This document summarizes the structures, metabolism, and roles of phenylalanine and tyrosine. It discusses how phenylalanine is converted to tyrosine in the liver by the enzyme phenylalanine hydroxylase. Tyrosine can then be used to synthesize important compounds like thyroid hormones, melanin, and catecholamines. The document also outlines several disorders related to phenylalanine and tyrosine metabolism, including phenylketonuria, tyrosinemia, alkaptonuria, and albinism.

1. Hari Sharan Makaju
M.Sc. Clinical Biochemistry
1st year

2.  Structure of phenylalanine and tyrosine
 Conversion of phenylalanine to tyrosine
 Metabolic fate of tyrosine
 Metabolic roles of tyrosine
 Related disorders

3.  Tyrosine possesses an extra –OH group at para position of
benzene ring.

4. PHENYLALANINE
 Aromatic & essential amino acid
 Both Glucogenic & Ketogenic.
 Phenylalanine is converted to tyrosine.
 The need for phenylalanine becomes minimal, if adequate
tyrosine is supplied in the food.
 This is called the sparing action of tyrosine on
phenylalanine.
 Predominant metabolism of phenylalanine occurs through
tyrosine and incorporated into various biologically
important compounds.
 Epinephrine, norepinephrine, dopamine, thyroid hormones &
the pigment melanin.
 Phenylalanine (Phe) is specified by the codons UUU and
UUC

5. Food and Nutrition Board (FNB) of the U.S. Institute of
Medicine set Recommended Dietary Allowances (RDA) :
For phenylalanine + tyrosine,
For adults 19 years and older - 33 mg/kg body weight/day

6.  Reaction involves hydroxylation of phenyl alanine at p-
position in benzene ring
 Enzyme: Phenyl alanine hydroxylase.
 Present in liver and the conversion occurs in Liver
 The reaction is complex and takes place in two activity -
 I. Reduction of O2 to H2O and conversion of phenylalanine to
tyrosine. Tertahydrobiopterin acts as H-donor to the
molecular O2
 II. Reduction of dihydrobiopterin, FH2 by NADPH,
catalysed by the enzyme Dihydrobiopterin reductase.

8. TYROSINE
 Aromatic amino acid
 synthesized from phenylalanine, and so is a non-
essential amino acid
 Tyrosine is degraded to produce as end products
‘Fumarate’ and ‘acetoacetate’.
 Fumarate is glucogenic, whereas acetoacetate is
ketogenic
 Tyrosine is specified by the codons UAU and UAC,
 Degradation of tyrosine
 Occurs mostly in liver.

9.  Transamination
 Production of homogentisic
acid
 Cleavage of aromatic ring
 Isomeriozatioin
 Hyrolysis

10.  Tyrosine first undergoes transamination to P-hydroxyphenyl pyruvate,
catalyzed by tyrosine transaminase
 pyridoxal phosphate dependent.
 is induced by glucocorticoids.

11.  Reaction catalyzed by the enzyme p-Hydroxyphenylpyruvate oxidase,a
copper-containing enzyme.
 It catalyzes oxidative decarboxylation as well as hydroxylation of the
phenyl ring of p-hydroxyl phenyl pyruvate to produce
homogentisate.
 requires ascorbic acid (Vit. C) and Vit. B12

12.  Homogentisate oxidase (iron metallo- protein) cleaves the benzene
ring of homogentisate to form 4-maleylacetoacetate.
 Molecular oxygen is required for this reaction to break the
aromatic ring.
 Inhibitor : α-α’-dipyridil

13.  4-Maleylacetoacetate undergoes isomerization to form 4-
fumaryl acetoacetate.
 Catalyzed by maleylacetoacetate isomerase

14.  Fumaryl acetoacetase (fumaryl acetoacetate hydrolase) brings about
the hydrolysis of fumaryl acetoacetate to liberate fumarate(glucogenic
product ) & acetoacetate(ketone body ).
 Hence, phenylalanine and tyrosine are partly glucogenic and partly
ketogenic.

15.  Synthesis of thyroid hormones: Thyroxine (T4) and
triiodothyronine (T3)
 Synthesis of melanin pigment
 Synthesis of catecholamines

16.  Thyroid hormones – Thyroxine (T4) &
triiodothyronine(T3)
 are synthesized from the tyrosine residues of the protein
thyroglobulin & activated iodine.
 Iodination of tyrosine ring occurs to produce mono &
diiodotyrosine from which triiodothyronine (T3) &
thyroxine (T4) are synthesized.
 The protein thyroglobulin undergoes proteolytic
breakdown to release the free hormones - T3 & T4.

17.  Greek word “Melan” means - black
 Melanin pigment gives the black color to the skin, hair
and eye.
 The synthesis of melanin occurs in melanosomes present
in melanocytes, the pigment producing cells.
 Tyrosine is precursor for melanin & only one enzyme,
namely tyrosinase (a copper containing oxygenase), is
involved in its formation.

