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Regulation of glycolysis and gluconeogenesis

Explore the regulation of metabolic pathways, a crucial balancing act in the body. Dive into glycolysis and gluconeogenesis, and understand when each pathway dominates. Discover how the body maintains this balance using fast-acting regulation like Le Chatelier's Principle and slow-acting regulation through transcriptional changes. Uncover the role of hormonal regulation in managing these metabolic pathways. Created by Jasmine Rana.

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  • mr pants teal style avatar for user Jane Yuan
    At she discusses insulin and glucagon binding on the cell to start a cascade. If they are hormones wouldn't they act inside the cell rather than on the surface?
    (7 votes)
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  • mr pink red style avatar for user nfarsio
    Instead of saying insulin promotes glycolysis and glucagon promotes gluconeogenesis, shouldn't we say insulin promotes storage of glucose into glycogen (which is essentially the opposite of what glycolysis does) and glucagon promotes breakdown of glycogen? I'm getting a little confused...
    (8 votes)
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    • purple pi purple style avatar for user Tonya Darghali
      Basically, insulin promotes anything that will decrease blood glucose levels. This can happen in two ways: either converting glucose--> pyruvate (glycolysis) or by converting glucose-->glycogen (glucogenesis). Glucagon does the opposite, it promotes any pathway that will increase blood glucose levels. That is either by converting glycogen--> glucose (glucogenolysis) or by converting carbs, AAs, pyruvate, or lactate --> glucose (gluconeogenesis).
      (21 votes)
  • female robot grace style avatar for user Anna
    I have read that there are 4 basic metabolic pathways for glucose.

    They are glycolysis, gluconeogenesis, glycogenolysis, and glycogenesis.

    What is the difference between these? I suspect that these are what they are:
    Glycolysis: glucose breakdown(happens in every cell)
    Gluconeogenesis: Glucose formation(happens in cells other than liver and muscle as well as liver and muscle)
    glycogenolysis: Glycogen breakdown(happens in liver and muscle)
    glycogenesis: Glycogen formation(happens in liver and muscle)
    (12 votes)
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  • piceratops seed style avatar for user ash.masters88
    At you are discussing pyruvate being converted into OAA during gluconeogenesis, but you also state the amino acids are converted into OAA during gluconeogenesis. Are one of these processes the major contributor of OAA or do both occur?

    (5 votes)
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  • blobby green style avatar for user laur.morrison
    also, she says that "if the cell is running out of atp so if it is running out of atp the cell probably wont want to be performing energy requiring processes such as gluconeogeneis" but i thought the whole point of gluconeogenesis was to produce atp when there is low glucose levels?
    (2 votes)
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  • leaf green style avatar for user Calvin Law
    Regarding OAA being a fast promoter for the Gluconeogenesis, why wouldn't it also drive Krebs Cycle given that OAA is a starting metabolite for the cycle? Does this relate to how much acetyl-CoA is involved? Thanks!
    (4 votes)
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    • leaf green style avatar for user sandracizinando
      The OAA in the gluconeogenesis is catalyzed with a different enzyme and if the glucose level is low their must be allosteric regulation of the enzymes in Krebs cycle. There must be basal level of glucose for all the metabolic pathways to function correctly. Anyway, when the level is restore, the TCA cycle will regenerate more OAA. This could happen but the cells have redundant mechanism (as shown in the video) to increase glucose ( they all work together)
      (1 vote)
  • blobby green style avatar for user laur.morrison
    can someone explain the allosteric regulation part with atp and glycolysis and gluconeogenesis for me please? im not quite understanding what she is saying
    (1 vote)
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    • marcimus red style avatar for user Laureen S.
      Enzymes generally have a catalytic site where the substrate binds for the catalytic reaction (enzyme stabilized transition state). However, enzymes may also have an allosteric site where molecules can bind to regulate the enzyme's activity or the enzyme's specificity towards the substrate. The molecules that bind to the regulatory sites on enzymes may inhibit the enzyme's activity or enhance the enzyme's activity.

      Glycolysis breaks down glucose and forms ATP, so when the cell has enough ATP, the cell should tell glycolysis to stop. Therefore, it seems reasonable that ATP would be a negative regulator of enzymes partaking in glycolysis. Lots of glycolysis --> increased concentration of ATP --> increased ATP binding to allosteric sites on glycolysis enzymes --> glycolysis stops.
      (3 votes)
  • purple pi purple style avatar for user Felicia Wright
    What mechanism in the muscles are using up ADP and creating AMP?
    (1 vote)
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  • blobby green style avatar for user kguer039
    Isn't gluconeogenesis activated by low levels of ATP?
    (1 vote)
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  • blobby green style avatar for user Chris Boris Alexander Wied Tøstesen
    At where you explain the "macro-application" of Le Chatelier's Principle - you conclude that:

    Insulin, being associated with release at high bloodglucose, should favor glycolysis and Glucagon should then favor gluconeogenesis.

