Amino Acidss & Aminoacidopathies
Amino Acidss & Aminoacidopathies
Amino Acidss & Aminoacidopathies
Aminoacidopathies
16/5/2015
Protein formation
When two amino acids condense, a dipeptide is
formed.
The carboxylate ion (COO-) of one amino acid
reacts with the protonated amine (NH3+) of a
second amino acid.
A water molecule is lost and an amide functional
group is formed. An amide bond is formed
between the two amino acids.
Chapter 9
19
2011 Pearson
Education, Inc.
Aminoacidopathies
class of rare inherited errors of
metabolism in which there is an enzyme
defect that inhibits the bodys ability to
metabolize certain amino acids
The abnormalities may involve
Activity of specific enzymes
Metabolic pathway
Or membrane transport system for amino
acids
Aminoacidopathies
These defects leads to accumulation of
amino acids , its precursors or by products
Excessive accumulation in blood or tissues
leads to physical symptoms of the disease
Clinical Manifestation
Aminoaciduria
CNS dysfunction:
Mental retardation
Seizure disorders
Behavioral disturbances
Metabolic ketoacidosis
Occasionally:
Liver disorders
Renal failure
Ocular lesions
Aminoacidopathies
PKU
Homocyctinuria
Hypertyrosinemia
Neurological
Maple-syrup urine
disease
Hyperglycenemia
Methyle melonic
aciduria
Citrullinemia
Carnosinemia
Hypopigmentation
Brown syndrome
Albinism
Chediac Higashi
syndrome
Phenyleketoneuria
autosomal recessive disorder
Incidence rate 1 in 14000
Common compared to other
aminoacidopathy
Deficiency of phenylanaline
hydroxylase
Phenylalanine is metabolized
via alterative pathway leading
to accumulation phenyle
pyruvic acid (deamination)
Accumulate in blood and urine
and gives musty odor to it
Phenyleketoneuria
Phenyl pyruvic acid is neurotoxic and in
undiagnosed newborn can cause severe
mental retardation due to brain damage,
which starts in 2nd and 3rd week post birth.
Early detection allows diet control therapy
low in phenylalanine up to the age of 5-6yrs
until normal metabolism develops, however
low IQ levels have been reported after
termination of special diet.
Phenylalanine > 1200 mole/l (upper limit
120 mole/l)
Tests of PKU
Detection of phe (Screening ):
Ferric chloride test
Guthrie test : bacterial inhibition assay for
phenylalanine that uses the ability of
phenylalanine to facilitate bacterial growth
in a culture medium with an inhibitor
(Bacillus subtilis and -2-thienylalanine).
Automated methods
Tests of PKU
principle of Guthrie test :
Spores of organism Bacillus subtilisare
incorporated into an agar plate containing -2thienylalanine (a metabolic antagonist to B.
Subtilis).
A filter paper disk, impregnated with dried
blood sample is placed onto the agar
If the blood phenylalanine level is higher than
2.5 mg/dl, the phenylalanine counteracts the
antagonist and the bacteria grows.
The sample should be collected prior to
administration of antibiotics or transfusion of
blood or blood products.
Tests of PKU
principle of Guthrie test :
Tests of PKU
Genetic pre-natal diagnosis of
PKU:
detection of carrier status in families
with PKU using DNA analysis
PKU is a complex polygenic disorder and
results in multiple independent
mutations at the PAH locus
Screening for mutations using PAH gene
probes
2. ALCAPTONURIA
AKU
Defect here
causes
alkaptonuria
Defect here
causes Type I
Tyrosinemia
Homogentisate
dioxygenase
Fumarylacetoacetate
hydrolase
Albinism
Autosomal recessive
Result from loss of TYROSINASE
enzyme in skin which converts tyr to
DOPA and DOPA to melanin pigments
Tyrosinemia
Tyrosine is an amino acid which is found in
most animal and plant proteins. The
metabolism of tyrosine in humans takes
place primarily in the liver
Hereditary tyrosinemia is a genetic
inborn error of metabolism associated
with severe liver disease in infancy.
The disease is inherited in an
autosomal recessive fashion.
Tyrosine catabolism defect
characterized by the excretion of tyrosine
and tyrosine catabolites in urine
Tyrosinemia
Type I tyrosinemia : caused by an absence
of
the
enzyme
fumarylacetoacetate
hydrolase (FAH)
most severe form of this aminoacidopathy
found in about 1 in 100,000 births
lead to liver and kidney failure
Type II tyrosinemia:
deficiency of the enzyme tyrosine
aminotransferase
occurs in fewer than 1 in 250,000 births
mentally retarded ,excessive tearing and
photophobia
Tyrosinemia
Diagnosis :
Elevation of tyrosine in plasma and
urine
MS/MS chromatography
Treatment :
Low protein diet
Drugs that inhibits maleylacetoacetic
acid and fumarylacetoacetic acid
formation
Homocystinuria
Autosomal recessive disorder
Incidence : 1 in 200,000 birth
Deficiency y of the enzyme
cystathionine- synthetase, necessary
for the metabolism of the methionine
amino acid, that results in elevated plasma
and urine levels of methionine and of the
precursor homocysteine
Urinary exertion of homocystein is >
300 mg/24 hrs
Homocystin
Homocystinuria
Signs and complications:
Increased risk of blood clot
(thrombosis)
Dislocation of eye lenses
Skeletal abnormality
Developmental delay
osteoporosis
Urinary homocysteine:
HPLC
Cystinuria
Autosomal recessive defect that is caused by
a defect in the amino acid transport system
rather than a metabolic enzyme deficiency
inadequate reabsorption of cystine during
the filtering process in the kidneys
Cystine
precipitates out of the urine and forms stones
in the kidneys,ureters, or bladder
Cystinuria
diagnosed by testing the urine for
cystine using cyanide nitroprusside,
which produces a red-purple color on
reaction with sulfhydryl groups