cAMP and AMP Roles

[sanguinee]

Can someone explain why cAMP promotes gluconeogenesis (via adenlyl cyclase/secondary messanger), yet AMP promotes glycolysis? Is it simply the structural differences that will promote one or the other cycles?

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[yeasureyoubetcha]

Can someone explain why cAMP promotes gluconeogenesis (via adenlyl cyclase/secondary messanger), yet AMP promotes glycolysis? Is it simply the structural differences that will promote one or the other cycles?

cAMP is a universal signal of an energy starved state. Its been a while since my biochem, but I believe cAMP is an inhibitor of PFK and/or an activator of Fructose-1,6-bisphosphatase (the reverse enzyme for PFK in the gluconeogenesis pathway). Buildup of AMP is more of a signal that energy is getting low and you need to speed up glycolysis to make more high energy phosphate bonds. It would therefore make sense that an increase in AMP would activate PFK. To address the last part of your post, structure is always related to function. Angstrom and picometer distances in proteins can still make a huge difference

 

[aldol16]

cAMP is a second messenger that is downstream of the epinephrine GPCR signaling pathway. So it makes sense that it would increase gluconeogenesis.

 

[NextStepTutor_2]

Can someone explain why cAMP promotes gluconeogenesis (via adenlyl cyclase/secondary messanger), yet AMP promotes glycolysis? Is it simply the structural differences that will promote one or the other cycles?

Hi @sanguine ! Short answer (as it is with a lot of biochem) is because that's what we have observed. Long answer is that control of the important enzymes of glycolysis/gluconeogenesis is accomplished in three ways:

Allosterics, enzyme modification (phosphorylation - see F2,6BP system) and managing protein synthesis of the enzyme (hormonal control of synthesis).

Some allosteric effectors, such as G6P, F2,6BP, acetyl-CoA, and AMP, have opposite effects on enzymes in glycolysis and gluconeogenesis, turning one off as it turns the other on. Others, such as Citrate, ATP, and F1,6BP affect only one of the pathways.

Allosteric regulation is organized so that molecules (like ATP and citrate), which are consistent with a "high" energy state of the cell, turn off glycolysis. Acetyl-CoA is consistent with a high energy state, and it turns off glycolysis and turns on gluconeogenesis as well. Conversely, molecules, such as AMP, which are indicative of a "low" energy state of the cell, turn on glycolysis and turn off gluconeogenesis. Coordinated controls insure than within a cell that futile cycles of glycolysis/gluconeogenesis are not occurring.

An enzyme system external to glycolysis and gluconeogenesis synthesizes and degrades a potent allosteric effector of the PFK/FBPase control point. The effector is fructose 2,6 bisphosphate (F2,6BP).

PFK-2 and FBPase themselves are allosterically regulated. The allosteric effectors of PFK-2 and FBPase - citrate (inhibits PFK-2), AMP (activates PFK-2), F6P (inhibits FBPase-2, activates PFK-2), and glyceraldehyde 3 phosphate (activates FBPase-2) - are all directed towards managing the cell's energy needs - inhibiting PFK-2/activating FBPase-2 when cells have plenty of energy and activating PFK-2/inhibiting FBPase-2 when cells need metabolic energy.

as @aldol16 pointed out, in lieu of just memorizing the biochem, if you can understand a molecule's role in the big picture, you can reason out what physiological processes it would logically activate or inhibit. Not foolproof, but a good start and useful when you just can't recall or don't know specific biochem triggers/pathways.

For more details, this link HERE goes into some depth (not too long).

Hope this helps, good luck!

 

[aldol16]

Allosteric regulation is organized so that molecules (like ATP and citrate), which are consistent with a "high" energy state of the cell, turn off glycolysis. Acetyl-CoA is consistent with a high energy state, and it turns off glycolysis and turns on gluconeogenesis as well. Conversely, molecules, such as AMP, which are indicative of a "low" energy state of the cell, turn on glycolysis and turn off gluconeogenesis. Coordinated controls insure than within a cell that futile cycles of glycolysis/gluconeogenesis are not occurring.

I think you should make clear that you're talking specifically about the liver here. ATP and citrate do downregulate glycolysis (not completely, since you still need energy) but after that, your answer becomes less clear. Acetyl-CoA is not necessarily onsistent with a high-energy state. Buildup of acetyl-CoA could be due to shunting off of the Krebs cycle intermediates to perform gluconeogenesis, which is indicative of an energy-deficient state. That's the whole reason why ketogenesis occurs. Not to mention that when you're in a high-energy state, there's no need to turn on gluconeogenesis - you obviously have enough glucose since you're producing excess energy. Instead, in a high-energy state, you want to do lipid biosynthesis, glycogenesis, etc.

Second, when you're in the "low-energy" state, you want gluconeogenesis on, not off. That's the whole point of gluconeogenesis. You want to turn glycolysis on in your tissues, turn it off in the liver, but turn gluconeogenesis on in the liver. You have it flipped.

