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Allosteric regulation and feedback loops

Video transcript

so today we're going to talk about how allosteric regulation can affect enzyme kinetics but first let's review the idea that enzymes 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 enzymes rate of product formation with respect to substrate concentration also remember that 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 can bind 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 enzyme and there can be any number of them as well so what do mean when we say regulators well we generally say that there are two types of regulators there are allosteric activators which increase enzymatic activity and activate them and allosteric inhibitors which decrease enzymatic activity and inhibit the enzymes so let's take a look at what we mean by increasing and decreasing enzymatic 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 and in this first graph I've drawn three different curves and the blue curve represents the enzyme functioning without an allosteric regulator at all the red curve represents an enzyme with an allosteric inhibitor and the green curve represents the enzyme analysis your activator and in this example the activators and inhibitors affect vo through 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 neck 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 in 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 be through reaction 1 and B forming see through reaction 2 and so on and so on now let's say that molecule F acted as an activator for the enzyme powering reaction 1 so it had a positive effect on enzyme ones activity now we would call this a positive feedback loop since molecule F increases the rate of reaction 1 which then causes even more F to be made since we've increased the rate of formation of molecule F now let's say molecule F had a negative effect on enzyme 1 we would call this a negative feedback loop since molecule F decreases the rate of reaction 1 which leads to a decrease in the rate of formation of 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 phosphofructokinase is an enzyme involved in glycolysis and it catalyzes the conversion of fructose 6-phosphate and ATP to form fructose 1 6 bisphosphate and adp now remember that glycolysis is a metabolic process that cells use to generate ATP so here are molecule F or downstream regulator from the last example is ATP and it turns out that ATP is an allosteric inhibitor of phosphodiesterase a cell saying we have ATP and we don't really need anymore and we don't need phosphofructokinase 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 phosphofructokinase we can call it a homo tropic inhibitor which is a new term and we call it a homo tropic inhibitor because the substrate and the regulator are the same molecule now am P which is used up ATP is an activator for phosphofructokinase and this also makes sense because if a MP levels are high then ATP levels are probably low and it's like the cell saying we need ATP so we do need frost but fructose kinase to push glycolysis along now since a.m. P is a regulating molecule but not an active site substrate for phosphofructokinase it would be considered a hetero tropic 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 multi-step 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 particular has a very negative Delta G and it's actually negative four point five kcal per mole and that means that it's not easily reversed since there will 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 a love story and how regulatory molecules can bind to allosteric sites instead of active sites second we learned that these allosteric regulators influence in enzymes kinetics by increasing or decreasing km of Emax and third we learned about what a feedback loop is and how in long multi-step processes like like pollicis the best control points are highly committing steps the ones with very negative Delta G values