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The activity of wild type and mutant phenylalanine hydroxylase with respect to the C-oxidation of phenylalanine and the S-oxidation of S-carboxymethyl-L-cysteine.
[classical phenylketonuria]
The
involvement
of
the
enzyme
,
phenylalanine
hydroxylase
(
PAH
)
,
in
the
S-
oxidation
of
S-
carboxymethyl-
L-
cysteine
(
SCMC
)
is
now
firmly
established
in
man
and
rat
.
However
,
the
underlying
role
of
the
molecular
genetics
of
PAH
in
dictating
and
influencing
the
S-
oxidation
polymorphism
of
SCMC
metabolism
is
as
yet
unknown
.
In
this
work
we
report
that
the
S-
oxidation
of
SCMC
was
dramatically
reduced
in
the
tetrahydrobiopterin
(
BH
(
4
)
)
responsive
mutant
PAH
proteins
(
I
65
T
,
R
68
S
,
R
261
Q
,
V
388
M
and
Y
414
C
)
with
these
enzymes
possessing
between
1
.
2
%
and
2
.
0
%
of
the
wild
type
PAH
activity
when
SCMC
was
used
as
substrate
.
These
same
mutant
proteins
express
between
23
%
and
76
%
of
the
wild
type
PAH
activity
when
phenylalanine
was
used
as
the
substrate
.
The
PAH
mutant
proteins
(
R
158
Q
,
I
174
T
and
R
408
W
)
that
result
in
the
classical
phenylketonuria
(
PKU
)
phenotype
expressing
0
.
2
-
1
.
8
%
of
the
wild
type
PAH
activity
when
using
phenylalanine
as
substrate
were
found
to
have
<
0
.
1
%
of
the
wild
type
PAH
activity
when
SCMC
was
used
as
the
substrate
.
Mutations
that
result
in
PAH
proteins
retaining
some
residual
PAH
activity
with
phenylalanine
as
substrate
have
<
2
.
0
%
residual
activity
when
SCMC
was
used
as
a
substrate
.
This
investigation
has
led
to
the
hypothesis
that
the
S-
oxidation
polymorphism
in
man
is
a
consequence
of
an
individual
carrying
one
mutant
PAH
allele
which
has
resulted
in
the
loss
of
the
ability
of
the
residual
PAH
protein
to
undertake
the
S-
oxidation
of
SCMC
in
vivo
.
Diseases
Validation
Diseases presenting
"the classical phenylketonuria"
symptom
classical phenylketonuria
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