What's the point of PFK2, F26BP etc.?

[pkrpkrpkr]

I'm studying metabolism and glycolysis. I can learn the facts but it bothers me when I don't understand WHY things are happening.

In glycolysis F6P is converted into F16BP by the use of enzyme PFK1.
This enzyme is stimulated by AMP, which I find logical. Low AMP means low
energy level in cell so we'd want to break down more sugar.
But PFK1 is also stimulated by F26BP. This is supposedly very important, but I don' really get it.

When there is a lot of F6P it is converted into F26BP. In this way (through the stimulation F26BP gives) PFK1 is converting more F6P into F16BP. But this really seems to go against the rule of Ocham's razor. Why is PFK1 not simply stimulated by its substrate (F6P)??? Also, if the substrate in high levels is converted into another molecule, then we are losing substrate molecules for the enzyme to use as substrate and transform into product?? Do you understand what I mean? Like if you were really hungry and all hot dogs were converted into cars. Then there would be nothing left to it? 😎

That is my first question.

The second question is this; AMP is stimulating PFK1, because AMP is a "signature" for low cell energy. But F26BP is a signature for HIGH cell energy levels as far as I'm concerned (F26BP is made when there is a lot of F6P and hence a lot of sugar coming into the system). Is this a case of trying to avoid a "futile cycle" where metabolites are being shuffled from one place to the other, never following a single direction all the way?? It seems strange to me. It's like if the cell was saying "true, (if AMP is high let's say) I do have a lot of ATP but I still have a lot of sugar lying around so I'll break it down anyways". Weird to me. 😳

I would just be very happy if someone could explain to me in a simple way what is the
use of these PFK2/FBPase2/PFK1/F26BP molecules being highly interconnected in the way they affect each other.

I've read on wiki but I couldn't find the underlying "reason" why all these molecules are needed, when this seems to have been made in a simpler way.

(sorry if English is bad, not native speaker)

---

Members don't see this ad.

 

[JackShephard MD]

I'm studying metabolism and glycolysis. I can learn the facts but it bothers me when I don't understand WHY things are happening.

In glycolysis F6P is converted into F16BP by the use of enzyme PFK1.
This enzyme is stimulated by AMP, which I find logical. Low AMP means low
energy level in cell so we'd want to break down more sugar.
But PFK1 is also stimulated by F26BP. This is supposedly very important, but I don' really get it.

When there is a lot of F6P it is converted into F26BP. In this way (through the stimulation F26BP gives) PFK1 is converting more F6P into F16BP. But this really seems to go against the rule of Ocham's razor. Why is PFK1 not simply stimulated by its substrate (F6P)??? Also, if the substrate in high levels is converted into another molecule, then we are losing substrate molecules for the enzyme to use as substrate and transform into product?? Do you understand what I mean? Like if you were really hungry and all hot dogs were converted into cars. Then there would be nothing left to it? 😎

That is my first question.

The second question is this; AMP is stimulating PFK1, because AMP is a "signature" for low cell energy. But F26BP is a signature for HIGH cell energy levels as far as I'm concerned (F26BP is made when there is a lot of F6P and hence a lot of sugar coming into the system). Is this a case of trying to avoid a "futile cycle" where metabolites are being shuffled from one place to the other, never following a single direction all the way?? It seems strange to me. It's like if the cell was saying "true, (if AMP is high let's say) I do have a lot of ATP but I still have a lot of sugar lying around so I'll break it down anyways". Weird to me. 😳

I would just be very happy if someone could explain to me in a simple way what is the
use of these PFK2/FBPase2/PFK1/F26BP molecules being highly interconnected in the way they affect each other.

I've read on wiki but I couldn't find the underlying "reason" why all these molecules are needed, when this seems to have been made in a simpler way.

(sorry if English is bad, not native speaker)

I think you understand for the most part. Occams razor is a terrible starting point for understanding why things work in the body. Create your own logical reason. You've put extra effort into making this not make sense.

 

[pkrpkrpkr]

I think you understand for the most part. Occams razor is a terrible starting point for understanding why things work in the body. Create your own logical reason. You've put extra effort into making this not make sense.

I know, should have gone studying maths instead LOL ;D
But I just think there should be some "reason" behind something so complex.
I know evolution doesn't work that way but it's strange with such a complicated
regulating system. It has to have something to do with the role of F26BP but I don't understand exactly what. With this system a lot of incoming sugar (glucose 6 phosphate) can "alarm the pathway" further down to hurry up with oxidation b/c more substrate is coming. But I don't understand the downside of not having this function (if this function indeed is the point).

 

[Boardz]

I'm trying to find the WHY out too and I'm getting nowhere.

Is this right?
high energy state = high atp = well fed state?