18.  Eumelanins :
 Insoluble, heterogenous, high molecular weight, black to
brown heteropolymers of 5, 6-dihydroxy indole and several
of its biosynthetic precursors, viz.
 Leucodopachrome and Dopachrome.
 Pheomelanins :
 Yellow to reddish-brown polymers, though of high
molecular weight are soluble in dilute alkali. They contain
sulphur.
 Trichochromes :
 These low molecular weight
compounds, contains sulphur and are related to
pheomelanins

19. I. Formation of DOPA:
 Hydroxylation of tyrosine by
tyrosinase((a copper containing
oxygenase) , to form dihydroxyphenyl
alanine or DOPA
II. Formation of DOPA quinone:
 Tyrosinase again acts on DOPA to form
dopaquinone
III. Formation of indolequinone:
 DOPA quinone is converted to
indolequinone through a series of
reactions involving decarboxylation and
oxidation of the side chain.
 The indolequinone is polymerized to
form melanin.

20.  Another pathway:
 Cysteine condenses with dopaquinone
& in the next series of reactions results
the synthesis of red melanins.
 The skin color of the individual is
determined by the relative
concentrations of black & red melanins.
 This, in turn, is dependent on many
factors, both genetic & environmental.
 These include the activity of tyrosinase,
the density of melanocytes, availability
of tyrosine etc.

21.  The presence of moles on the body represents a localized
severe hyperpigmentation due to hyperactivity of melanocytes.
 Localized absence or degeneration of melanocytes results in
white patches on the skin commonly known as leucoderma.
 Albinism is an inborn error with generalized lack of melanin
synthesis.
 Tyrosinase is present in melanoblasts and produces DOPA (
useful in melanin synthesis)

22. Catecholamines
 Epinephrine
 Nor-epinephrine
 Dopamine
They are produced by the adrenal medulla
and sympathetic ganglia.
Catecholamines are derived from tyrosine.

23. Tyrosine is taken up actively by cells of
adrenal medulla pheochromocytes and
neuroglial cells
1. Conversion of tyrosine to DOPA (In
mitochondrion)
2. Conversion of DOPA to dopamine (In
cytoplasm)
3. Conversion of dopamine to
norepinephrine (In granules/vesicles)
4. Conversion of Nor-epinephrine to
epinephrine (In cytosol)

24.  Tyrosine hydroxylase:
 Tyrosine is hydroxylated to 3,4-
dihydroxyphenylalanine (DOPA)
by tyrosine hydroxylase.
 It is a rate limiting enzyme &
requires tetrahydrobiopterin as
coenzyme.

25.  DOPA-decarboxylase:
 DOPA undergoes PLP-dependent
decarboxylation to give dopamine.
 In Parkinsonism, the dopamine content
in brain is reduced.
 As dopamine will not enter into the brain
cells, the precursor, L-DOPA is used as a
drug in Parkinsonism.
 Alpha methyl DOPA will inhibit DOPA
decarboxylase & prevent production of
epinephrine; so it is an antihypertensive
drug

26.  Dopamine from cytosol enters Chromaffin
granules of Pheochromocytes or granulated
vesicles of brain cells or nerve endings.
 Dopamine is hydroxylated to
Norepinephrine by the enzyme Dopamine-
β-hydroxylase, a Copper-containing
enzyme.
 Vit C is required for the reaction.

27.  Nor-epinephrine comes out of the chromaffin
granules into cytosol, where it is methylated.
 CH3 group is donated by “active” methionine
(S adenosyl methionine) and the enzyme
catalyzing the reaction is N-methyl
transferase.
 This reaction does not take place in nerve
cells, where synthesis stops at Norepinephrine
stage.
 Epinephrine after synthesis in cytosol moves
back to chromaffin granules, where it is stored

28.  Increases in blood pressure
 Adrenaline also increases the rate & force of myocardial
contraction.
 Epinephrine causes relaxation of smooth muscles of bronchi
 Adrenaline is anti-insulin in nature, it increases
glycogenolysis & stimulates lipolysis.
 Adrenaline is released from adrenal medulla in response to
flight, fight, exercise and hypoglycemia

29.  The half-life of epinephrine is 2-5 minutes.
 Epinephrine is catabolized in tissues, by catechol-O-methyl
transferase (COMT) to metanephrine.
 It is then acted upon by mono amine oxidase (MAO).
 MAO will oxidatively deaminate metanephrine.
 The major end product is 3-hydroxy-4- methoxy mandelic acid or
vanillyl mandelic acid (VMA).
 Normally VMA is excreated 2-6 mg/24 hrs
 VMA is Increased in pheochromocytoma and neuroblastoma

31. 1.Phenylketonuria (PKU)
2.Tyrosinemia type II
3.Neonatal tyrosinemia (Tyrosinemia type III)
4.Alkaptonuria
5.Tyrosinemia type I
6.Albinism

33.  Most common metabolic disorder in amino acid metabolism
 Type I Hyper phenylalaninemia
 Autosomal recessive with Incidence of PKU is 1 in 10,000 births
 Due to deficiency of the hepatic enzymes, phenylalanine hydroxylase,
encoded by the PAH gene
 Defect in dihydrobiopterin reductase is also reported
 PKU primarily causes the accumulation of phenylalanine in tissues
and blood & excretion in urine

