Nature,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 20, 2025
The
mammalian
fatty
acid
synthase
(FASN)
enzyme
is
a
dynamic
multienzyme
that
belongs
to
the
megasynthase
family.
In
mammals,
single
gene
encodes
six
catalytically
active
domains
and
flexibly
tethered
acyl
carrier
protein
(ACP)
domain
shuttles
intermediates
between
sites
for
biosynthesis1.
FASN
an
essential
in
development
through
role
acids
have
membrane
formation,
energy
storage,
cell
signalling
modifications.
Thus,
promising
target
treatment
of
large
variety
diseases
including
cancer,
metabolic
dysfunction-associated
liver
disease,
viral
parasite
infections2,3.
multi-faceted
mechanism
nature
protein,
particular
ACP,
made
it
challenging
understand
at
molecular
level.
Here
we
report
cryo-electron
microscopy
structures
human
multitude
conformational
states
with
NADPH
NADP+
plus
acetoacetyl-CoA
present,
ACP
stalled
dehydratase
(DH)
enoyl-reductase
(ER)
domains.
We
show
activity
vitro
de
novo
lipogenesis
cells
inhibited
by
mutations
ACP-DH
ACP-ER
interfaces.
Together,
these
studies
provide
new
insights
into
shuttling
mechanism,
implications
developing
improved
FASN-targeted
therapeutics.
Nature Reviews Drug Discovery,
Journal Year:
2022,
Volume and Issue:
21(4), P. 283 - 305
Published: Jan. 14, 2022
Fatty
acids
are
essential
for
survival,
acting
as
bioenergetic
substrates,
structural
components
and
signalling
molecules.
Given
their
vital
role,
cells
have
evolved
mechanisms
to
generate
fatty
from
alternative
carbon
sources,
through
a
process
known
de
novo
lipogenesis
(DNL).
Despite
the
importance
of
DNL,
aberrant
upregulation
is
associated
with
wide
variety
pathologies.
Inhibiting
core
enzymes
including
citrate/isocitrate
carrier
(CIC),
ATP-citrate
lyase
(ACLY),
acetyl-CoA
carboxylase
(ACC)
acid
synthase
(FAS),
represents
an
attractive
therapeutic
strategy.
challenges
related
efficacy,
selectivity
safety,
several
new
classes
synthetic
DNL
inhibitors
entered
clinical-stage
development
may
become
foundation
class
therapeutics.
De
(DNL)
maintenance
whole-body
cellular
homeostasis,
but
pathway
broad
range
conditions,
cardiovascular
disease,
metabolic
disorders
cancers.
Here,
Steinberg
colleagues
provide
overview
physiological
pathological
roles
assess
strategies
agents
currently
in
therapeutically
target
them.
Journal of Hematology & Oncology,
Journal Year:
2023,
Volume and Issue:
16(1)
Published: Sept. 12, 2023
Abstract
Lipid
metabolic
reprogramming
is
an
emerging
hallmark
of
cancer.
In
order
to
sustain
uncontrolled
proliferation
and
survive
in
unfavorable
environments
that
lack
oxygen
nutrients,
tumor
cells
undergo
transformations
exploit
various
ways
acquiring
lipid
increasing
oxidation.
addition,
stromal
immune
the
microenvironment
also
reprogramming,
which
further
affects
functional
phenotypes
responses.
Given
metabolism
plays
a
critical
role
supporting
cancer
progression
remodeling
microenvironment,
targeting
pathway
could
provide
novel
approach
treatment.
This
review
seeks
to:
(1)
clarify
overall
landscape
mechanisms
cancer,
(2)
summarize
landscapes
within
their
roles
progression,
(3)
potential
therapeutic
targets
for
metabolism,
highlight
combining
such
approaches
with
other
anti-tumor
therapies
new
opportunities
patients.
Oncogenesis,
Journal Year:
2022,
Volume and Issue:
11(1)
Published: Aug. 9, 2022
Abstract
Lipids
are
essential
constituents
for
malignant
tumors,
as
they
absolutely
required
tumor
growth
and
dissemination.
Provided
by
the
microenvironment
(TME)
or
cancer
cells
themselves
through
activation
of
de
novo
synthesis
pathways,
orchestrate
a
large
variety
pro-tumorigenic
functions.
Importantly,
TME
cells,
especially
immune
cancer-associated
fibroblasts
(CAFs)
adipocytes
(CAAs),
also
prone
to
changes
in
their
lipid
content,
which
hinder
promote
aggressiveness.
In
this
review,
we
address
significant
findings
contribution
progression
towards
metastatic
disease
poor
response
therapeutic
treatments.
We
highlight
benefits
targeting
pathways
preclinical
models
slow
down
metastasis
development
overcome
chemo-and
immunotherapy
resistance.