 

[JackShephard MD]

I know, should have gone studying maths instead LOL ;D
But I just think there should be some "reason" behind something so complex.
I know evolution doesn't work that way but it's strange with such a complicated
regulating system. It has to have something to do with the role of F26BP but I don't understand exactly what. With this system a lot of incoming sugar (glucose 6 phosphate) can "alarm the pathway" further down to hurry up with oxidation b/c more substrate is coming. But I don't understand the downside of not having this function (if this function indeed is the point).

What exactly is your question? Try to write a clear short question.

 

[Hotei]

I think I understand what they are asking.

PFK1 is stimulated by its substrate, F6P. However, in the body, the amount of stimulation from F6P alone is not usually enough for biologically significant changes (if the body needs energy, F6P stimulation alone won't make PFK1 as fast as it needs to be).

F26BP regulation becomes significant at very high levels of F6P. The F6P levels are so high that for whatever reason, the system has become clogged and needs to relieve its pressure. There's more F6P than the body knows what to do with. So PFK2, which is floating around, converts some F6P into F26BP, which stimulates PFK1 to get rid of the huge excess of F6P. The body needs to use another tool to speed up PFK1 even more. You are losing PFK1 substrate molecules to F26BP because there are TOO MANY PFK1 substrate molecules, and PFK1 cannot take care of all these molecules by itself.

F26BP is not necessarily a signal of high energy levels. It's a signal of high glucose levels. Remember that the energy from glucose comes when it is broken down later on in glycolysis and then after that in the Krebs cycle and oxidative phosphorylation. So, if you have F26BP formed and are talking about glycolysis, the energy-generating steps haven't happened yet.. Instead I would say excess F26BP is because the organism just ate a lot and has a lot of POTENTIAL energy that it needs to modify and break down. Imagine if a hungry person just ate. They probably have low AMP because the food hasn't been turned into energy yet. But they also have high F26BP levels because they just ingested a lot of carbs that the body broke down into glucose. They need to MAKE energy with the glucose, because glucose floating around by itself isn't energy. It has the potential to become energy that the body can use for other activities but that hasn't happened yet.

The downside of not having F26BP as a regulator is that the body cannot turn glucose into energy very quickly. It's all about speed. If you only had F6P as a stimulator for PFK1, it would take quite a while to turn glucose into energy. If you are an organism and you need to run from a predator or get in a fight, you would die because you couldn't generate energy quickly enough to fight or run. So I think even from an evolutionary perspective it can be explained. Hope this helps.

 

[ijn]

I think Kaplan gave a pretty good explanation of the purpose of PFK2. It's only physiologically significant in the liver. Remember that citrate inhibits PFK1. 2,6 FBP is basically an override switch in the liver. When it's present it allows glycolysis to continue despite high citrate levels.

 

[GTP]

I think I understand what they are asking.

PFK1 is stimulated by its substrate, F6P. However, in the body, the amount of stimulation from F6P alone is not usually enough for biologically significant changes (if the body needs energy, F6P stimulation alone won't make PFK1 as fast as it needs to be).

F26BP regulation becomes significant at very high levels of F6P. The F6P levels are so high that for whatever reason, the system has become clogged and needs to relieve its pressure. There's more F6P than the body knows what to do with. So PFK2, which is floating around, converts some F6P into F26BP, which stimulates PFK1 to get rid of the huge excess of F6P. The body needs to use another tool to speed up PFK1 even more. You are losing PFK1 substrate molecules to F26BP because there are TOO MANY PFK1 substrate molecules, and PFK1 cannot take care of all these molecules by itself.

F26BP is not necessarily a signal of high energy levels. It's a signal of high glucose levels. Remember that the energy from glucose comes when it is broken down later on in glycolysis and then after that in the Krebs cycle and oxidative phosphorylation. So, if you have F26BP formed and are talking about glycolysis, the energy-generating steps haven't happened yet.. Instead I would say excess F26BP is because the organism just ate a lot and has a lot of POTENTIAL energy that it needs to modify and break down. Imagine if a hungry person just ate. They probably have low AMP because the food hasn't been turned into energy yet. But they also have high F26BP levels because they just ingested a lot of carbs that the body broke down into glucose. They need to MAKE energy with the glucose, because glucose floating around by itself isn't energy. It has the potential to become energy that the body can use for other activities but that hasn't happened yet.

The downside of not having F26BP as a regulator is that the body cannot turn glucose into energy very quickly. It's all about speed. If you only had F6P as a stimulator for PFK1, it would take quite a while to turn glucose into energy. If you are an organism and you need to run from a predator or get in a fight, you would die because you couldn't generate energy quickly enough to fight or run. So I think even from an evolutionary perspective it can be explained. Hope this helps.

