Seven Amino Acids Are

Degraded to Acetyl-CoA

Dr. Nikhat Siddiqi

 All the amino acids that form pyruvate can

also form acetyl CoA via pyruvate
dehydrogenase.
In addition portions of the carbon
skeletons of seven amino acids
tryptophan, lysine, phenylalanine,
tyrosine, leucine, isoleucine, and
threonineyield acetyl-CoA and/or
acetoacetyl-CoA, the latter being
converted to acetyl-CoA.
Dr. Nikhat Siddiqi

Catabolic pathways for tryptophan, lysine,

phenylalanine,
tyrosine, leucine, and isoleucine

Dr. Nikhat Siddiqi

Phenylalanine
Phenylalanine and its oxidation product tyrosine (both with
nine carbons) are degraded into two fragments, both of
which can enter the citric acid cycle: four of the nine carbon
atoms yield free acetoacetate, which is converted to
acetoacetyl-CoA and thus acetyl-CoA, and a second fourcarbon fragment is recovered as fumarate.
Eight of the nine carbons of these two amino acids thus enter
the citric acid cycle; the remaining carbon is lost as CO2.
Phenylalanine, after its hydroxylation to tyrosine, is also the
precursor of dopamine, a neurotransmitter, and of
norepinephrine and epinephrine, hormones secreted by the
adrenal medulla.
Melanin, the black pigment of skin and hair, is also derived
from tyrosine.
Dr. Nikhat Siddiqi

Phenylalanine

Dr. Nikhat Siddiqi

 Phenylalanine is hydroxylated to tyrosine by phenylalanine

hydroxylase.
Phenylalanine hydroxylase (also called phenylalanine-4monooxygenase) is one of a general class of enzymes
called mixed-function oxidases, all of which catalyze
simultaneous hydroxylation of a substrate by an oxygen
atom of O2 and reduction of the other oxygen atom to H2O.
Phenylalanine hydroxylase requires the cofactor
tetrahydrobiopterin, which carries electrons from NADH to
O2 and becomes oxidized to dihydrobiopterin in the
process. It is subsequently reduced by the enzyme
dihydrobiopterin reductase in a reaction that
requires NADH.

Dr. Nikhat Siddiqi

Dr. Nikhat Siddiqi

Phenylketonuria
A genetic defect in phenylalanine
hydroxylase, the first enzyme in
the catabolic pathway for
phenylalanine, is responsible for the
disease phenylketonuria (PKU),
the most common cause of elevated
levels of phenylalanine
(hyperphenylalaninemia).
Dr. Nikhat Siddiqi

Phenylketonuria
In individuals with PKU, a secondary, normally little-used pathway
of phenylalanine metabolism comes into play.
In this pathway phenylalanine undergoes transamination with
pyruvate to yield phenylpyruvate.
Phenylalanine and phenylpyruvate accumulate in the blood and
tissues and are excreted in the urinehence the name
phenylketonuria.
Much of the phenylpyruvate, rather than being excreted as such,
is either decarboxylated to phenylacetate or reduced to
phenyllactate.
Phenylacetate imparts a characteristic odor to the urine, which
nurses have traditionally used to detect PKU in infants.
The accumulation of phenylalanine or its metabolites in early life
impairs normal development of the brain, causing severe mental
retardation.
Dr. Nikhat Siddiqi

Alternative pathways for catabolism of

phenylalanine in phenylketonuria

Dr. Nikhat Siddiqi

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Phenylketonuria
Phenylketonuria can also be caused
by a defect in the enzyme that
catalyzes the regeneration of
tetrahydrobiopterin.

Dr. Nikhat Siddiqi

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Alkaptonuria
Another inheritable disease of
phenylalanine catabolism is
alkaptonuria, in which the defective
enzyme is homogentisate
dioxygenase.
Less serious than PKU, this condition
produces few ill effects, although large
amounts of homogentisate are excreted
and its oxidation turns the urine black.
Dr. Nikhat Siddiqi

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Alkaptonuria
Alkaptonuria is of considerable historical
interest.
Archibald Garrod discovered in the early 1900s
that this condition is inherited, and he traced
the cause to the absence of a single enzyme.
Garrod was the first to make a connection
between an inheritable trait and an enzyme, a
great advance on the path that ultimately led
to our current understanding of genes and the
information pathways.
Dr. Nikhat Siddiqi

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Tyrosine
Transamination of tyrosine to phydroxyphenylpyruvate is catalyzed
by tyrosine -ketoglutarate
transaminase (tyrosine
aminotransferase).
P-hydroxyphenylpyruvate forms
homogentisate catalysed by phydroxyphenylpyruvate dioxygenase
where ascorbic acid is the reductant.
Dr. Nikhat Siddiqi

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 Homogentisate oxidase opens the aromatic

ring to form maleylacetoacetate.
Isomerization of maleylacetoacetate-cis,
trans isomerase resulting in the formation
of fumarylacetoacetate.
Hydrolysis of fumarylacetoacetate forms
fumarate and acetoacetate catalysed by
fumarylacetoacetate hydrolase.
The acetoacetate forms acetyl CoA plus
acetate catalyzed by -ketothiolase.
Dr. Nikhat Siddiqi

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Tyrosine

Dr. Nikhat Siddiqi

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Metabolic defects
Refer to the enzymes in the figure.

Dr. Nikhat Siddiqi

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Tryptophan
Tryptophan breakdown is the most complex of
all the pathways of aminoacid catabolism in
animal tissues; portions of tryptophan (four of
its carbons) yield acetyl-CoA via acetoacetylCoA.
Some of the intermediates in tryptophan
catabolism are precursors for the synthesis of
other biomolecules, including nicotinate, a
precursor of NADand NADP in animals;
serotonin, a neurotransmitter in vertebrates;
and indoleacetate, a growth factor in plants.
Dr. Nikhat Siddiqi

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Catabolic pathways for tryptophan, lysine,

phenylalanine,
tyrosine, leucine, and isoleucine

Dr. Nikhat Siddiqi

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Tryptophan
Tryptophan oxygenase catalyzes cleavage
ofindole ring with incorporation of two
atoms of molecular oxygen forming Nformylkynurenine.
Hydrolytic removal of formyl group of Nformylkynurenine catalyzed by kynurenine
formylase of mammalian liver produces
kynurenine.
Further metabolism yields -keto adipate
which is converted to acetoacetyl CoA.
Dr. Nikhat Siddiqi

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Tryptophan

Dr. Nikhat Siddiqi

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 Kynurenine and hydroxykynurenine

are converted to hydroxyanthranilate
by kynureninase, a pyridoxal
phosphate enzyme.
Hartnup disease, an autosomal
recessive trait results in defective
intestinal and renal transport of
neutral amino acids including
tryptophan
Dr. Nikhat Siddiqi

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Tryptophan as precursor

Dr. Nikhat Siddiqi

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Lysine
Lysine is an entirely ketogenic amino
acid.
There is an initial transamination of
the -amino group which requires ketoglutarate as the acceptor and
cosubstrate.
The resulting compound is ketoadipate which forms acetoacetyl
CoA.
Dr. Nikhat Siddiqi

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Leucine
Leucine and isoleucine also give
acetyl CoA. More details will be
explained in branched chain amino
acid catabolism.

Dr. Nikhat Siddiqi

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Dr. Nikhat Siddiqi

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