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Page 4 of 12 Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78

proteolysis provides amino acids, the transamination of alanine feeds with PYR the neoglucogenic route.
Since cAMP inhibits Fructose 2-6 bis phosphate (Fruc 2-6 bisP), it cancels the inhibition of neoglucogenesis
and blocks glycolysis; glucose is now produced. We have to add that hypoglycemia decreases glycolysis in
erythrocytes, which form less 2-3 DPG. Thus, oxygen is retained by hemoglobin and less is delivered and
reduced by other cells, their NADH/NAD ratio increases, closing their citrate condensation that starts
the Krebs cycle, more OAA goes to neoglucogenesis. Glycogenolysis is activated as well (phosphorylated
phosphorylase a, is ON), while phosphorylated glycogen synthase is OFF. The other nutrient are ketone
bodies; we know that PKA and Src activate a protein LKB1 by phosphorylation, it will stimulate AMP
kinase, which inhibits acetyl CoA carboxylase (ACC) at the start of the fatty acid synthesis pathway. The
inhibition of ACC decreases the product malonyl CoA, which is an inhibitor of the mitochondria carnityl
transporter of fatty acids, allowing then fatty acid to enter in mitochondria. There, beta oxidation forms
acetyl CoA, then ketone bodies, acetoacetate, particularly in liver. The malonyl CoA inhibition of the fatty
acid transporter blocks the degradation of fatty acid when their synthesis is activated and vice versa. The
ketone bodies are delivered to other cells, where they give back acetyl CoA by the reverse pathway (thiolase
operating in both directions).

Second finality: the production of energy, and selection of glycolytic or fatty acid sources of acetyl CoA.
Even when glucagon, epinephrine and cortisol are released for making glucose and nutrients, muscles can
reverse the situation and keep their glycolytic pathway operational, with little or no neoglucogenesis; on
the other hand, glycogenolysis is still possible (Figure 1 red pathways and red box). This muscle exception
is presumably linked to the fact that muscles have to be ready for escaping predators. How are the effects
of cAMP on neoglucogenesis cancelled? Muscle activity is associated to the movement of charges along T
tubules until reticulum sacs with ryanodine receptors in the depth of the muscle, the depolarization releases
calcium in the cytosol initiating muscle contraction. Calcium will also stimulate a phosphodiesterase
(PDE) converting cAMP into AMP, which restores the synthesis of Fruc2-6 bisP, the allosteric activator
of glycolysis, and inhibitor of neoglucogenesis. In parallel, calcium stimulates calcineurin phosphatase,
which dephosphorylates an inhibitor (I1) of a major phosphatase PP1 that gets activated, leading in fine to
the dephosphorylation and activation of PK and PDH, which opens the glycolytic supply of acetyl CoA to
the Krebs cycle. The citrate condensation starts, (the NADH/NAD ratio decreases via oxygen reduction).
Then, since ATP is low and AMP elevated, the inhibition isocitrate dehydrogenase by ATP is cancelled
and the citric acid cycle ”turns”, which decreases the citrate efflux from mitochondria and closes the fatty
acid synthesis route (via ATP citrate lyase and ACC). The elevated AMP activates AMP kinase, which
inhibits ACC; a low level of malonyl CoA may now open the beta oxidation of fatty acid and the fatty acid
source of acetyl CoA, when glucose is missing. Well, exactly the same glycolytic energetic finality (red
pathway Figure 1) will eventually operate in anabolism when insulin is released; because insulin elicits the
activation of a phospholipase that splits phosphatidyl inositol (4-5) Bis P (PIP2) into diacyl glycerol (DAG)
and inositol 1,4,5 Phosphate (IP3). The latter, will act on IP3 receptors of the reticulum, releasing calcium
in the cytosol. Calcium stimulates as described above, a PDE neutralizing the inhibitory effect of cAMP on
Fruc 2-6 bisP synthesis, and activates calcineurin, then PP1, PK and PDH, which stimulates glycolysis and
opens the glycolytic entry of the Krebs cycle. But here is a new regulator to consider: DAG. If the level of
DAG is low, presumably when DAG is converted into monoacyl glycerol, the glycolytic route forms acetyl
CoA as above (Figure 1 second red box). However, if DAG increases, it will activate protein kinase C (PKC)
and the latter elicits the synthesis of a new inhibitor of PP1 known as CPI 17, which keeps PK and PDH
phosphorylated and inhibited, and closes the glycolytic supply of acetyl CoA. The fatty acid source of acetyl
CoA will have to be opened. Since AMP is elevated, it stimulates AMP kinase, which inhibits ACC and
the fatty acid synthesis pathway. With malonyl CoA being low, fatty acid beta oxidation is now permitted,
opening the fatty acid supply of acetyl CoA, (Figure 1 black pathway and black box). The third finality: the
anabolic synthesis of new constituents depends essentially on Insulin and IGF. It is represented by the green
pathways, plus the glycolytic red pathway, and green box for switches. The effect of insulin on its tyrosine
kinase receptor elicits anabolism: The synthesis of glycogen, of fatty acids and triglycerides (TAG), of