Metabolism of
phenylalanine & tyrosine
Objective
• At the end of this lecture, student
will be able to
– Explain the metabolism of phenylalanine
& tyrosine and their metabolic disorders
Metabolism of phenylalanine
& tyrosine
• Phenylalanine and tyrosine are structurally
related aromatic amino acids
• Phenylalanine is an essential amino
acid while tyrosine is non-essential
• Besides its incorporation into
proteins, the only function of phenyl alanine is its conversion to tyrosine
• For this reason, ingestion of tyrosine
can reduce the dietary requirement of phenylalanine
• This phenomenon is referred to as
‘sparing action’ of tyrosine on
phenylalanine
Biosynthesis (conversion of Phenylalanine and Tyrosine)
• Degradation of phenylalanine mostly
occurs through tyrosine
• Phenylalanine is hydroxylated at
para-position by phenylalanine hydroxylase to produce tyrosine(
p-hydroxyphenylalanine)
• This is an irreversible reaction
and require phenylalanine hydroxylase
and specific coenzyme biopterin, which is structurally related to folate
• The active form of biopterin is
tetrahydrobiopterin
• In the phenylalanine hydroxylase
reaction, tetrahydrobiopterin is oxidized to dihydrobiopterin
• Tetrahydrobiopterin is regenerated
by NADPH-dependent dihydrobiopterin reductase
• The enzyme phenylalanine hydroxylase
(liver) convert phenylalanine to tyrosine, the reaction involves the
incorporation of one atom of molecular oxygen (O2) into the para
position of phenylalanine while the other atom of O2 is reduced to
form water
• Tetrahydrobiopterin that supplies
the reducing equivalents which, in turn, are provided by NADPH
• Defect in phenylalanine hydroxylase
leads to phenylketonuria (PKU)
DISORDERS OF TYROSINE
(PHENYLALANINE) METABOLISM
• Phenylketonuria: Defective
phenylalanine hydroxylase
• Tyrosinemia type II: Defective Tyrosine
transaminase
• Neonatal tyrosinemia: Defective
p-hydroxyphenyl pyruvate dioxygenase (Tyrosinemia type III)
• Alkaptonuria: defective homogentisate
oxidase
• Tyrosinemia type I: Defective
fumarylacetoacetate hydroxylase and/or maleyl acetoacetate isomerase
• Albinism: Defective tyrosinase
Metabolic disorders
Phenylketonuria (PKU)
• Deficiency
of phenylalanine hydroxylase – classical
• New
variant – due to deficiency of dihydrobiopterin reductase
• Mental
retardation
• Effect
on pigmentation
• Treatment-
Dietary approach
Tyrosinemia type II:
• Very
rare
• Herpetiformic
keratitis
• Palmoplanter
hyperkeratosis with ulcers
• PMR,
growth retardation
• Dietary
treatment
• Richner-Hanhart
syndrome
• Defective
enzyme: tyrosine transaminase
• Accumulation
of tyrosine and its metabolites
• Skin
(dermatitis) and eye lesions
• Mental
retardation
Neonatal Tyrosinemia
• Absence
of p-hydroxyl phenyl pyruvate dioxygenase
• Well
responded to ascorbic acid therapy
Tyrosinemia type 1
• Deficiency
of fumarylacetoacetyl hydroxylase and/or maleylacetoacetyl isomerase
• Causes:
• Liver
failure
• Poly
neuropathy
• Rickets
• Renal
tubular dysfunction
Alkaptonuria
• Deficiency
of Homogentisate oxidase
Albinism
• Lack
of synthesis of pigment melanin
• Defect
in tyrosinase-enzyme responsible for synthesis of melanin
• Deficiency
or lack of the enzyme tyrosinase.
• Decrease
in melanosomes of melanocytes.
• Impairment
in melanin polymerization.
• Lack
of protein matrix in melanosomes.
• Limitation
of substrate (tyrosine) availability.
• Presence
of inhibitors of tyrosinase.
Summary
• Children
with Alkaptonuria are asymptomatic, besides producing brown or black urine
• Treatment
for classic PKU is a strict PHE-restricted diet supplemented by a medical
formula containing amino acids and other nutrients