Nature Communications,
Journal Year:
2021,
Volume and Issue:
12(1)
Published: Sept. 6, 2021
Abstract
Homeostasis
is
one
of
the
fundamental
concepts
in
physiology.
Despite
remarkable
progress
our
molecular
understanding
amino
acid
transport,
metabolism
and
signaling,
it
remains
unclear
by
what
mechanisms
cytosolic
concentrations
are
maintained.
We
propose
that
transporters
primary
determinants
intracellular
levels.
show
a
cell’s
endowment
with
can
be
deconvoluted
experimentally
used
this
data
to
computationally
simulate
translocation
across
plasma
membrane.
Transport
simulation
generates
close
those
observed
vitro.
Perturbations
system
replicated
silico
applied
systems
where
only
transcriptomic
available.
This
work
explains
homeostasis
at
systems-level,
through
combination
secondary
active
transporters,
functionally
acting
as
loaders,
harmonizers
controller
generate
stable
equilibrium
all
concentrations.
International Journal of Molecular Sciences,
Journal Year:
2018,
Volume and Issue:
19(4), P. 954 - 954
Published: March 23, 2018
Branched
chain
amino
acids
(BCAAs),
including
leucine
(Leu),
isoleucine
(Ile),
and
valine
(Val),
play
critical
roles
in
the
regulation
of
energy
homeostasis,
nutrition
metabolism,
gut
health,
immunity
disease
humans
animals.
As
most
abundant
essential
(EAAs),
BCAAs
are
not
only
substrates
for
synthesis
nitrogenous
compounds,
they
also
serve
as
signaling
molecules
regulating
metabolism
glucose,
lipid,
protein
synthesis,
intestinal
via
special
network,
especially
phosphoinositide
3-kinase/protein
kinase
B/mammalian
target
rapamycin
(PI3K/AKT/mTOR)
signal
pathway.
Current
evidence
supports
their
derivatives
potential
biomarkers
diseases
such
insulin
resistance
(IR),
type
2
diabetes
mellitus
(T2DM),
cancer,
cardiovascular
(CVDs).
These
closely
associated
with
catabolism
balance
BCAAs.
Hence,
optimizing
dietary
BCAA
levels
should
have
a
positive
effect
on
parameters
health
diseases.
This
review
focuses
recent
findings
metabolic
pathways
regulation,
underlying
relationship
to
related
processes.
Journal of Hematology & Oncology,
Journal Year:
2020,
Volume and Issue:
13(1)
Published: Aug. 17, 2020
Abstract
Cancer
is
characterized
as
a
complex
disease
caused
by
coordinated
alterations
of
multiple
signaling
pathways.
The
Ras/RAF/MEK/ERK
(MAPK)
one
the
best-defined
pathways
in
cancer
biology,
and
its
hyperactivation
responsible
for
over
40%
human
cases.
To
drive
carcinogenesis,
this
promotes
cellular
overgrowth
turning
on
proliferative
genes,
simultaneously
enables
cells
to
overcome
metabolic
stress
inhibiting
AMPK
signaling,
key
singular
node
metabolism.
Recent
studies
have
shown
that
can
also
reversibly
regulate
hyperactive
MAPK
phosphorylating
components,
RAF/KSR
family
kinases,
which
affects
not
only
carcinogenesis
but
outcomes
targeted
therapies
against
signaling.
In
review,
we
will
summarize
current
proceedings
how
MAPK-AMPK
signalings
interplay
with
each
other
well
implications
clinic
treatment
inhibition
modulators,
discuss
exploitation
combinatory
targeting
both
novel
therapeutic
intervention.
Frontiers in Chemistry,
Journal Year:
2018,
Volume and Issue:
6
Published: June 22, 2018
SLC7A5,
known
as
LAT1,
belongs
to
the
APC
superfamily
and
forms
a
heterodimeric
amino
acid
transporter
interacting
with
glycoprotein
CD98
(SLC3A2)
through
conserved
disulfide.
The
complex
is
responsible
for
uptake
of
essential
acids
in
crucial
body
districts
such
placenta
blood
brain
barrier.
LAT1/CD98
heterodimer
has
been
studied
over
years
unravel
transport
mechanism
role
each
subunit.
Studies
conducted
intact
cells
demonstrated
that
mediates
Na+
pH
independent
antiport
acids.
Some
novel
insights
into
function
LAT1
derived
from
studies
proteoliposomes
reconstituted
recombinant
human
LAT1.
