section 17.3
Metabolism of Some Individual Amino Acids
n h
R -g ro u p
5 ,6 ,7 ,8 -T e tra h y d ro b io p te rin
P ara -q u in o n o id
d ihydrop teridin e
O rtho-q u in o n o id
d ihydrop teridin e
"Q uinonoid" dihydrob iopterins
7,8-D ih yd ro b io p terin
FIGURE 17-21
Structures of biopterin derivatives.
a heel prick onto filter paper. Treatment of phenylalanine
hydroxylase deficiency consists of a diet low in pheny-
lalanine but which maintains normal nutrition. This diet
is effective in preventing mental retardation, and its con-
In the
o H
CH,— C— N— CH
Phenylacety (glutamine
FIGURE 17-22
Formation of metabolites of phenylalanine that accumulate in abnormal
amounts and are excreted in phenylketonuria.
tinuation throughout the first decade, or for life, may be
Treatment of biopterin and biopterin reductase defi-
ciency consists not only of regulating the blood levels of
phenylalanine but of supplying the missing form of coen-
zyme and the precursors of neurotransmitters, namely,
dihydroxyphenylalanine and 5-hydroxytryptophan, along
with a compound that inhibits peripheral aromatic de-
carboxylation. This compound is necessary because the
amine products do not cross the blood-brain barrier.
Successfully treated females who have reached repro-
ductive age may expose their offspring (who are obli-
gate heterozygotes) to abnormal embryonic and fetal de-
velopment. These effects include spontaneous abortion,
microcephaly, congenital heart disease, and intrauterine
growth retardation, and they correlate with the plasma
level of phenylalanine of the pregnant mother. Thus,
reinstitution of a low-phenylalanine diet during pre-
and postconception periods may be necessary. The diet
should also restrict intake of phenylalanine-containing
substances, such as the synthetic sweetener aspartame (
l -
aspartyl-L-phenylalanyl methyl ester). Because defective
myelination occurs in the brain in PKU, there is an in-
creased incidence of epileptic seizures and abnormal elec-
troencephalograms are common. The biochemical basis
for the severe mental impairment is not understood. One
factor may be inhibition of glutamate decarboxylase by
phenylpyruvate and phenylacetate:
~OOC— (CH2)2—CH—
Glutamate decarboxylase
C 02
~OOC— (CH2)3— NH3+
The substrate is an excitatory neurotransmitter and the
product an inhibitory one in the central nervous system. •
Abnormal indole derivatives in the urine and low
levels of serotonin (a product of tryptophan metabolism) in
blood and brain point to a defect in tryptophan metabolism
in PKU.
5-Hydroxytryptophan decarboxylase,
of 5-hydroxytryptophan to
serotonin, is inhibited
in vitro
by some of the metabolites
of phenylalanine. Phenylalanine hydroxylase is similar to
the enzyme that catalyzes the hydroxylation of tryptophan
to 5-hydroxytryptophan, a precursor of serotonin.
In vitro,
phenylalanine is also found to inhibit the hydroxylation of
tryptophan. The mental defects associated with PKU may
be caused by decreased production of serotonin. High
phenylalanine levels may disturb the transport of amino
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