Biology Reference
In-Depth Information
NETWORKS
PFK-1
Glc
F6P
F1,6BP
Mass-Energy
Glucose
G6P
Pyr
ATP
Pi
GLUT1,
GLUT 4
PFK-2
F2,6BPase
F 2,6 BP
TIGAR
AMP:ATP
AMPK-P
p53
AMP
ROS
AMP
LKB1/CaMKK β
ROS
AMPK
FLUXOME
Signaling
SIRT1
FOXO
PGC1 α
NAD + : NADH
ROS
Transcriptome
Proteome & PTMs
Informaon
Genome
Fig. 2.2 The AMP-activated protein kinase (AMPK) signaling network and interactions with
mass-energy and information networks. This figure depicts the main components of the AMPK
signaling network and its interactions with the metabolome, genome-transcriptome-proteome, and
other signaling paths.
AMPK : this network includes the kinase (AMPKK) and the phosphatase (PP2C), representing an
ultrasensitive cellular energy sensor, as it is allosterically modulated by AMP (Hardie and Hawley
2001 ; Hardie et al. 1999 ). Environmental stressors such as starvation or hypoxia produce changes
in the metabolome (e.g., rising AMP and falling ATP). An increased AMP binds to sites located on
the γ subunit of AMPK, whereas high concentrations of ATP are inhibitory. Apart from being an
allosteric activator, AMP also inhibits dephosphorylation of AMPK. AMPK is activated 1,000-
fold by the combined effect of activation by its upstream kinases, neuronally enriched calcium/
calmodulin-dependent protein kinase
β
(CaMKK
β
) or LKB1, together with its allosteric stimulator
AMP (Suter et al. 2006 ).
Targets of the AMPK signaling network are components of the metabolome in glycolysis (PFK-2,
F2,6BP, GLUT), oxidative phosphorylation (ROS), and other pathways; the latter are not indicated
but may comprise fatty acid (FA) oxidation and anabolism, e.g., triacylglycerol synthesis, glycogen,
FAs, protein, and cholesterol. In the feedback from AMPK signaling to the metabolome, the
dashed lines indicate activation through phosphorylation by AMPK-P of PFK-2 and glucose
transport by increasing the levels of glucose transporters (GLUT1 and GLUT4). The increase in
PFK-2 activity augments the level of the allosteric regulator F2,6BP that in turn activates PFK-1;
the activity of the latter is also enhanced by the decrease in ATP. Thus, activation of glycolysis
under ischemic conditions results in alteration of the fluxome as a result of the concerted action of
AMPK signaling and the metabolome.
SIRT1: depicted is the interaction of the AMPK network with SIRT1 and their impact on the
acetylation status of PGC-1
and other transcriptional regulators such as the FOXO family of
transcription factors. Activation of AMPK in muscle by means of pharmacological intervention
(metformin) or physiology (fasting or exercise) triggers an increase in the NAD + /NADH ratio
which activates SIRT1. AMPK induces the phosphorylation of PGC-1 α and primes it for
subsequent deacetylation by SIRT1(Canto et al. 2009 ). Deacetylation of PGC-1 α is a key mecha-
nism by which AMPK triggers PGC-1 α activity in cultured myotubes and in skeletal muscle.
α
 
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