Download INBORN ERRORS OF AMINO ACIDS METABOLISM

INBORN ERRORS OF AMINO
ACIDS METABOLISM
TYROSINE METABOLISM
Tyrosine
Tyrosine is formed
from phenylalanine by
phenyl alanine
hydroxylase. During the
reaction, BH4 is
oxidized to dihydro biopterin (BH2).
Tyrosine, like cysteine,
is formed from an
essential amino acid
and is, therefore, non
essential only in the
presence of adequate
dietary phenylalanine.
Degradation of Phenylalanine to Tyrosine
PA hydro-xylase
tetrahydrobiopterin
+O2
The reaction requires molecular
oxygen and the coenzyme tetra
hydrobiopterin (BH4), which can
be synthesized from guanosine
triphosphate (GTP) by the body.
One atom of molecular oxygen
becomes the hydroxyl group of
tyrosine, and the other atom is
reduced to water. During the
reaction, BH4 is oxidized to
dihydro - biopterin (BH2). BH4 is
regenerated from BH2 by NADHrequiring dihydro pteridine
reductase.
Degradation of TYROSINE & Aromatic Amino Acids
Acetoacetate, fumarate, and pyruvate — are common intermediates.
Molecular oxygen is used to break an aromatic ring.
homogentisate
oxidase
fumarylacetoacetase
INBORN ERRORS OF AMINO ACIDS METABOLISM
Alcaptonuria - inherited disorder of the
tyrosine metabolism caused by the
absence of homogentisate oxidase.
 homogentisate 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
Alcaptonuria
Accumulation of oxidized homogentisic acid
pigment in connective tissue (ochronosis)
Aortic valve stenosis in alcaptonuria
Arthritis of the spine is a complication
of alkaptonuria ochronosis
Phenylalanine
Albinism –
genetically
determined lack or
deficit of enzyme
tyrosinase
Tyrosine
DOPA
Tyroxine
tyrosinase
Dopamine
Tyrosinase in
melanocytes
oxidases tyrosine
to DOPA and
DOPA-chinone
Norepinephrine
Epinephrine
Melanin
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
Tyrosinemia is an extremely rare but treatable hereditary disorder.
When the body cannot break down tyrosine, high levels build up in
the blood and form a toxic substance (known as succinylacetone) in
the liver, kidneys, and central nervous system. This means that if
tyrosinemia isn't treated, it may cause liver and kidney damage and
brain-related problems, such as problems with learning.
There are three types of tyrosinemia. The type a child has depends
on which enzyme they are lacking. Children with tyrosinemia type 1
(HT-1) are deficient in an enzyme called fumarylacetoacetate
hydrolase. If not recognized and treated right away, the condition
could be fatal for a child at an early age. However, with treatment,
tyrosine levels in the blood can be managed.
Dietary restriction of tyrosine and phenylalanine in the treatment
of hereditary tyrosinemia type 1 (HT-1).
A deficiency of the enzyme fumarylacetoacetase leads to an accumulation of
the novel and extremely toxic compound succinylacetone
Tyrosinaemia type 1
A deficiency of the enzyme fumarylacetoacetase leads to
an accumulation of the novel and extremely toxic
compound succinylacetone . This is detected by urine
organic acid analysis. Tyrosine concentrations in body
fluids are also elevated but can be variable.
Affected children typically present with severe liver
disease and renal Fanconi syndrome.
The drug nitisinone inhibits an enzyme higher in the
pathway, 4 hydroxyphenylpyruvate dioxygenase. This
prevents the synthesis of succinylacetone and
dramatically improves prognosis. Patients continue to
need dietary therapy to prevent tyrosine accumulation.