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Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism.
[primary hyperoxaluria type 1]
PH
1
(
primary
hyperoxaluria
type
1
)
is
a
severe
inborn
disorder
of
glyoxylate
metabolism
caused
by
a
functional
deficiency
of
the
peroxisomal
enzyme
AGXT
(
alanine-glyoxylate
aminotransferase
)
,
which
converts
glyoxylate
into
glycine
using
L-
alanine
as
the
amino-group
donor
.
Even
though
pre-genomic
studies
indicate
that
other
human
transaminases
can
convert
glyoxylate
into
glycine
,
in
PH
1
patients
these
enzymes
are
apparently
unable
to
compensate
for
the
lack
of
AGXT
,
perhaps
due
to
their
limited
levels
of
expression
,
their
localization
in
an
inappropriate
cell
compartment
or
the
scarcity
of
the
required
amino-group
donor
.
In
the
present
paper
,
we
describe
the
cloning
of
eight
human
cytosolic
aminotransferases
,
their
recombinant
expression
as
His
6
-
tagged
proteins
and
a
comparative
study
on
their
ability
to
transaminate
glyoxylate
,
using
any
standard
amino
acid
as
an
amino-group
donor
.
To
selectively
quantify
the
glycine
formed
,
we
have
developed
and
validated
an
assay
based
on
bacterial
GO
(
glycine
oxidase
)
;
this
assay
allows
the
detection
of
enzymes
that
produce
glycine
by
transamination
in
the
presence
of
mixtures
of
potential
amino-group
donors
and
without
separation
of
the
product
from
the
substrates
.
We
show
that
among
the
eight
enzymes
tested
,
only
GPT
(
alanine
transaminase
)
and
PSAT
1
(
phosphoserine
aminotransferase
1
)
can
transaminate
glyoxylate
with
good
efficiency
,
using
L-
glutamate
(
and
,
for
GPT
,
also
L-
alanine
)
as
the
best
amino-group
donor
.
These
findings
confirm
that
glyoxylate
transamination
can
occur
in
the
cytosol
,
in
direct
competition
with
the
conversion
of
glyoxylate
into
oxalate
.
The
potential
implications
for
the
treatment
of
primary
hyperoxaluria
are
discussed
.
Diseases
Validation
Diseases presenting
"standard amino acid as an amino-group donor"
symptom
primary hyperoxaluria type 1
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