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A random Abstract
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Our Team
Structural basis of multifunctionality in a vitamin B12-processing enzyme.
[homocystinuria without methylmalonic aciduria]
An
early
step
in
the
intracellular
processing
of
vitamin
B
(
12
)
involves
CblC
,
which
exhibits
dual
reactivity
,
catalyzing
the
reductive
decyanation
of
cyanocobalamin
(
vitamin
B
(
12
)
)
,
and
the
dealkylation
of
alkylcobalamins
(
e
.
g
.
methylcobalamin
;
MeCbl
)
.
Insights
into
how
the
CblC
scaffold
supports
this
chemical
dichotomy
have
been
unavailable
despite
it
being
the
most
common
locus
of
patient
mutations
associated
with
inherited
cobalamin
disorders
that
manifest
in
both
severe
homocystinuria
and
methylmalonic
aciduria
.
Herein
,
we
report
structures
of
human
CblC
,
with
and
without
bound
MeCbl
,
which
provide
novel
biochemical
insights
into
its
mechanism
of
action
.
Our
results
reveal
that
CblC
is
the
most
divergent
member
of
the
NADPH-dependent
flavin
reductase
family
and
can
use
FMN
or
FAD
as
a
prosthetic
group
to
catalyze
reductive
decyanation
.
Furthermore
,
CblC
is
the
first
example
of
an
enzyme
with
glutathione
transferase
activity
that
has
a
sequence
and
structure
unrelated
to
the
GST
superfamily
.
CblC
thus
represents
an
example
of
evolutionary
adaptation
of
a
common
structural
platform
to
perform
diverse
chemistries
.
The
CblC
structure
allows
us
to
rationalize
the
biochemical
basis
of
a
number
of
pathological
mutations
associated
with
severe
clinical
phenotypes
.
