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Allosteric regulation and feedback loops

Created by Ross Firestone.

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  • blobby green style avatar for user Paul Atreides
    At , a note pops up saying that an activator will increase Km. I don't understand that - I thought that an activator reduces the substrate concentration needed to reach Vmax, which decreases Km. Can someone explain this? Thanks!
    (20 votes)
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  • female robot amelia style avatar for user Cristina
    At and onward, it is said that allosteric regulation can affect either Vmax or Km. Yet all of my MCAT books state that noncompetitive inhibitors, which work via allosteric sites, will ONLY affect Vmax, and do not affect Km. This is in contrast to competitive inhibitors, which work via the active site, and affect Km but not Vmax. Can anyone explain this discrepancy?
    (10 votes)
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  • leafers tree style avatar for user Ronald B
    Is phosphofructokinase a transferase? Or an oxidoreductase?
    (1 vote)
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  • piceratops seed style avatar for user J Kwon
    Is there a way to conceptually think about the change of Vmax or Km? Like when Vmax increases, does that mean there's more enzymes available to make product? I have a hard time understanding what it exactly means
    (2 votes)
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    • marcimus pink style avatar for user Sofia Gruber
      Vmax is the maximum rate of the reaction. A change in the maximum rate relates to how efficiently the enzyme is working. If we see a decrease in Vmax, we can assume that a noncompetitive inhibitor is changing how well the enzyme is working.
      Km is the affinity the enzyme has for the substrate, If Km is increased, the enzyme has less affinity for a substrate. In the case of a competitive inhibitor, it will bind to the enzyme's active site, decreasing the affinity of the enzyme to the substrate.
      (6 votes)
  • female robot grace style avatar for user Premed Nerd
    So with an allosteric activator the Km value is increased and so is the Vmax value? I don't understand if you are trying to activate an allosteric site to inhibit the enzyme how does that increase the speed?
    (2 votes)
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    • starky tree style avatar for user Mary
      Allosteric activation means that it changes the activation site for easier binding, resulting in a faster catalysis. I belief you confused allosteric inhibition and activation, the allosteric binding can enhance both inhibition and activation of the enzyme.
      (2 votes)
  • blobby green style avatar for user Lynette Yung
    at it mentions that the reaction is not easily revered - I understand that this is because there is a negative delta G (therefore the reaction is going "forward"/ left to right). But why is it not easily reversible? What is considered a "high" delta G? Many thanks in advance!!
    (1 vote)
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  • blobby green style avatar for user Rui Ong
    Can the effect of the concentration of AMP be considered a positive feedback loop? How far down the stream before a product can be considered "out of the loop", or do positive/negative feedback loops only describe the immediate reaction?
    (1 vote)
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    • male robot hal style avatar for user Gene Sazhnyev
      Both positive and negative feedback loops describe the effect of an intermediate or product of a metabolic pathway on an enzyme that participates in the linked series of reactions. Thus, any metabolite, regardless of how far down the pathway it is, has the potential to be an allosteric regulator and participate in a feedback loop. However, AMP is not a product or intermediate of glycolysis; hence, its contribution as an allosteric activator of phosphofructokinase cannot be considered as a positive feedback loop.

      P.S. If you are still confused on the topic, please check the Wikipedia page on Metabolic Pathways that I developed, and in which I thoroughly describe these topics: https://en.wikipedia.org/wiki/Metabolic_pathway
      (3 votes)
  • aqualine ultimate style avatar for user fransiadeleon
    @ What does a "control point" for a reaction mean?
    (2 votes)
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  • piceratops seedling style avatar for user yaconopd
    How did he determine from those graphs that the activator was decreasing Km and increasing Vmax?
    (1 vote)
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  • female robot grace style avatar for user Premed Nerd
    So with an allosteric activator the Km value is increased and so is the Vmax value? I don't understand if you are trying to activate an allosteric site to inhibit the enzyme how does that increase the speed?
    (1 vote)
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    • blobby green style avatar for user Lisa Mailat
      Enzymes have allosteric sites, but not all regulators that bind to these sites inhibit enzyme function. This depends on whether or not the regulator is an activator or an inhibitor. Allosteric activators increase enzyme function by either lowering Km or increasing Vmax, and allosteric inhibitors decrease enzyme function by either increasing Km or lowering Vmax
      (1 vote)

