutraSweet contains a phenylalanine derivative
Phenylketonuriacs also have
to be careful to avoid
processed foods and
beverages containing the food
additive aspartame
(aspartyl-phenylalanine
methyl ester).
Albinism – genetically
determined lack or deficit of
enzyme Tyrosinase
Phenylalanine
Tyroxine
Tyrosine
Tyrosinase in melanocytes
oxidases tyrosine to DOPA and
DOPA-chinone.
Melanin
tyrosinase
DOPA
Symptoms of albinism:
 inhibition of production or lack
of melanin in skin, hair, eyes
 increased sensitivity to
sunlight
 increased risk of skin cancer
development
 sun burns
 photophobia
 decrease of vision acuity
 strabismus, nystagmus
Dopamine
Norepinephrine
Epinephrine
Tyrosinemia:
occur in several forms. They may
be caused by a deficit of enzymes
which catalyze either the
transamination of tyrosine (II),
or oxidation of phydroxyphenylpyruvate (III) and
hydrolysis of fumarylacetoacetate
(I).
A low-tyrosine diet may be very
useful.
Plasma levels of tyrosine are
elevated, and large amounts of
tyrosine, phydroxyphenylpyruvate, –lactate,
and –acetate are excreted into
the urine (tyrosyluria).
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