 

[NextStepTutor_2]

I think you should make clear that you're talking specifically about the liver here. ATP and citrate do downregulate glycolysis (not completely, since you still need energy) but after that, your answer becomes less clear. Acetyl-CoA is not necessarily onsistent with a high-energy state. Buildup of acetyl-CoA could be due to shunting off of the Krebs cycle intermediates to perform gluconeogenesis, which is indicative of an energy-deficient state. That's the whole reason why ketogenesis occurs. Not to mention that when you're in a high-energy state, there's no need to turn on gluconeogenesis - you obviously have enough glucose since you're producing excess energy. Instead, in a high-energy state, you want to do lipid biosynthesis, glycogenesis, etc.

Second, when you're in the "low-energy" state, you want gluconeogenesis on, not off. That's the whole point of gluconeogenesis. You want to turn glycolysis on in your tissues, turn it off in the liver, but turn gluconeogenesis on in the liver. You have it flipped.

For the human body, gluconeogenesis is largely restricted to the liver, kidney, and GI tract, so perhaps my assumption was that it was clear enough.

Lots of ways to explain this complex biochem, and the OP did not cite a specific cell type, so I went for one of the most common. I may have gotten too detailed for the MCAT, but it helps to provide context. Some things cannot be simplified further if you want to understand them.

Long story short, the MCAT will NOT expect you to get bogged down in these details to the same Level I have for purposes of instruction, or even to the level of most undergrad courses. Reasoning trumps memorization and the understanding that they are signaling molecules coupled to other physiological processes is the real take away, not any exception to biochem trends.

gluconeogenesis = used when body is in NEED of glucose (low E levels, High E needs)
glycolysis = breakdown/metabolism of glucose, for the purpose of E generation when the body is in NEED of energy

In the liver, AMP stimulates phosphofructokinase, whereas ATP and citrate inhibit it. Fructose 1,6-bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. A high level of AMP indicates that the energy charge is low and signals the need for ATP generation. Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are abundant. Under these conditions, glycolysis is nearly switched off and gluconeogenesis is promoted.


The way OP used question I took it to mean they thought they might be antagonistic processes in a body need sense while in reality they are related processes (metabolically speaking) and a reciprocally regulated (they can both be up-regulated at same time though both are never very high at the same time, building and then utilizing glucose for fuel) and OP thought the structural difference in the molecules could explain their effect (not entirely accurate and well beyond the scope of the AAMC to boot).


Hope this helps, good luck!

 

[aldol16]

Long story short, the MCAT will NOT expect you to get bogged down in these details to the same Level I have for purposes of instruction, or even to the level of most undergrad courses. Reasoning trumps memorization and the understanding that they are signaling molecules coupled to other physiological processes is the real take away, not any exception to biochem trends.

I understand. I am a graduate student in chemistry so I know that reasoning is a much more valuable skill to have.

In the liver, AMP stimulates phosphofructokinase, whereas ATP and citrate inhibit it. Fructose 1,6-bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. A high level of AMP indicates that the energy charge is low and signals the need for ATP generation. Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are abundant. Under these conditions, glycolysis is nearly switched off and gluconeogenesis is promoted.

This is what I have a problem with. Everything is fine up to the point where you claim that glycolysis is switched off and gluconeogenesis is promoted. This is only true if your high levels of ATP coincide with low blood glucose levels. This is because gluconeogenesis is not only energy-intensive but also shunts intermediates from the TCA cycle such that oxidative phosphorylation in the liver can no longer occur. If that happens, then reductive biosynthesis also grinds to a halt - the same biosynthesis that you want to be doing when you're well-fed. So instead, what you're doing if you have an energy glut is making lipids for storage, replenishing TCA cycle intermediates, and storing excess glucose as glycogen. Perhaps these figures will help make my point clearer:

 

[Thoroughbred_Med]

I think you should make clear that you're talking specifically about the liver here. ATP and citrate do downregulate glycolysis (not completely, since you still need energy) but after that, your answer becomes less clear. Acetyl-CoA is not necessarily onsistent with a high-energy state. Buildup of acetyl-CoA could be due to shunting off of the Krebs cycle intermediates to perform gluconeogenesis, which is indicative of an energy-deficient state. That's the whole reason why ketogenesis occurs. Not to mention that when you're in a high-energy state, there's no need to turn on gluconeogenesis - you obviously have enough glucose since you're producing excess energy. Instead, in a high-energy state, you want to do lipid biosynthesis, glycogenesis, etc.

Second, when you're in the "low-energy" state, you want gluconeogenesis on, not off. That's the whole point of gluconeogenesis. You want to turn glycolysis on in your tissues, turn it off in the liver, but turn gluconeogenesis on in the liver. You have it flipped.

let's note that gluconeogenesis is always on in the liver, FOR the LIVER, as this is the liver's primary form of energy... not the glycogen it stores.

 

[aldol16]

let's note that gluconeogenesis is always on in the liver, FOR the LIVER, as this is the liver's primary form of energy... not the glycogen it stores.

Yeah, that's basal metabolism. For that matter, glycolysis is always on everywhere. We're talking about regulation of metabolism here and the difference between high-energy and well-fed states. The liver's primary source of "food" are alpha-keto acids from AA degradation. By "turn on," I mean upregulate and by "turn off," I mean downregulate. These are not my terms.