Cell Reports,
Год журнала:
2024,
Номер
43(11), С. 114976 - 114976
Опубликована: Ноя. 1, 2024
Core
components
of
the
N-glycosylation
pathway
are
known,
but
metabolic
and
post-translational
mechanisms
regulating
this
in
normal
disease
states
remain
elusive.
Using
a
multi-omic
approach
zebrafish,
we
discovered
mechanism
whereby
O-GlcNAcylation
directly
impacts
expression
abundance
two
rate-limiting
proteins
N-linked
glycosylation
pathway.
We
show
model
an
inherited
disorder
PMM2-CDG,
congenital
disorders
that
phosphomannomutase
deficiency
is
associated
with
increased
levels
UDP-GlcNAc
protein
O-GlcNAcylation.
O-GlcNAc
modification
increases
transcript
both
NgBR
Dpagt1
pmm2
Orphanet Journal of Rare Diseases,
Год журнала:
2023,
Номер
18(1)
Опубликована: Авг. 29, 2023
Abstract
Congenital
disorders
of
glycosylation
are
a
group
more
than
160
rare
genetic
defects
in
protein
and
lipid
glycosylation.
Since
the
first
clinical
report
1980
PMM2-CDG,
most
common
CDG
worldwide,
research
made
great
strides,
but
nearly
all
them
still
missing
cure.
diagnosis
has
been
at
rapid
pace
since
introduction
whole-exome/whole-genome
sequencing
as
diagnostic
tool.
Here,
we
retrace
history
by
analyzing
patents
associated
with
topic.
To
this
end,
explored
Espacenet
database,
extracted
list
patents,
then
divided
into
three
major
groups:
(1)
Drugs/therapeutic
approaches
for
CDG,
(2)
Drug
delivery
tools
(3)
Diagnostic
CDG.
Despite
enormous
scientific
progress
experienced
last
30
years,
tools,
drugs,
biomarkers
urgently
needed.
International Journal of Molecular Sciences,
Год журнала:
2022,
Номер
23(15), С. 8725 - 8725
Опубликована: Авг. 5, 2022
Advances
in
research
have
boosted
therapy
development
for
congenital
disorders
of
glycosylation
(CDG),
a
group
rare
genetic
affecting
protein
and
lipid
glycosylphosphatidylinositol
anchor
biosynthesis.
The
(re)use
known
drugs
novel
medical
purposes,
as
drug
repositioning,
is
growing
both
common
disorders.
latest
innovation
concerns
the
rational
search
repositioned
molecules
which
also
benefits
from
artificial
intelligence
(AI).
Compared
to
traditional
methods,
repositioning
accelerates
overall
discovery
process
while
saving
costs.
This
particularly
valuable
diseases.
AI
tools
proven
their
worth
diagnosis,
disease
classification
characterization,
ultimately
availability
biomarkers
reliable
models
critical
new
drugs,
especially
heterogeneous
diseases
such
CDG.
work
reviews
literature
related
CDG,
discovered
by
serendipity
or
through
systemic
approach.
Recent
advances
are
outlined
well
stakeholders'
views
on
Trends in Cell Biology,
Год журнала:
2023,
Номер
33(11), С. 903 - 912
Опубликована: Май 15, 2023
Evolutionary
cell
biology
explores
the
origins,
principles,
and
core
functions
of
cellular
features
regulatory
networks
through
lens
evolution.
This
emerging
field
relies
heavily
on
comparative
experiments
genomic
analyses
that
focus
exclusively
extant
diversity
historical
events,
providing
limited
opportunities
for
experimental
validation.
In
this
opinion
article,
we
explore
potential
laboratory
evolution
to
augment
evolutionary
toolbox,
drawing
inspiration
from
recent
studies
combine
with
biological
assays.
Primarily
focusing
approaches
single
cells,
provide
a
generalizable
template
adapting
protocols
fresh
insight
into
long-standing
questions
in
biology.
Biochimie,
Год журнала:
2024,
Номер
222, С. 123 - 131
Опубликована: Март 6, 2024
PMM2-CDG,
a
disease
caused
by
mutations
in
phosphomannomutase-2,
is
the
most
common
congenital
disorder
of
glycosylation.
Yet,
it
still
lacks
cure.
Targeting
phosphomannomutase-2
with
pharmacological
chaperones
or
inhibiting
phosphatase
activity
phosphomannomutase-1
to
enhance
intracellular
glucose-1,6-bisphosphate
have
been
proposed
as
therapeutical
approaches.
We
used
Recombinant
Bacterial
Thermal
Shift
Assay
assess
binding
substrate
analog
and
specific
an
FDA-approved
drug
-
clodronate.
also
deepened
clodronate
enzyme
assays
silico
docking.
Our
results
confirmed
selective
shed
light
on
such
binding.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Май 5, 2024
Mutations
in
glycosylation
pathways,
such
as
N-linked
glycosylation,
O-linked
and
GPI
anchor
synthesis,
lead
to
Congenital
Disorders
of
Glycosylation
(CDG).
CDGs
typically
present
with
seizures,
hypotonia,
developmental
delay
but
display
large
clinical
variability
symptoms
affecting
every
system
the
body.
This
suggests
modifier
genes
might
influence
phenotypes.
Because
similar
physiology
symptoms,
there
are
likely
common
genetic
modifiers
between
CDGs.
Here,
we
use
evolution
a
tool
identify
CDG
genes.
Protein
is
evolutionarily
conserved
from
yeast
mammals.
Evolutionary
rate
covariation
(ERC)
identifies
proteins
evolutionary
rates
that
indicate
shared
biological
functions
pathways.
Using
ERC,
identified
strong
signatures
same
different
Genome-wide
analysis
showing
significant
ERC
synthesis
revealed
ncRNA
modification
DNA
repair
proteins.
We
also
patterns
based
on
cellular
sub-localization
enzymes.
Functional
testing
highest
scoring
candidates
validated
interactions
novel
disease
pathways
allows
for
rapid
prioritization
potential
modifiers,
which
can
provide
better
understanding
pathophysiology
therapeutic
targets.
