Biochem question on fructose-1,6-bisphosphate

[spezimdoc]

Why do ATP and citrate activate fructose-1,6-bisphosphate since the purpose of gluconeogeneiss is to produce glucose in the liver during the fasting state? Wouldn't the fasting state be characterized by increasing levels of AMP and less citrate in the liver? I can see how it has the opposite allosteric activators as PFK-1... I'm just trying to get the big picture...

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[Mortal_Lessons]

Why do ATP and citrate activate fructose-1,6-bisphosphate since the purpose of gluconeogeneiss is to produce glucose in the liver during the fasting state? Wouldn't the fasting state be characterized by increasing levels of AMP and less citrate in the liver? I can see how it has the opposite allosteric activators as PFK-1... I'm just trying to get the big picture...

I think you've definitely hit upon a paradox. There's a nice image in RR Biochem (p. 89) centered on the regulation of PFK-1. Insulin, by way of activating PFK-2, in addition to AMP, activates PFK-1, whereas glucagon, by way of activating PFK-2 phosphatase, in addition to ATP/Citrate inhibits PFK-1. The pairing of insulin (signaling fed state) with AMP (which it seems would signal fasting state) seems paradoxical. Why isn't insulin paired with ATP/citrate? I think it has to do with competing forces taking place in the liver. In the fed state, there is plenty of exogenous glucose around, and the liver can use this glucose to make fatty acid, by activating glycolysis (via insulin-mediated PFK-1 activation) and forming acetyl-coA, etc. At the same time, this process will produce a lot of citrate which will inhibit PFK-1 and favor gluconeogensis. I think the glucose formation that this is favoring is glucose that's destined to become stored as glycogen and not necessarily glucose that's being pumped into the bloodstream. To come at it from the fasting state, glucagon promotes inhibition of PFK-1, and thus favors gluconeogenesis. This is glucose that's going to be pumped out into the bloodstream. In the fasting state, AMP will also start to rise, but we see that its effects are opposite those of glucagon-it turns on PFK-1. This makes sense because the cell needs energy and glycosis is the way in which it can obtain this energy. As I've been typing this I think I've hit upon the kernel of truth that is guiding these seemingly paradoxical ideas: insulin/glucagon are the global regulators while ATP-citrate/AMP are the local regulators of the selfish cell.