PHENYLALANINE METABOLISM

2.  It is aromatic & essential amino acid.
 Both Glucogenic & Ketogenic.
 Phenylalanine is converted to tyrosine.
 Referred to as 'sparing action' of tyrosine
on phenylalanine.

3.  Predominant metabolism of phenylalanine
occurs through tyrosine.
 Tyrosine is incorporated into proteins & is
involved in the synthesis of variety of
biologically important compounds-
epinephrine, norepinephrine, dopamine,
thyroid hormones & the pigment melanin.

4.  Degradation of phenylalanine mostly occurs
through tyrosine.
 Phenylalanine is hydroxylated at para-
position by phenylalanine hydroxylase to
produce tyrosine.
 This reaction is irreversible, & requires
specific coenzyme biopterin, which is
structurally related to folate.

5.  Active form of biopterin is tetrahydrobiopterin.
 Tetrahydrobiopterin is oxidized to
dihydrobiopterin.
 Tetrahydrobiopterin is then regenerated by an
NADPH-dependent dihydrobiopterin
reductase.
 Phenylalanine hydroxylase is present in liver.

6.  In the conversion of phenylalanine to
tyrosine, the reaction involves incorporation
of one atom of molecular oxygen into para-
position of phenylalanine while the other
atom O2 is reduced to form water.
 Tetrahydrobiopterin supplies reducing
equivalents.

9.  Phenylalanine is converted to tyrosine, a
single pathway is responsible for the
degradation of both these amino acids.
 Occurs mostly in liver.
 Tyrosine first undergoes transamination to P-
hydroxyphenyl pyruvate, catalyzed by
tyrosine transaminase (PLP dependent)

10.  p-hydroxy phenylpyruvate hydroxylase (or
dioxygenase) is a copper-containing
enzyme.
 It catalyzes oxidative decarboxylation as
well as hydroxylation of the phenyl ring of
p-hydroxy phenyl pyruvate to produce
homogentisate.

11.  This reaction involves a shift in hydroxyl
group from para position to meta position &
incorporates a new hydroxyl group at para
position to give 2,5-dihydroxyphenylacetic
acid or homogentisic acid.
 This step requires ascorbic acid.

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.

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 &
acetoacetate.
 Fumarate is an intermediate in citric acid
cycle & can serve as precursor for
gluconeogenesis.

15.  Acetoacetate is a ketone body from which
fat can be synthesized.
 Phenylalanine & tyrosine are both
glucogenic & ketogenic amino acids.

18.  Melanin is a pigment of skin, hair & 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.

19.  Tyrosinase hydroxylates tyrosine to form 3,4-
dihydroxy-phenylalanine (DOPA).
 DOPA can act as a cofactor for tyrosinase.
 DOPA is converted to dopaquinone by
tyrosinase.
 Dopaquinone in subsequent couple of
reactions occur spontaneously, forming
leucodopachrome followed by 5,6-dihydroxy
indole.

20.  The oxidation of 5,6-dihydroxyindole to indole
5,6-quinone is catalyzed by tyrosinase.
 DOPA serves as a cofactor.
 This reaction, inhibited by tyrosine regulates
the synthesis of melanin.
 Melanochromes are formed from indole
quinone, which on polymerization are
converted to black melanin.

21.  Another pathway:
 Cysteine condenses with dopaquinone & in the
next series of reactions results the synthesis of
red melanins.
 Melanin-the color pigment:
 The skin color of the individual is determined
by the relative concentrations of black & red
melanins.

22.  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.
 The presence of moles on the body represents
a localized severe hyperpigmentation due to
hyperactivity of melanocytes.

23.  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.

26.  Thyroid hormones - Thyroxine
(tetraiodothyronine) & triiodithyronine - are
synthesized from the tyrosine residues of
the protein thyroglobulin & activated iodine.

27.  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.

29.  Catecholamines are derived from tyrosine.
 The name catechol refers to the
dihydroxylated phenyl ring (catechol nucleus).
 The amine derivatives of catechol are called
catecholamines.

30.  Tyrosine is the precursor for the synthesis of
catecholamines, namely dopamine,
norepinephrine (noradrinaline) &
epinephrine (adrinaline)
 Conversion of tyrosine to catecholamines
occurs in adrenal medulla & central nervous
system.

31.  Tyrosine hydroxylase:
 Tyrosine is hydroxylated to 3,4-
dihydroxyphenylalanine (DOPA) by tyrosine
hydroxylase.
 It is a rate limiting enzyme & requires
tetrahydrobiopterin as coenzyme.
 In contrast to this enzyme, tyrosinase present
in melanocytes converts tyrosine to DOPA.

32.  Two different enzyme systems exist to convert
tyrosine to DOPA.
 DOPA-decarboxylase:
 DOPA undergoes PLP-dependent
decarboxylation to give dopamine.
 Dopamine is a catecholamine.
 Dopamine is an inhibitor of prolactin secretion
 Dopamine is neurotransmitter in substantia
nigra, extrapyramidal tract, & striatal tract.

33.  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.

34.  Nor epinephrine:
 Dopamine is further hydroxylated to nor-
epinephrine or noradrenaline
 The term “nor” denotes that the molecule
does not contain the "R" or methyl group.
 Methylation of norepinephrine by S-
adenosylmethionine gives epinephrine.

35.  Epinephrine:
 Nor-epinephrine is methylated by the
enzyme N-methyl transferase to epinephrine
or adrenaline.
 S-adenosyl methionine (SAM) is the methyl
donor.
 It is mainly produced by adrenal medulla &
adrenergic nerve endings.

36.  The difference between epinephrine &
norepinephrine is only a methyl group.
 In adrenal medulla, synthesis of the
hormones, norepinephrine & epinephrine is
prominent.
 Norepinephrine is produced in certain areas
of brain while dopamine is predominantly
synthesized in substantia nigra.

38.  They cause the increase in blood pressure.
 Adrenaline also increases the rate & force of
myocardial contraction.
 Adrenaline is anti-insulin in nature, it
increases glycogenolysis & stimulates
lipolysis.
 Serve as neurotransmitters in the brain ANS.

39.  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.

40.  The major end product is 3-hydroxy-4-
methoxy mandelic acid or vanillyl mandelic
acid (VMA).
 Homovanillic acid (HVA) in Urine:
 It is also called methoxy hydroxy phenyl
acetic acid.
 HVA is the main urinary metabolite of DOPA
& dopamine.

43.  Textbook of Biochemistry-u Satyanarayana
 Textbook of Biochemistry-DM Vasudevan