    But since glucagon has the following effects...
    Glukagon receptors ligation => G-prot(a-unit) dissociate => adenyl cyclase activated => cAMP => PKA => (3-fold effect):
    1. Inhibition of glycogenesis
    2. Activation of phosphorylase kinase A =>
    phosforylase B to A => Increased glycolysis =>
    increased *[cell glu]*
    3. Inhibition of phosphorylase kinase B to A.
    (more of 2.)

    SO in the liver this increased glucose concentration has the "out" of being dephosphorylated (Glc-6-phosphatase) and going to the blood, but it seems to me that if that out is not present (muscle cells) it would push the reaction towards glycolysis, opposite the conclusion??

    Is this simply not happening at a scale worth consideration?

    Thank you in advance for your answer :) great videos
    (1 vote)
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Video transcript

- [Instructor] At its most simplistic level, regulation of metabolic pathways inside of the body is really just a fancy word for a balancing act that's occurring in the body. So, to illustrate this, I have a seesaw and we've been learning about two metabolic pathways: glycolysis, which is the process of breaking down glucose into pyruvate; and gluconeogenesis, which is essentially the opposite in which we start out with pyruvate and through a little bit of a different route we end up back at glucose. And when we're talking about the regulation of these particular pathways, we're essentially asking ourself, "When is glycolysis the predominant pathway and when is gluconeogenesis the predominant pathway?" The body wants to make sure that we either have a net breakdown of glucose, in the case of glycolysis, or that we have a net production of glucose, in the case of gluconeogenesis. So now the next question is, "How does the body "accomplish this balancing act?" And to answer this question, the way I like to think about it is to think about it along a spectrum. There are very fast-acting forms of regulation that take place on the order of seconds, and there are very very slow forms of regulation that can take up to hours or even days to occur. So let's talk about each of these in a little bit more detail. The major principle that helps me understand fast-acting forms of regulation is a good old principle from general chemistry: Le Chatelier's Principle. So if you remember, Le Chatelier's Principle talks about anything that's in equilibrium and it says that if there's any change to this equilibrium, let's say more products are added or reactants are taken away, the equilibrium will adjust to essentially counter that change and return the system back to equilibrium. So what does this mean in the context of metabolic pathways like glycolysis and gluconeogenesis? So let's remind ourselves that in glycolysis, glucose is converted to pyruvate through several reactions that are all in equilibrium with one another, and so we can essentially think about this metabolic pathway as a series of equilibria. And so imagine, for example, if we had an influx of glucose, let's say we've just eaten a big meal, and a huge bunch of glucose has entered our body and our blood stream. What will happen to this equilibrium? Well, we can return to Le Chatelier's Principle and say that if we have a rise in glucose, it will essentially push this entire equilibria towards the production of pyruvate. And so you can see that in this example, Le Chatelier's Principle allows this equilibrium to adjust within seconds to just a simple influx of glucose to promote glycolysis. Le Chatelier's Principle also applies to gluconeogenesis. So remember that in gluconeogenesis, something unique starts to happen after blood glucose levels have been low for a while. Amino acids being to break down and form this metabolite called oxaloacetate, and remember that oxaloacetate plays its unique role in its conversion of pyruvate back to glucose which occurs in gluconeogenesis. Remember that it's kind of this intermediary. So pyruvate is converted to oxaloacetate and then essentially reenters the equilibria to form glucose. So you can imagine that if we have an influx of oxaloacetate, the equilibria will be pushed towards the opposite direction, that is, towards the production of glucose. Now in addition, I wanna briefly mention another form of fast-acting regulation, which is call allosteric regulation. So what is allosteric regulation? Recall that all metabolic pathways have unique enzymes that catalyze or facilitate each step of the reactions along the metabolic pathways. So you can imagine that if we have an enzyme here, I'm just drawing a simple structure, it has what's called an active site, where it actually binds the substrate of interest so it binds the, let's say, glucose molecule here, but in addition there are also molecules within a cell that we call allosteric regulators and these, by definition, bind to a portion of the enzyme that is not the active site. So let's say we have an allosteric molecule that binds to a separate portion like right here. Now this allosteric molecule can have one of two effects. We say that allosteric molecules can be inhibitory, that is, by inhibiting enzymes, inhibit the pathway that utilizes those enzymes, or these allosteric interactions can be positive, that is, promote the action of enzymes and therefore promote the overall reaction in which those enzymes are involved. So to put this in context with glycolysis and gluconeogenesis above, it turns out that ATP is actually a big allosteric regulator of one of these two pathways. So recall that gluconeogenesis requires ATP, a net amount of ATP, to produce glucose. It's an anabolic building up pathway. On the other hand, in glycolysis, there is a net release of ATP and the