Metabolic Disorders of Phenylalanine and Tyrosine. Phenylketonuria (PKU)

2. Phenylalanine
Tyrosine
Phenylalanine
hydroxylase
Tyrosine
transaminase
p-hydroxyphenylpyruvate
p-HPP
dioxygenase
Homogentisate
Homogentisate
oxidase
4-Maleylacetoacetate
Maleylacetoacetate
isomerase
4-Fumaylacetoacetate
Fumarylacetoacetate
hydrolase
Fumarate Acetoacetate
Phenylket onuria
Tyrosinemia t ype II
N eonat al t yrosinemia
A lkapt onuria
t yrosinemia t ype I

4. Phenylketonuria (PKU) is the most common metabolic
disorder (inborn error) in amino acid metabolism.
Genetic: An autosomal recessive defect.
Incidence : About 1 in 10,000 newborns.
Enzyme defect: Phenylalanine hydroxylase,
Variant of PKU: due to a defect in dihydrobiopterin
reductase (relatively less)
The net outcome: phenylalanine is not converted to
tyrosine.
Leads to: PA and its derivative levels  in blood.

5. Phenylalanine
Tyrosine
Dihydro-
biopterin
Tetrahydro-
biopterin
Phenylalanine
hydroxylase
O2
H2O
– CH2-CH-COOH
NH2
_
– CH2-CH-COOH
NH2
_
HO –
Dopamine Epinephrine
MelaninThyroid
hormones
PKU

6. Phenylalanine Tyrosine
Phenylalanine
hydroxylase
PKU
Alanine
Pyruvate
Transaminase
Phenylpyruvate
Phenylacetate Phenyllactate
H2O
CO2

7. The disease acquired its name (PKU) from the high
levels of the keto acid, phenylpyruvate in urine.
Phenylpyruvate further converted to metabolites
like…
phenylacetate,
Phenyllactate and
phenylacetyl glutamine
All these compounds are excreted in the urine.
Presence of phenylacetate in the urine gives it a
mouesy odour.

8. In PKU, accumulation of phenylalanine & its
metabolites in the body.
Leads to many clinical & biochemical manifestations.
Mental
Retardation
Failure To
Walk or Talk
Failure Of
Growth
Seizures Very Low IQ
(below 50)
Hypopigmentation
(light skin colour, fair
hair, blue eyes)

9. • Screening the newborn babies for the  plasma levels of
PA (PKU, 20–65 mg/dl; normal 1–2mg/dl)
• a bacterial (Bacillus subtilis) bioassay for phenylalanine.
Guthrie
test
• Phenylketones in urine can be detected by this
test, (a green colour is obtained in the test).
• This test is not specific
Ferric
Chloride
Test
• The gene for human PA hydroxylase has been
cloned.
• Prenatal diagnosis of PKU can also be done by
DNA probes.
DNA
probes

10. The maintenance of plasma phenylalanine conc.
within the normal range is a challenging task in the
treatment of PKU.
This is done by selecting foods with low
phenylalanine content.
Dietary intake of phenylalanine should be adjusted
by measuring plasma levels.
Early diagnosis & treatment for 4–5 years can
prevent the damage to brain.
However, the restriction to protein diet should be
continued for many more years in life.

12. Other name: Richner- Hanhart syndrome
Genetic: An autosomal recessive defect.
Incidence : fewer than 1 in 250,000 individuals.
Enzyme defect: Tyrosine Transaminase,
The net outcome: blockade in the routine
degradative pathway of tyrosine.
Leads to: Accumulation and excretion of tyrosine &
its metabolites.
Ty r o s i n e m i a t y p e I I

13. Tyrosine
HO – – CH2-CH-COOH
NH2
_
Tyrosine
transaminase
Glutamate
α-ketoglutarate
p-hydroxyphenylpyruvate
HO – – CH2-C-COOH
O
=
Ty r o s i n e m i a t y p e I I
p-hydroxyphenylpyruvate,
p-hydroxyphenyllactate,
phydroxyphenylacetate,
N-acetyltyrosine,
tyramine

14. C l i n i c a l f e a t u r e s o f
Ty r o s i n e m i a t y p e I I
Distinctive clinical features of Tyrosinemia type II due
to intracellular crystallization of tyrosine include…
Skin
lesions
Eye lesions .
rarely, Mental
retardation.

15. Neonatal tyrosinemia

16. Degradation of
Phenylalanine To tyrosine
p-hydroxyphenylpyruvate
HO – – CH2-C-COOH
O
=
p-HPP
dioxygenase
Homogentisate
– CH2-COOH
Dehydroascorbate
H2O, CO2
Ascorbate
This is mostly a temporary condition and usually
responds to ascorbic acid.

17. Alkaptonuria

18. Other name: Black urine disease
Genetic: An autosomal recessive defect.
Incidence : 1 in 25,000.
Enzyme defect: homogentisate oxidase,
The net outcome: Homogentisate accumulates in
tissues and blood, and is excreted into urine.
A l k a p t o n u r i a
Alkaptonuria has great historical importance.
Garrod conceived the idea of inborn errors of metabolism
from his observation on alkaptonuria.

19. C l i n i c a l f e a t u r e s A l k a p t o n u r i a
Homogentisate
– CH2-COOH
Homogentisate
oxidase
4-Maleylacetoacetate
– CH2-COOHC
CO-
O
O
=
O
O2
Bezooquinone acetate
Urine
Oxidation
Ochronosis
Polymerization
Alkapton
Deposition in
connective tissue, bones &
various organs (nose, ear etc.)
Al k a p t o n u r i a

20. C l i n i c a l f e a t u r e s A l k a p t o n u r i a

21. Change in colour of the urine on standing to brown or
dark has been the simple traditional method to
identify alkaptonuria.
The urine gives a positive test with ferric chloride
and silver nitrate.
D i a g n o s i s o f A l k a p t o n u r i a

22. Tyrosinosis or tyrosinemia
type I

23. Other name: Tyrosinosis
Genetic: An autosomal recessive rare but serious
disorder.
Incidence : 1 in 1,00,000.
Enzyme defect: fumarylacetoacetate hydroxylase,
The net outcome: It causes liver failure, rickets,
renal tubular dysfunction and polyneuropathy.
Tyrosine, its metabolites and many other amino acids
are excreted in urine..
t y r o s i n e m i a t y p e I

24. In acute tyrosinosis, the infant exhibits diarrhea,
vomiting, and ‘cabbage-like’ odor.
Death may even occur due to liver failure within one
year.
For the treatment, diets low in tyrosine,
phenylalanine and methionine are recommended.
t y r o s i n e m i a t y p e I

25. Albinism

26. Other name: Tyrosinosis
Genetic: An autosomal recessive defect.
Incidence : 1 in 20,000.
Enzyme defect: Tyrosinase
The net outcome: lack of synthesis of the pigment
melanin.
A l b i n i s m

27. Lack of melanin in albinos makes them sensitive to
sunlight.
Increased susceptibility to skin cancer
(carcinoma).
Photophobia (intolerance to light) is associated
with lack of pigment in the eyes.
However, there is no impairment in the eyesight
of albinos.
Their entire body, including their hair, is
characteristically white.
C l i n i c a l f e a t u r e s o f a l b i n i s m

28. ….