Aminoaciduria. Overview of Amino Acid Catabolism. 1st phase R emoval of the α-amino groups 2 nd phase C arbon skeletons of the α- ketoacids are converted to common intermediates of energy producing and other metabolic pathways. 1st phase of catabolism of amino acids:
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Removal of the α-amino groups
Carbon skeletons of the α-ketoacidsare converted to common intermediates of energy producing and other metabolic pathways
1st phase of catabolism of amino acids:
Removal of the α-amino groups
With production of
Small amount excreted in urine
2ndphase of A. A. catabolism
Breakdown of the resulting carbon skeletons of amino acids
Giving 7 intermediates
Oxalacetate, a-ketoglutarate, Pyruvate, Fumarate, Succinyl CoA
Acetyl CoA & Acetoacetyl CoA
Glucogenic Amino Acids
Amino acids whose catabolism
yields pyruvate or one of the
intermediates of citric acid cycle
i.e. substrates of gluconeogenesis
& therefore can give rise to GLUCOSE
Ketogenic Amino Acids
Amino Acids whose catabolism
Yields acetyl CoA or acetoactyl CoA
i.e. finally give rise to ketone bodies
Leucine& lysine are the only
exclusively ketogenic amino acids
& therefore cannot give rise to glucose
Inherited metabolic diseases
or Congenital metabolic diseases
They are a large group of genetic disorders, resulting in metabolicdefects due to
a genetically determined specificdefects in a protein.
Defects in proteins result from a single gene mutationwhich leads to reduced or
absent gene product or production of a different protein with abnormal
inborn errors of metabolism
inborn errors of metabolism
X-linked disorders in nuclear DNA.
Detection of inborn errors of metabolism
Inherited disorders may be detected in different stages during life
may be found during screening (as such performed on family members of a patient with muscular dystrophy).
some inherited disorders can be detected before birth (as cystic fibrosis).
As for phenylketonuria
Many disorders involving single gene defects become apparent clinically (give symptoms & signs).
1- The disease should not be clinically apparent at the time of screening
2- The disease should have a relatively high incidence in the population screened.
3- The disease should be treatable & so results of screening test must be obtained before
irreversible damage is likely to have occurred.
4- Screening test should be simple & reliable.
1- Phenylketonuria (PKU)
Causes of Phenylketonuria (PKU)
1- Deficiency of phenylalanine hydroxylase
2- Deficiency in enzymes that synthesize or reduce the coenzyme dihydrobiobterin
(DHBP synthetase & DHBP reductase)
In this case, simply restricting dietary phenylalanine will not reverse CNS defects due to deficiency of neurotransmitters
Metabolic & clinical effects of phenylketonuria
Phenylalanine & its metabolites phenylpyruvic, phenylacetate &
phenyllactate accumulates resulting in their rise in blood
& excretion in urine (phenylketonuria).
Persistent postnatal hyperphenylalaninemia causes irreversible brain
damage ending in mental retardation (by age of one year) & convulsions.
Most untreated patients show IQ below 50
Tyrosinelevels are reduced ending in deficiency of melanin formation resulting in
decreased pigmentation (hypopigmentation) in hair & eyes.
Also, the hydroxylation of tyrosine by tyrosinase (the first step in melanin
pigment formation) is competitively inhibited by high levels phenylalanine.
Early diagnosis of PKU is important because the disease is treatable by dietary means.
Newborn with PKU frequently has normal blood levels of phenylalanine (PA) at birth
As the mother clears increased blood PA in her fetus through placenta. So, test performed at birth may show false –ve results.
PA begins to be elevated when newborn takes milk (containing proteins) for at least 24 hours
Accordingly, feeding with milk for 48 hours is sufficient to raise the newborn blood PA to levels that can be used for diagnosis.
Diagnosis of Phenylketonuria cont.
Neonatal Screening Program for PKU
- A disk of a filter paper containing blood from a heel
prick is placed on plates impregnated with a microorganism, Bacillus subtilis,
which requires phenylalanine for growth, the only source being the
- The growth of the organism is a positive test.
Principles of treatment of PKU
phenylalanine between 4 – 8 years leads to mental retardation.
However, life-long treatment by diet restriction of phenylalanine is preferred
Protocol of treatment:
2- Maple Syrup Urine Disease (MSUD)
1- Accumulation of these amino acids & their metabolites (a-ketoacids) in
blood lead to toxic CNS effects.
2- Characteristic maple syrup odor in urine (due to the amino acid isoleucine)
Elevated branched-chain amino acids & their metabolites in blood & urine
Newborns suspected to have MSUD should be tested within 24 hours of birth to start treatment early (to avoid toxic effects)
Synthetic formula that contains limited amounts of leucine, isoleucine & valine
sufficient to provide amino acids necessary for normal growth & development
without producing toxic effects.
3- Disorders of tyrosine amino acid metabolism
Disorders of tyrosine amino acid metabolism lead to the following consequences:
1- Deficiency of melanin pigments (Albinism)
Tyrosine is the precursor of melanin (by tyrosinase enzyme)
Deficiency of tyrosine leads to albinism.
Albinism refers to a group of conditions in which a defect in tyrosine metabolism
(deficiency of tyrosinase) results in deficiency in the production of melanin resulting in the
partial or full absence of pigment from the skin, hair & eyes.
2- Deficiency of neurotransmitters:
Tyrosine is the precursor of DOPA
DOPA is converted to dopamine & catecholamine(neurotransmitters)
Disturbance of these neurotransmitters may cause Parkinson’s disease.
4- Disorders of tyrosine amino acid metabolism Alkaptonuria
( enzyme in tyrosine metabolism)
cannot be further metabolized & thus accumulates resulting in:
1- Excretion of homogentisic acid in urine in excessive amounts
(homogentisic aciduria) which is oxidized to dark pigments
2- Homogentisic acid is deposited in connective tissue ending in
degenerative changes in large joints (arthritis).
metabolism)resulting in inability to metabolize amino acid methionine & homocysteine
- CNS manifestations: mental retardation, seizures, etc
- Vascularthrombosis (complicated by CHD & strokes)