Fructose-2,6-bisphosphate question

[HopefulMDclass2020]

F-2,6-BP is really giving me some issues. I understand that it increases in concentration when insulin is present and decreases in concentration when glucagon is present, as well as its roles in regulating fructose-1,6-biphosphatase and PFK. Okay, well maybe not understand as much as memorized.

Why is it, that fructose-1,6-bisphosphatase (rate-limiting step in gluconeogensis) is stimulated by ATP and inhibited by AMP and fructose 2,6-bisphosphate?

We know that insulin in released in the "fed" state, which would typically correspond to high levels of ATP. It seems backwards that it is stimulated by ATP and at the same time inhibited by a hormone that typically corresponds to the fed state.

Any clarification would be highly appreciated!

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[MrRed]

Fructose-2,6-bisphosphate is in good supply when glycolysis is occurring in the cell at a relatively high rate. When glycolysis is the prevailing reaction (in terms of glycolysis vs. gluconeogenesis) you obviously don't want to have gluconeogenesis going on as well, this would be a futile cycle.

In my Lehninger Principles of Biochem. book I see no reference to FBPase-1 being stimulated by ATP; only that it is inhibited strongly by AMP and F-2,6-BP and stimulated by citrate. Now, we know that gluconeogenesis is stimulated in general by glucagon. This makes sense as glycogenolysis is also stimulated by glucagon, generally, and the body wants to replace the glucose stores it is draining as glycogenolysis occurs. After all, much of the body, and especially THE BRAIN needs glucose -- and in the fasted state of course the body is not sure when the next meal will be had.

So, I suspect you might be relieved of your confusion knowing that ATP does not actually stimulate FBPase-1 directly. I also suspect that your confusion might be in directly linking insulin to a high ATP state inside of the cell. Sure, in general in the fed state there will be more freely available macromolecules present for the upkeep of ATP producing reactions -- however in the fasted state the cell still needs ATP (of course you realize this)! Sure, replenishing glucose stores is important for many reasons during a fast -- but not as important as making sure the cell has enough ATP to function at that very moment. When ATP is high -- specifically during a fast -- this signals to the cell that okay, I can now put energy into replenishing glucose stores (and of course this is mainly referring to hepatocytes/other liver and to a more minor extent kidney cells). This high ATP level is, I suspect, indirectly translated to the enzyme FBPase-1 through the lack of inhibition by AMP at the time and the stimulation by citrate.

I do hope this helped some of your confusion -- haven't slept much in the past several days so I do apologize if my writing is a bit hard to follow right now. If you are still unclear I will definitely try to resolve some issues upon having a bit more sleep

 

[tturchi51]

What mr. red said is very true, but between your question and his explanation I can see how this is confusing as I got confused myself haha. But here is my notes on it and this website I found has good info that will answer your question better than I prolly can. https://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/gluconeo.htm



Either Glycolysis OR gluconeogenesis will occur, neither at the same time. These are reciprocal of each other in order to keep homeostasis. Think of it in terms of the reciprocal relationship with your girlfriend. If you are hungry and she cooks for you, whenever she wants to watch some chick flick you do it in order to keep the relationship in balance.

Fed State

Glucagon-is released when cells need more glucose(fasting), turns off glycolysis (bc no glucose to go through glycolysis)
- triggers phosphorylation of enzymes by PKA (increases cAMP cascade)
- increasing cAMP-decreases fruct2-6biphosphate

Rate limiters

fructose-1,6-biphosphatase- is inhibited by AMP(stimulated by ATP)
PFK-inhibited by ATP (stimulated by AMP)


Remember that fructose2,6biphosphate is a bi-functional enzyme that makes and degrades an allosteric regulator

Fructose-2,6-bisphosphate allosterically activates the Glycolysis enzyme Phosphofructokinas

Fructose-2,6-bisphosphate also activates transcription of the gene for Glucokinase, the liver variant of Hexokinase that phosphorylates glucose to glucose-6-phosphate, the input to Glycolysis

Fructose-2,6-bisphosphate allosterically inhibits the gluconeogenesis enzyme Fructose-1,6-bisphosphatase.

Thanks for asking this question and sorry if I made it more confusing!

 

[kingtal0n]

fixed

Remember that phosphofructokinase 2/fructose-2,6-bisphosphatase is a bi-functional enzyme that makes and degrades an allosteric regulator

Fructose1,6biphosphate can not go backwards and turn into glucose

And more interesting to me is that plain ingested fructose has its own initial kinase

 

[tturchi51]

thank you !

 

[HopefulMDclass2020]

First off, thank you all for your comment! Second, okay, so we are saying that we need to make sure the liver cells satisfies its own ATP requirements first before it undergoes gluconeogensis. Okay, so my last issue is this. Gluconeogensis is stimulated by glucagon while implies the fasted state. As a result of the fasted state, I would assume ATP would be low in the liver cell. However, we also know that glucagon stimulates beta-oxidation. So essentially big picture, glucagon will stimulate beta-oxidation that will supply the ATP needed for the liver function to function and then the ATP will indirectly stimulate fructose-1,6-biphosphatase and allow gluconeogensis to occur. Sound logical?

Again, thank you guys!

 

[tturchi51]

Correct! Fatty Acids undergo beta ox. -->Acetyl CoA goes through TCA-->ATP-->gluconeogenesis

--> means yield or points to the produce