Using
this
experimental
tool,
it
preferred
substrate
histidine
not
required
being,
plausibly,
involved
routing
plasma
membrane.
Since
3D
structure
available,
homology
models
have
built
on
basis
AdiC
E.coli.
Crucial
residues
recognition
gating
identified
using
combined
approach
bioinformatics
site-directed
mutagenesis
coupled
functional
assays.
Over
years,
interest
around
increased
because
important
diseases
neurological
disorders
cancer.
Therefore,
became
an
pharmacological
target
together
other
nutrient
membrane
transporters.
Moving
knowledge
structure/function
relationships,
two
cysteine
residues,
lying
binding
site,
exploited
designing
thiol
reacting
covalent
inhibitors.
lead
compounds
characterized
whose
efficacy
tested
cancer
cell
line.
Nature Communications,
Journal Year:
2021,
Volume and Issue:
12(1)
Published: Jan. 14, 2021
Abstract
Many
tumour
cells
show
dependence
on
exogenous
serine
and
dietary
glycine
starvation
can
inhibit
the
growth
of
these
cancers
extend
survival
in
mice.
However,
numerous
mechanisms
promote
resistance
to
this
therapeutic
approach,
including
enhanced
expression
de
novo
synthesis
pathway
(SSP)
enzymes
or
activation
oncogenes
that
drive
synthesis.
Here
we
inhibition
PHGDH,
first
step
SSP,
cooperates
with
depletion
one-carbon
metabolism
cancer
growth.
In
vitro,
PHGDH
combined
leads
a
defect
global
protein
synthesis,
which
blocks
an
ATF-4
response
more
broadly
impacts
protective
stress
amino
acid
depletion.
vivo,
combination
diet
inhibitor
shows
efficacy
against
tumours
are
resistant
drug
alone,
evidence
reduced
availability.
ATF4-response
seen
vitro
following
complete
available
is
not
mice,
where
treatment
lower
but
do
eliminate
serine.
Our
results
indicate
will
augment
depleted
diet.
Molecular Metabolism,
Journal Year:
2021,
Volume and Issue:
52, P. 101261 - 101261
Published: May 24, 2021
A
strong
association
of
obesity
and
insulin
resistance
with
increased
circulating
levels
branched-chain
aromatic
amino
acids
decreased
glycine
has
been
recognized
in
human
subjects
for
decades.More
recently,
metabolomics
genetic
studies
have
confirmed
expanded
upon
these
observations,
accompanied
by
a
surge
preclinical
that
identified
mechanisms
involved
the
perturbation
acid
homeostasis-
how
events
are
connected
to
dysregulated
glucose
lipid
metabolism,
elevations
(BCAA)
may
participate
development
resistance,
type
2
diabetes
(T2D),
other
cardiometabolic
diseases
conditions.In
cohorts,
BCAA
related
metabolites
now
well
established
as
among
strongest
biomarkers
obesity,
T2D,
cardiovascular
diseases.
Lowering
ketoacid
(BCKA)
feeding
BCAA-restricted
diet
or
activation
rate-limiting
enzyme
catabolism,
dehydrogenase
(BCKDH),
rodent
models
clear
salutary
effects
on
homeostasis,
but
restriction
more
modest
short-term
T2D
subjects.
Feeding
rats
diets
enriched
sucrose
fructose
result
induction
ChREBP
transcription
factor
liver
increase
expression
BCKDH
kinase
(BDK)
suppress
its
phosphatase
(PPM1K)
resulting
inactivation
key
lipogenic
ATP-citrate
lyase
(ACLY).
These
emergent
links
between
BCAA,
glucose,
metabolism
motivate
ongoing
possible
causal
actions
Trends in Endocrinology and Metabolism,
Journal Year:
2021,
Volume and Issue:
32(6), P. 367 - 381
Published: March 29, 2021
Targeting
tumor
cell
metabolism
is
an
attractive
form
of
therapy,
as
it
may
enhance
treatment
response
in
therapy
resistant
cancers
well
mitigate
treatment-related
toxicities
by
reducing
the
need
for
genotoxic
agents.
To
meet
their
increased
demand
biomass
accumulation
and
energy
production
to
maintain
redox
homeostasis,
cells
undergo
profound
changes
metabolism.
In
addition
diversion
glucose
metabolism,
this
achieved
upregulation
amino
acid
Interfering
with
availability
can
be
selectively
lethal
has
proven
a
cancer
specific
Achilles'
heel.
Here
we
review
biology
behind
such
dependencies
discuss
how
these
vulnerabilities
exploited
improve
therapies.
