phenyl alanine and tyrosine METABOLIC PATHWAY

THESE ARE IMPORTANT AMINO ACIDS THAT HAVE ROLE IN HUMANS AND HAVE VARIOUS BIOCHEMICAL ABNORMALITIES

1. Phenylalanine and tyrosine
metabolism
Neuruscience module
Second year MBBS
20.2.25

6. L-Phenylalanine
L-Tyrosine
P-Hydroxyphenyl pyruvate
Homogentisate
Maleylacetoacetate
Fumaryl acetoacetate
Fumarate + Acetoacetate
H
4
-biopterin
H
2-biopterin
NADP
+
NADPH + H
+
-ketoglutarate
Glutarate
PLP
O
2
CO
2
Vitamin C, Cu
2+
O
2
Vitamin C, Fe
2+
Glutathione
H
2
O
Dihydrobiopterin
reductase
Phenylalanine hydroxylase
Tyrosine transaminase
P-Hydroxyphenyl pyruvate hydroxylase
Homogentisate oxidase
Maleyacetoacetate isomerase
Fumaryl acetoacetate hydroxylase
Classic PKU
Tyrosinaemia type-II
Neonatal tyrosinaemia
Alkaptonuria
Tyrosinosis or
tyrosinaemia type-I
Atypical PKU
Catabolic pathway
for phenylalanine
and tyrosine
showing metabolic
disorders

7. Metabolic disorders of phenylalanine & tyrosine
• Phenylketonuria (PKU)
-Inability to convert phenylalanine to tyrosine.
- 1:20,000 newborn.
- High level of phenylalanine in pregnant women.
- Accumulation of toxic derivatives of phenylalanine.
- PKU name because of high level of keto acid
phenylpyruvate in urine.
- Patients are mentally retarded (Untreated patients).
- Myelination of nerves is defective, reflaxes are
hyperactive.
- Life threatening, half are dead by age 20 & ¾ by age
30.

8. Phenyl Ketonuria(PKU)
Six types of hyper phenylalaninaemia have been described

9. Phenylalanine
Phenylpyruvate
Phenylacetate Phenyllactate
Phenylacetylglutamine
-ketoglutarate
Glutamate
Glutamate
H
2O
Transamination
Oxidative decarboxylation Reduction
Alternative
pathways of
phenylalanine
catabolism in
phenylketonurics

10. • Classes
• Characteristic of PKU
1.Increased level of- -
Phenylalanine, phenyl acetate, phenyl lactate,
phenyl pyruvate, phenyl acetyl glutamine in tissue,
plasma & urine.
2. Neurological symptoms-
- Mental retardation, failure to walk, to talk,
seisures, psychoses, tremor, failure to grow.
3. Hypopigmentation-
- Defect of melanin, so fair hairs, light color of
skin, blue eyes.

11. Types of phenylketonuria with their defects
Type of PKU Defects
Classic phenylketonuria or
hyperphenylalaninaemia type-I
Defect in phenylalanine hydroxylase
Atypical phenylketonuria
Hyperalaninaemia type-II and III
Defect in dihydrobiopterin reductase
Hyperalaninaemia type-IV and V Defect if dihydrobiopterin synthesis

12. •Treatment of PKU- Low phenylalanine diet.
•Test of PKU- Urine of newborns assayed by addition of
FeCl
3
Olive color in presence of phenylalanine.
- Gene for human phenylalanine hydroxylase has
been cloned.

13. Tyrosinemia
Three types-
- Tyrosinemia I
- Tyrosinemia II
- Benign transient neonatal tyrosinemia.
Type I-
- Defect fumaryl-acetoacetate hydrolase.
- Causes liver failure, rickets, renal tubular
dysfunction & polyneuropathy.
- Tyrosine metabolites & other amino acids excreted
in urine.
- Death occur due to liver failure within 1 yr.
- Diet low in tyrosine, phenyalanine & methionine.

14. Type II- Richner-Hanhart syndrome- Defect tyrosine
transaminase.- Blockage of routine pathway.-
Accumulation & excretion of tyrosine & its
metabolites.- Characterized by skin & eye lesions.
Neonatal tyrosinemia-- Defect P-hydroxyphenyl pyruvate
dioxygenase.- High tyrosine levels in premature
infants & full-term infants of LBW, due to immature liver.
- 4 to 8 week levels decreases (normal).
Therapy overall:- Diet low in phenylalanine & tyrosine,
with vitamin-C .

