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Alkyl-dihydroxyacetonephosphate synthase. Fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency.
[neonatal adrenoleukodystrophy]
Peroxisomes
play
an
indispensible
role
in
ether
lipid
biosynthesis
as
evidenced
by
the
deficiency
of
ether
phospholipids
in
fibroblasts
and
tissues
from
patients
suffering
from
a
number
of
peroxisomal
disorders
.
Alkyl-dihydroxyacetonephosphate
synthase
,
a
peroxisomal
enzyme
playing
a
key
role
in
the
biosynthesis
of
ether
phospholipids
,
contains
the
peroxisomal
targeting
signal
type
2
in
a
N-
terminal
cleavable
presequence
.
Using
a
polyclonal
antiserum
raised
against
alkyl-dihydroxyacetonephosphate
synthase
,
levels
of
this
enzyme
were
examined
in
fibroblast
cell
lines
from
patients
affected
by
peroxisomal
disorders
.
Strongly
reduced
levels
were
found
in
fibroblasts
of
Zellweger
syndrome
and
rhizomelic
chondrodysplasia
punctata
patients
,
indicating
that
the
enzyme
is
not
stable
in
the
cytoplasm
as
a
result
of
defective
import
into
peroxisomes
.
In
a
neonatal
adrenoleukodystrophy
patient
with
an
isolated
import
deficiency
of
proteins
carrying
the
peroxisomal
targeting
signal
type
1
,
the
precursor
form
of
alkyl-dihydroxyacetonephosphate
synthase
was
detected
at
a
level
comparable
to
that
of
the
mature
form
in
control
fibroblasts
,
in
line
with
an
intraperoxisomal
localization
.
A
patient
with
an
isolated
deficiency
in
alkyl-dihydroxyacetonephosphate
(
DHAP
)
synthase
activity
had
normal
levels
of
this
protein
.
Analysis
at
the
cDNA
level
revealed
a
missense
mutation
leading
to
a
R
419
H
substitution
in
the
enzyme
of
this
patient
.
Expression
of
a
recombinant
protein
carrying
this
mutation
in
Escherichia
coli
yielded
an
inactive
enzyme
,
whereas
a
comparable
control
recombinant
enzyme
was
active
,
providing
further
proof
that
this
substitution
is
responsible
for
the
inactivity
of
the
enzyme
and
the
phenotype
.
In
line
with
this
result
is
the
observation
that
wild-
type
alkyl-
DHAP
synthase
activity
can
be
inactivated
by
the
arginine-modifying
agent
phenylglyoxal
.
The
enzyme
is
efficiently
protected
against
this
inactivation
when
the
substrate
palmitoyl-
DHAP
is
present
at
a
saturating
concentration
.
The
gene
encoding
human
alkyl-dihydroxyacetonephosphate
synthase
was
mapped
on
chromosome
2
q
31
.