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Aspartoacylase catalytic deficiency as the cause of Canavan disease: a structural perspective.
[canavan disease]
Canavan
disease
(
CD
)
is
a
fatal
,
childhood
neurological
disorder
caused
by
mutations
in
the
ASPA
gene
,
leading
to
catalytic
deficiencies
in
the
aspartoacylase
(
ASPA
)
enzyme
and
impaired
N-
acetyl-l-aspartic
acid
metabolism
in
the
brain
.
To
study
the
possible
structural
defects
triggered
by
these
mutations
,
four
ASPA
missense
mutations
associated
with
different
disease
severities
have
been
structurally
characterized
.
These
mutant
enzymes
each
have
overall
structures
similar
to
that
of
the
native
ASPA
enzyme
,
but
with
varying
degrees
of
alterations
that
offer
explanations
for
the
respective
loss
of
catalytic
activity
.
The
K
213
E
mutant
,
a
nonconservative
mutant
associated
with
a
mild
disease
phenotype
,
has
minimal
structural
differences
compared
to
the
native
enzyme
.
In
contrast
,
the
loss
of
van
der
Waals
contacts
in
the
F
2
95
S
mutant
and
the
loss
of
hydrophobic
and
hydrogen
bonding
interactions
in
the
Y
231
C
mutant
lead
to
a
local
collapse
of
the
hydrophobic
core
structure
in
the
carboxyl-terminal
domain
,
contributing
to
a
decrease
in
protein
stability
.
The
structure
of
the
E
285
A
mutant
,
the
most
common
clinical
mutant
,
reveals
that
the
loss
of
hydrogen
bonding
interactions
with
the
carboxylate
side
chain
of
Glu
285
disturbs
the
active
site
architecture
,
leading
to
altered
substrate
binding
and
lower
catalytic
activity
.
Our
improved
understanding
of
the
nature
of
these
structural
defects
provides
a
basis
for
the
development
of
treatment
therapies
for
CD
.
Diseases
Validation
Diseases presenting
"has minimal structural differences compared to the native enzyme"
symptom
canavan disease
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