34. Pregnant mothers with untreated PKU can
give birth to children with severe defects
 congenital malformations
 microcephaly
 severe mental retardation
 Careful treatment with diet is compatible
with normal outcome for fetus

35.  Alternative pathway for
catabolism of phenylalnine in
phenylaketonuria.
phenypyruvate,
phenylacetate,
phenyllactate and
phenylglutamine

36. 1.Effect on CNS
 Mental retardation, failure to walk or talk, failure of
growth, seizures and tremor
 Hypotyrosinemia:low[tyrosine],low neurotransmitters
 (loss of biogenic amines at critical stages in postnatal
brain maturation)
 Defective brain myelination (chronic and irreversible)

37. 2. Effect on pigmentation
• Melanin is the pigment synthesized from tyrosine by
tyrosinase
• Accumulation of phenylalanine competitively inhibits
tyrosinase and impairs melanin formation
• The result is hypopigmentation that causes light skin
color, fair hair, blue eyes
3. Elevated levels of phenylalnine, phenylpyruvate,
phenylactate and phenylacetate are found in plasma
& urine giving mousey odor

38.  Normal level in newborns: 1 -2 mg/dl
 PKU: >20 mg/dl
 Guthrie test: performed after the baby is
fed with breast milk for a couple of days.
 Bacterial growth(Bacillus subtilis) is
proportional to the phenylalanine content
in the patient’s blood.
• Phenylpyruvate in urine can be detected by ferric chloride test (green color) –
non specific test
• Tandem mass spectrometry (MS/MS). Measurements done using MS/MS
determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio
will be elevated in PKU.

39.  Richner-Hanhart syndrome
 Defect in enzyme tyrosine
transaminase
 Results in blockage in the
routine degradative pathway
of tyrosine
 Characterized by skin and
eye lesions as well as
neurologic problems

41.  Caused by absence of enzyme p-hydoxyphenyl pyruvate
dioxygenase
 Mostly temporary condition and usually responds to ascorbic
acid
 Substrate inhibition of the enzyme is overcome by the presence
of ascorbic acid

42.  First described by Lusitanus in 1649
 Autosomal recessive disorder with 1 in 25,000 births
 Defective enzyme: homogentisate oxidase in tyrosine metabolism
 Homogentisate accumulates in tissues and blood and is excreted into
urine
 On standing, Homogentisate gets oxidized to corresponding
quinones, which polymerize to give black or brown color
 Urine resembles coke in color
 Chromatography for quanitification of Homogentisate

43.  Homogentisate gets oxidized by polyphenol oxidase to
benzoquinone acetate which undergoes polymerization to
produce a pigment called alkapton
 Deposition occurs in connective tissue, bones and various
organs (nose, ear) resulting in a condition known as ochronosis
 Arthritis; due to deposition of pigment alkaptons in the joints
 Treatment by consumption of protein diet with relatively low
phenylalanine content

45.  Due to deficiency of the enzymes: fumarylacetoacetate hydroxylase
 Rare but serious disorder
 Causes liver failure, rickets, renal tubular dysfunction and
polyneuropathy
 Tyrosine and its metabolites are excreted in urine
 In acute tyrosinosis, the infant exhibits diarrhea, vomiting and
cabbage-like odor
 Death may seen due to liver failure within 1 year

46.  Fumarylacetoacetate on reductioin form succinylacetoacetate
 Decarboxylation of succinylacetoacetate to Succinylacetone
 Accumulation of 5-aminolevulinic acid (ALA) as the result of
inhibition of ALA dehydratase by Succinylacetone,

47.  High succinylacetone levels (diagnostic). tyrosine
levels: normal or slightly elevated.
 Methionine: high
 Delta-aminolevulinic acid: high
 Alfa-feto protein: very high (marker of
hepatocellular carcinoma)

48.  Albino – white
 Inborn error due to lack of synthesis of the melanin pigment
 Defect in tyrosinase enzyme
 Autosomal recessive disorder with 1 in 20,000
Biochemical basis:
1.Deficiency or lack of the enzyme tyrosinase
2.Decrease in melanosomes of melanocytes
3.Impairment in melanin polymerization
4.Limitation of substrate (tyrosine) availability
5.Lack of protein matrix in melanosomes

49.  Types of Albinism
a) Oculocutaneous albinism:
 Decreased pigmentation of skin and eyes.
 They can be differentiated by clinical
presentation and biochemical and other features.
 Such ‘albinos’ can be biochemically of two types:
(i) ‘Tyrosinase’ negative albinos
(ii) ‘Tyrosinase’ positive albinos
b) Ocular albinism:
 Affects only eye and not the skin.
 Occurs both as autosomal recessive and as an X-
linked trait

50.  Lack of melanin pigments makes skin sensitive to sunlight
 Increased susceptibility to skin cancer
 Photophobia with lack of pigment in the eyes
Ocular
albinism
Oculocutaneous albinism Oculocutaneous albinism

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