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Methionine and serine formation in control and mutant human cultured fibroblasts: evidence for methyl trapping and characterization of remethylation defects.
[homocystinuria without methylmalonic aciduria]
The
conversion
of
labeled
formate
to
methionine
and
serine
,
as
a
measure
of
remethylation
of
homocysteine
to
methionine
and
folate
coenzyme
cycling
,
has
been
studied
in
control
and
mutant
human
fibroblasts
.
Fibroblasts
in
monolayer
culture
were
incubated
with
[
14
C
]
formate
,
and
labeled
methionine
sulfone
and
serine
were
determined
in
hydrolysates
of
oxidized
cell
proteins
.
In
control
cells
,
methionine
and
serine
were
clearly
measurable
(
n
=
21
,
1
.
7
-
5
.
5
and
2
.
4
-
9
.
7
nmol
/
mg
protein
/
16
h
,
respectively
)
.
In
contrast
,
methionine
formation
was
reduced
in
cells
from
patients
with
methylenetetrahydrofolate
reductase
(
MR
)
deficiency
(
MR
mutant
,
n
=
11
,
0
.
05
-
0
.
44
)
,
combined
methylmalonic
aciduria
/
homocystinuria
[
cobalamin
(
cbl
)
C
/
D
mutant
,
n
=
12
,
0
.
014
-
0
.
13
)
,
and
methionine
synthase
deficiency
(
MS
mutant
,
n
=
3
,
0
.
04
-
0
.
23
)
.
Furthermore
,
serine
formation
was
low
in
cblC
/
D
mutant
(
0
.
08
-
0
.
98
)
and
MS
mutant
(
0
.
17
-
0
.
94
)
cells
,
but
normal
or
high
in
MR
mutant
cells
(
5
.
2
-
11
.
4
)
.
Growth
of
cblC
/
D
mutant
cells
in
medium
supplemented
with
high
concentrations
of
hydroxo-cbl
resulted
in
significant
increases
of
both
methionine
and
serine
formation
.
Taken
together
these
findings
provide
clear
evidence
for
the
existence
of
the
formate
to
serine
pathway
described
by
W
.
B
.
Strong
and
V
.
Schirch
in
cultured
fibroblasts
and
indicate
that
disturbed
MS
function
due
to
a
specific
genetic
disorder
is
associated
with
reduced
serine
formation
in
vitro
,
which
reflects
availability
of
reduced
folate
coenzymes
.
The
correction
of
this
defect
by
vitamin
B
12
alone
,
in
cblC
/
D
mutant
cell
lines
,
correlates
well
with
the
clinical
response
in
the
patients
and
fits
in
well
with
the
idea
that
reduced
availability
of
folate
coenzymes
occurs
in
functional
MS
deficiency
,
in
agreement
with
the
methyl
trap
hypothesis
.
Diseases
Validation
Diseases presenting
"a specific genetic disorder is"
symptom
homocystinuria without methylmalonic aciduria
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