15. L-Tyrosine
P-Hydroxyphenylpyruvate Tyramine
P-Hydroxyphenyllactate P-Hydroxyphenylacetate
N-Acetyltyrosine
Acetyl-CoA
CoA-SH
Tyrosine
transaminase
Dehygrogenase
Tyrosine
decarboxylase
Tyrosine
oxidase &
dehydrogenase
CO
2
Alternative catabolic pathway for tyrosine in tyrosinaemia

16. Alkaptonuria
-Inherited metabolic disorder.
- Defect in the enzyme homogentisate oxidase.
- Homogentisate excreted in urine & urine becomes
dark color due to oxidation of homogentisate with O
2.
- Later patient may having dark colored pigment
deposition on connective tissue, called ochronosis.
- Ochronosis leads to tissue damage & may develop
arthritis, backache.
Treatment
Not life threatening, condition is not treated.

17. Formation of alkapton bodies
Homogentisate
Benzoquinone acetate
Ochronosis
(Black coloured alkapton bodies
that binds to connective tissue)
Oxidation
Polymerization

18. Albinism
-Defect in tyrosinase causes albinism.
- Patient can not synthesis melanin pigment.
Symptoms
Photophobia, nystagmus, white hair & skin.

19. Tyrosine
3,4-Dihydroxyphenylalanine (DOPA)
Dopaquinone
Leucodopachrome
5,6-Dihydroxyindole
Indole 5,6-quinone
Cysteine
Melanin polymer RED
Melanin polymer BLACK
Melanochrome
O
2
H
2
O
O
2
H
2O
H
2
O
O
2
Tyrosinase
Tyrosinase
Tyrosinase
Cysteine
Metabolism of tyrosine-biosynthesis of
melanin

20. Dopa Tyrosine Dopa
Dopamine Thyroxine Dopaquinone
Norepinephrine
Epineprine
Melanine pigment
Catecholamines
Neurotransmitter
Biosynthesis of biologically important
compounds from tyrosine
• Tyrosine is precursor of many compounds like DOPA,
Tyroxine, Dopamine.

21. Biosynthesis of Thyroid hormone:Thyroid hormone
- Thyroxine (tetraiodothyronine)- Triiodothyronine
• Synthesized from the tyrosine residues of protein
thyroglobulin and iodine.

22. Metabolism
of tyrosine-
synthesis
of thyroid
hormone

23. Biosynthesis of catecholamines:
• Catechol refers to dihydroxylated phenyl ring.
OH
OH
Catechol
• Amines derivatives of catechol called catecholamines.
- Dopamine, norepinephrine (noradrenaline) and
epinephrine (adrenalin) synthesize from tyrosine takes
place in -Adrenal medulla
- Central nervous system
1.Thyrosine hydroxylated to 3,4-dihydroxyphenylalanine
(DOPA) by enzyme tyrosine hydroxylase.
2. DOPA Dopamine, which hydroxylated to
produce norepinephrine.
Decarboxylation
PLP dependent

24. CH
2
- CH-COO
-
NH
3
+
HO
CH
2- CH-COO
-
NH
3
+
HO
HO
HO
HO
CH
2
- CH
2
-NH
3
+
HO
HO
CH- CH
2
-NH
3
+
OH
CH- CH
2-N-CH
3
+
OH H
HO
HO
O
2
H
4
-Biopterin
H
2-Biopterin
H
2O
O
2
H
2
O
Ascorbate
Dehydroascorbate
S-Adenosyl
methionine
(CH3)
S-Adenosyl
homocysteine
Tyrosine
Dihydroxyphenylalanine (DOPA)
CO
2
Dopamine
Norepinephrine Epinephrine
Tyrosine
hydroxylase
Aromatic amino
acid decarboxylase
PLP
Dopamine
-
hydroxylase
Phenylethanolamine
N-methyltransferase
Metabolism of
tyrosine-
synthesis of
catcholamines

25. 3. Methylation of norepinehrine by S-adenosyl methionine
gives epinephrine.
Difference only methyl group (nor-no methyl group).
Functions:
Norepinephrine & epinephrine
- Regulate carbohydrate & lipid metabolism.
- Stimulate degradation of TG & glycogen.
- Increases BP
Dopamine & norepinephrine
- Neurotransmitter in brain & autonomous nervous
system.

26. Treatment:
-Dopamine not enter in the brain.
- DOPA Dopamine in brain, alleviates the symptoms.
- Side effect (produce in other tissue).
-Dopa-analogs-inhibit dopa decarboxylase in various
tissue, not enter in brain (BBB).
- Carbidopa- & -methyl-dopa used.
Dopamine & Parkinson’s disease
- Elderly people (above 60% being affected).
- Muscular rigidity, tremors, expressionless face,
lethargy involuntary movement.
• Decreased production of dopamine.
• Degeneration of certain parts of brain (substantia nigra &
coeruleus locus).

27. IN BORN ERROR OF
AROMATIC AMINO ACIDS METABOLISM
Boy with untreated PKU
Urine of Alkaptonuria patient
Black pigmentation in Alkaptonuria patient

28. IN BORN ERROR OF
AROMATIC AMINO ACIDS METABOLISM
Herpetiformic Keratitis
Palmoplanter
Hyperkeratosis
Tyrosinemia Type I