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Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria.
[homocystinuria without methylmalonic aciduria]
Patients
with
the
cblC
vitamin
B
(
12
)
(
cobalamin
,
cbl
)
disorder
are
defective
in
the
intracellular
synthesis
of
adenosylcobalamin
and
methylcobalamin
and
have
combined
homocystinuria
and
methylmalonic
aciduria
.
While
other
vitamin
B
(
12
)
disorders
are
treatable
with
high
dose
cyanocobalamin
(
CNCbl
)
or
hydroxocobalamin
(
OHCbl
)
,
cblC
patients
respond
well
to
OHCbl
but
not
to
CNCbl
.
Patient
mutations
were
introduced
into
recombinant
MMACHC
(
cblC
)
protein
and
the
binding
of
CNCbl
and
OHCbl
was
examined
.
Three
mutations
were
analyzed
:
G
147
D
,
associated
with
early
onset
,
vitamin
B
(
12
)
unresponsive
disease
;
R
161
Q
,
associated
with
late
onset
disease
that
is
highly
responsive
to
OHCbl
;
and
H
122
A
,
selected
to
test
the
hypothesis
that
H
122
is
central
to
a
proposed
vitamin
B
(
12
)
binding
motif
on
MMACHC
.
We
report
here
that
wild-
type
MMACHC
binds
both
OHCbl
and
CNCbl
with
similar
,
tight
affinity
(
K
(
d
)
=
5
.
7
microM
)
.
We
also
report
that
MMACHC
binds
CNCbl
in
the
base-off
form
,
with
the
dimethylbenzimidazole
(
DMB
)
base
of
cobalamin
displaced
from
coordination
with
the
cobalt
.
In
this
form
,
wild-
type
MMACHC
is
able
to
reductively
decyanate
CNCbl
to
cob
(
II
)
alamin
requiring
only
the
presence
of
NADPH
and
FAD
.
We
demonstrate
that
MMACHC
with
the
G
147
D
mutation
is
unable
to
bind
either
CNCbl
or
OHCbl
,
providing
a
straight
forward
explanation
for
the
absence
of
response
to
either
vitamin
form
.
However
,
we
show
that
MMACHC
containing
the
R
161
Q
mutation
binds
OHCbl
with
wild-
type
affinity
,
but
is
disturbed
in
binding
CNCbl
and
has
impaired
decyanation
.
Finally
,
we
show
that
H
122
A
has
reduced
binding
,
but
like
R
161
Q
,
it
binds
OHCbl
more
tightly
than
CNCbl
,
suggesting
that
this
histidine
is
not
absolutely
required
for
binding
.
These
studies
suggest
that
the
ability
of
mutant
MMACHC
to
respond
to
vitamin
therapy
depends
on
its
ability
to
bind
the
vitamin
with
significant
affinity
,
and
for
CNCbl
,
also
on
its
ability
to
bind
in
the
base-off
form
to
facilitate
reductive
decyanation
.
These
studies
emphasize
the
continued
use
of
OHCbl
with
cblC
patients
for
maximum
therapeutic
effect
.
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"early onset"
symptom
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