oxidative breakdown of glucose. And so we have a lot of ATP in a cell, think about, for a moment, which of these two pathways would be favored. Indeed, gluconeogenesis would probably be favored because it requires ATP. On the other hand, if there's a lot of ATP, that's kind of a sign to the cell to say, "Hey, we don't need to perform as much glycolysis "because we already have enough ATP available." And it does turn out that ATP is actually an allosteric regulator of a couple enzymes in glycolysis. And specifically, it's a negative allosteric regulator, or an inhibitor, of these couple enzymes. Essentially it's putting the breaks on glycolysis and saying, "We have enough energy "and we don't need to produce any more." On the other hand, it turns out that there is also a molecule, AMP, in the body which is basically a sign that the cell has used up all of its ATP, in other words, ATP has been dephosphorylated, and turned into AMP which is a sign that that cell is running out of ATP. So if the cell is running out of ATP, the cell probably won't want to be performing energy-requiring processes such as gluconeogenesis, and indeed, AMP is a negative allosteric regulator of one of the enzymes in gluconeogenesis. Alright, so that kind of finishes up our discussion of fast-acting forms of regulation. So now let's talk briefly about slow-acting forms of regulation. So these types of regulation often take advantage of transcriptional changes within the cell. So what do I mean by that? So let's first remind ourselves what transcription is. So remember that transcription is a process of taking DNA and making an mRNA transcript and then translating this in the cytosol of the cell to a protein product and when we're talking about proteins oftentimes we're talking about enzymes. So I'm just gonna go write that here since it's relevant for our discussion. And so you can imagine for example that this might be very useful if the organism is in a longterm fasting state. It will want to essentially up-regulate the transcription of enzymes that promote something like gluconeogenesis so that it can dump glucose into the blood. And notice here that even visually as it's implied here this process of going from DNA to mRNA to enzymes is going to take much longer than a simple Le Chatelier or allosteric regulation and so that's why this process is more of an adaptive process that allows the organism to adapt to more of long term changes that it experiences in its environment. Now finally I want to add in one more form of regulation between fast- and slow-acting regulation which is called hormonal regulation. So what is hormonal regulation? Well it's exactly what it sounds like. It's the ability for the body to essentially produce specific hormones which are simply molecules that travel in the blood to regulate whether glycolysis or gluconeogenesis is on or off. And the two hormones that the body uses to regulate glycolysis and gluconeogenesis and pretty much, actually, all metabolic pathways, are insulin and another hormone called glucagon. And depending on whether there is more insulin or more glucagon, the body will be more likely to do glycolysis or more likely to do gluconeogenesis. So let's talk about how that decision is made. Now hormones, like insulin and glucagon, are usually released by the body whenever the body deviates from a particular set point. Now in the case of regulation of metabolism, the set point that we're interested in is the blood glucose level, and if we return back to our analogy here, this seesaw here, this pivot point we can think about as our set point. The blood glucose level: it's a specific amount of glucose that the body wants to have in the blood at all times. Now to get more specific, if the blood glucose level rises it actually stimulates the body to release the hormone insulin, and if the blood glucose levels decrease, it stimulates the body to release the hormone glucagon. And so with that in mind, take a moment to think about which hormone, insulin or glucagon, promotes glycolysis, and which of these two hormones promotes gluconeogenesis. Basically this is actually a macro-application of Le Chatelier's Prinicple, right? If we have too much blood glucose level, we want to get rid of it. How do we get rid of it? We break it down. And so indeed, insulin promotes glycolysis. On the other hand, when blood glucose levels are low, we want to return the equilibrium to normal, we want to pump more glucose back into the blood and we know that gluconeogenesis can accomplish that for us. And so glucagon indeed promotes gluconeogenesis. Now briefly at the end I want to talk about why I decided to put hormonal changes between fast- and slow-acting forms of regulation. So to talk about this, we need to understand a little bit how hormones interact with target cells. So cells in our body have particular receptors that will bind to the hormones that are floating around in the blood stream. So once these receptors bind to a particular hormone, whether it be insulin or glucagon, it actually causes a series of particular reactions to occur inside of the cell to modify oftentimes enzymes that are involved in metabolic pathways. So I'll just abbreviate that with the letter E. And these modifying reactions that occur in the cell are oftentimes phosphorylation reactions, that is, either the gain or the loss of a phosphate group oftentimes on an enzyme in a metabolic pathway. And so with that in mind, you can appreciate how modification by phosphorylation is a lot faster than starting with a DNA transcript and then going to mRNA and then translating into enzymes, but it is indeed a bit slower than the second-to-second Le Chatelier and allosteric regulation that can occur in a cell as well.