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Consequences of missense mutations for dimerization and turnover of alanine:glyoxylate aminotransferase: study of a spectrum of mutations.
[primary hyperoxaluria type 1]
Alanine
:
glyoxylate
aminotransferase
(
AGT
)
is
a
liver
peroxisomal
enzyme
,
deficiency
of
which
results
in
primary
hyperoxaluria
type
1
(
PH
1
)
.
More
than
65
PH
1
-
related
mutations
are
now
documented
in
the
AGT
gene
(
AGXT
)
,
of
which
about
50
%
are
missense
.
We
have
generated
a
spectrum
of
15
missense
changes
including
the
most
common
PH
1
mutation
,
G
170
R
,
and
expressed
them
on
the
appropriate
background
of
the
major
or
minor
allele
,
in
an
Escherichia
coli
overexpression
system
and
in
a
rabbit
reticulocyte
transcription
/
translation
system
.
We
have
investigated
their
effects
on
enzyme
activity
,
dimerization
,
aggregation
,
and
turnover
.
The
effect
of
pyridoxal
phosphate
(
PLP
)
on
dimerization
and
stability
was
also
investigated
.
Although
all
15
mutant
AGTs
were
expressed
as
intact
proteins
in
E
.
coli
,
only
three
:
G
41
R
and
G
41
V
on
the
major
allele
,
and
the
common
mutation
G
170
R
,
resulted
in
significant
amounts
of
enzymatic
activity
.
Dimerization
failure
was
a
frequent
observation
(
13
/
15
)
except
for
G
41
V
and
D
183
N
.
Dimerization
was
poor
with
S
187
F
but
was
substantially
improved
with
PLP
.
Proteasome-mediated
protein
degradation
was
observed
for
all
the
mutations
except
G
41
R
on
the
major
allele
,
G
41
V
,
D
183
N
,
G
170
R
,
and
S
218
L
.
Increases
in
the
stability
of
the
mutant
enzymes
in
the
presence
of
PLP
were
small
;
however
,
G
41
R
on
the
minor
allele
showed
a
direct
relationship
between
its
half
life
and
the
concentration
of
PLP
.
The
minor
allele
AGT
product
and
many
of
the
mutants
were
subject
to
a
limited
non-proteasomal
proteolytic
cleavage
when
ATP
was
depleted
.
Diseases
Validation
Diseases presenting
"limited non-proteasomal proteolytic cleavage"
symptom
primary hyperoxaluria type 1
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