You are an OG

 

[Snuke]

Also, don't neglect the importance of insulin. After a meal, insulin levels are high, which decreases cAMP and therefore protein kinase A is more deactivated. Activated pkA keeps the PFK2/FBP2 phosphorylated and active, so when pkA is deactivated, FBP2 is more dephosphorylated.

When FBP2 is dephosphylated, PFK2 is active, which signals the cell to make more PFK1.

In essence, it's simply a secondary reaction to speed up glycolysis while deactivating gluconeogenesis, since dephosphorylated FBP2 inhibits the gluconeogenesis pathway.

I know it's an older thread, but I was wondering the same question and found this thread useful, but missing the insulin component.

 

[Charles_Carmichael]

I think Kaplan gave a pretty good explanation of the purpose of PFK2. It's only physiologically significant in the liver. Remember that citrate inhibits PFK1. 2,6 FBP is basically an override switch in the liver. When it's present it allows glycolysis to continue despite high citrate levels.

+1.

The way I remember it, in the liver, the PFK-2 product (F-2,6-BP) "overrides" the normal feedback inhibition of PFK-1 by high ATP and citrate levels. Because the liver plays an important role in fatty acid synthesis and because acetyl-CoA is required for fatty acid synthesis, you don't want the glycolytic pathway shutting down in the liver once ATP and citrate levels are high. You want to continue down the glycolytic pathway to provide the substrate for fatty acid synthesis -- acetyl-CoA (which involves pyruvate dehydrogenase converting pyruvate to acetyl-CoA). This is where PFK-2, whose activity is stimulated by insulin, steps in and F-2,6-BP activates PFK-1 to allow glycolysis to continue.

Make sense?

 

[Jamary]

"The most potent allosteric regulator of the glycolysis and gluconeogenesis pathways is fructose-2,6-bisphosphate (F2,6BP). As shown in Figure 16.6, F2,6BP activates phosphofructokinase (also called PFK1) - the enzyme in glycolysis that converts fructose-6-phosphate to fructose-1,6-bisphosphate. F2,6BP also inhibits fructose-1,6-bisphosphatase (F1,6BPase) - the enzyme in gluconeogenesis that accomplishes the opposite reaction. In fact, F1,6BP is ten times more sensitive to F2,6BP than AMP, another reciprocal regulator. The complex regulatory system involving F2,6BP is shown in Figure 16.7.

A single polypeptide contains both of the activities necessary to synthesize and degrade F2,6BP. The synthetic activity is called phosphofructokinase-2 (PFK2). To distinguish PFK2 from phosphofructokinase (the glycolysis enzyme), the latter enzyme is sometimes called PFK1. The catalytic activity that breaks down F2,6BP is referred to as fructose-2,6-bisphosphatase (F2,6BPase). Interconversion of PFK2 and F2,6BPase is accomplished by a cAMP-stimulated phosphorylation of PFK2 (by cAMP-dependent protein kinase) to form F2,6BPase.

Thus, in the presence of cAMP (which is produced in response to glucagon or epinephrine action), destruction of F2,6BP is favored. Because PFK1 is stimulated by F2,6BP, but F1,6BPase (the corresponding gluconeogenesis enzyme) is inhibited by F2,6BP, cAMP produced by glucagon or epinephrine will turn off glycolysis and turn on gluconeogenesis. Thus, due to hormonal control of F2,6BP, glycolysis and gluconeogenesis respond rapidly to hormonal regulation.

Summary

1. F2,6BP activates PFK1 (glycolysis) and inhibits F1,6BPase (gluconeogenesis)

2. PFK2 makes F2,6BP from F6P

3. F2,6BPase breaks down F2,6BP to F6P

4. PFK2 is converted to F2,6BPase by cAMP-dependent protein kinase by phosphorylation (requires cAMP - stimulated by glucagon or epinephrine)

5. F2,6BPase is converted back to PFK2 in absence of cAMP

So, when epinephrine or glucagon stimulates cells -> cAMP is produced ->cAMP-dependent protein kinase is activated -> PFK2 is converted to F2,6BPase ->F2,6BP is broken down -> Fructose 1,6-bisphophatase (gluconeogenesis) is activated and PFK1 (glycolysis) is inhibited.

In the absence of epinephrine/glucagon stimulation (or with insulin stimulation), cAMP is broken down -> cAMP-dependent protein kinase is inactivated -> F2,6BPase is converted to PFK2 -> F2,6BP is made -> PFK1 (glycolysis) is stimulated and fructose-1,6-bisphsophatase (gluconeogenesis) is inhibited."

This is the link where I took the info, I have the same question and this help me to understand it. Remember PFK-2 and F2,6BPase are two functional domains of the same enzyme, and this regulation is very important because allow quick regulation of glycolysis and gluconegenesis (both) in response to changes in the energy state or energy necessity of the cell.

http://www.pearsonhighered.com/mathews/ch16/c16f2bgr.htm