Video transcript

Voiceover: So, today we're going to talk about how allosteric regulation can affect enzyme kinetics. But first, let's review the idea that an enzyme's catalysis can be divided into two steps. First, the binding of enzymes to substrate, and second the formation of products. And using this information, we can derive the Michaelis-Menten Equation, which allows us to look at an enzyme's rate of product formation with respect to substrate concentration. Also remember substrates will typically bind to enzymes at the active site. So what do we mean when we say allosteric regulation? Well, we know that enzymes usually have an active site where substrates combined, but enzymes can also have what we call an allosteric site. And these allosteric sites are places on the enzyme where any enzyme regulator can bind. And I've put this star here just to point out that allosteric sites can be anywhere on a enzyme. There can be any number of them as well. So what do we mean when we say regulators? Well, we generally say there are two types of regulators. There are allosteric activators, which increase enzymatic activity and activate them, and allosteric inhibitors, which decrease ezymatic activity and inhibit the enzymes. So let's take a look at what we mean by increasing and decreasing ezymatic activity from a kinetic perspective. So, remember the Michaelis-Menten equation, and if we're assuming substrate concentration to be constant, then there are two ways to influence enzymatic activity, or VO. In this first graph, I've drawn three different curves. The blue curve represents the enzyme functioning without an allosteric regulator at all. The red curve represents the enzyme with an allosteric inhibitor, and the green curve represents the enzyme with an allosteric activator. And in this example, activators and inhibitors affect VO by either increasing or decreasing KM since the V max values seem to be pretty close between the three curves. So an activator here might be decreasing KM. Now, in this next example, we have the same three colored curves, but instead of KM changing significantly, the regulators seem to be changing V max. With the activator increasing the V max value. So, now that we've talked about activators and inhibitors, let's introduce the idea of the feedback loop. And, the basic idea is that a feedback loop is when you have downstream products regulating upstream reactions. And I understand this can be a mouthful, so let me show you this little reaction sequence, where we have A forming B through reaction one, and B forming C through reaction two, and so on and so on. Now let's say that molecule F acted as an activator for the ezyme powering reaction one. So it had a positive effect on enzyme one's activity. Now we would call this a positive feedback loop since molecule F increases the rate of reaction one, which then causes even more F to be made, since we've increased the increase the rate of formation of molecule F. Now, let's say that molecule F had a negative effect on enzyme one, we would call this a negative feedback loop since molecule F decreases the rate of reaction one, which leads to a decrease in the rate of formation in molecule F. So, let's look at an example of a feedback loop just to really drive home the point if you're still confused. Now, phosphofructokianase is an enzyme involved in glycolysis, and it catalyzes the conversion of fructose six phosphate and ATP to form fructose one six bisphosphate and ADP. Now, remember that glycolysis is a metabolic process that cells use to generate ATP. So, here, our molecule F, or downstream regulator from the last example, is ATP. and it turns out that ATP is an allosteric inhibitor of phosphofructokianase. And this makes sense because if ATP is at a high level, it's like the cell saying "We have ATP and we don't really need any more. "And we don't need phosphofructokianase "to push glycolysis along." So this would be a good example of a negative feedback loop. Since making ATP slows down glycolysis, and thus slows down the rate of ATP production. Now, because ATP is both an allosteric regulator and a substrate for phosphofructokianase, we can call it a homotropic inhibitor, which is a new term, and we call it a homotropic inhibitor because the substrate and the regulator are the same molecule. Now AMP, which is used up ATP, is an activator for phosphofructokianase, and this also makes sense because if AMP levels are high, then ATP levels are probably low. And it's like the cell saying "We need ATP." So we do need phosphofructokianase to push glycolysis along. Now, since AMP is a regulating molecule but not an active site substrate for phosphofructokianase it would be considered a heterotropic activator since the substrate and regulator are different. Now, the final point I want to make is that specific reactions make excellent control points for long, multistep processes. And remember that glycolysis is a ten step sequence. So why is there so much regulation going on for this one step? Well, this reaction in particular has a very negative delta G, and it's actually negative 4.5 kCal per mol. And that means that it's not easily reversed since there'll be a big release of energy from the reaction, and this makes THIS step of glycolysis an excellent control point for ALL ten steps together, since it's more or less a one way reaction. So, what did we learn? Well, first, we learned about the concept of allostery, and how regulatory molecules bind to allosteric sites instead of active sites. Second, we learned that these allosteric regulators influence an enzyme's kinetics by increasing KM or V max, and third we learned about what a feedback loop is, and how in long, multi-step processes like glycolysis, the best control points are highly committing steps, the ones with very negative delta G values.