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Mutational analysis of aspartoacylase: implications for Canavan disease.
[canavan disease]
Mutations
that
result
in
near
undetectable
activity
of
aspartoacylase
,
which
catalyzes
the
deacetylation
of
N-
acetyl-l-aspartate
,
correlate
with
Canavan
Disease
,
a
neurodegenerative
disorder
usually
fatal
during
childhood
.
The
underlying
biochemical
mechanisms
of
how
these
mutations
ablate
activity
are
poorly
understood
.
Therefore
,
we
developed
and
tested
a
three
-dimensional
homology
model
of
aspartoacylase
based
on
zinc
dependent
carboxypeptidase
A
.
Mutations
of
the
putative
zinc-binding
residues
(
H
21
G
,
E
24
D
/
G
,
and
H
116
G
)
,
the
general
proton
donor
(
E
178
A
)
,
and
mutants
designed
to
switch
the
order
of
the
zinc-binding
residues
(
H
21
E
/
E
24
H
and
E
24
H
/
H
116
E
)
yielded
wild-
type
aspartoacylase
protein
levels
and
undetectable
ASPA
activity
.
Mutations
that
affect
substrate
carboxyl
binding
(
R
71
N
)
and
transition
state
stabilization
(
R
63
N
)
also
yielded
wild-
type
aspartoacylase
protein
levels
and
undetectable
aspartoacylase
activity
.
Alanine
substitutions
of
Cys
124
and
Cys
152
,
residues
indicated
by
homology
modeling
to
be
in
close
proximity
and
in
the
proper
orientation
for
disulfide
bonding
,
yielded
reduced
ASPA
protein
and
activity
levels
.
Finally
,
expression
of
several
previously
tested
(
E
24
G
,
D
68
A
,
C
152
W
,
E
214
X
,
D
249
V
,
E
285
A
,
and
A
305
E
)
and
untested
(
H
21
P
,
A
57
T
,
I
143
T
,
P
183
H
,
M
195
R
,
K
213
E
/
G
274
R
,
G
274
R
,
and
F
2
95
S
)
Canavan
Disease
mutations
resulted
in
undetectable
enzyme
activity
,
and
only
E
285
A
and
P
183
H
showed
wild-
type
aspartoacylase
protein
levels
.
These
results
show
that
aspartoacylase
is
a
member
of
the
caboxypeptidase
A
family
and
offer
novel
explanations
for
most
loss
-of-function
aspartoacylase
mutations
associated
with
Canavan
Disease
.
Diseases
Validation
Diseases presenting
"putative zinc-binding residues"
symptom
canavan disease
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