Competitive, Uncompetitive and Noncompetitive Inhibition

so as we discussed previously many of the biological processes that exist in nature for example in the cells of our body are catalyzed by enzymes so enzymes speed up the rates of chemical reactions and that essentially produces the same amount of product as without the enzyme but it produces that product at a much higher rate now the thing about that is we don't always want to produce some given product at a high rate sometimes we want to basically stop the production of a product because simply we have too much of that product inside our cell or inside the environment in the first place and so what that means is for the biological systems such as our cells to actually function effectively and efficiently they have to have a way of actually controlling and regulating the activity and the functionality of enzymes and one way by which we can actually control the activity of enzymes is by using these special molecules and in some cases ions to basically inhibit the activity of these enzymes and these are known as enzymatic inhibitors so once again in order to function effectively biological systems must be able to regulate and control the activity and the functionality of enzymes special agents we call inhibitors can bind on to enzymes and inhibit or block their activity so there are two categories of inhibitors we have irreversible inhibitors and we have reversible inhibitors so let's begin by briefly focusing on irreversible inhibitors so in irreversible inhibition that particular inhibitor basically binds onto the enzyme very tightly very strongly it binds so strongly that it's very unlikely that it's ever going to actually dissociate from that enzyme so if we take a look in the following chemical reaction we have the enzyme and our irreversible inhibitor and so because the is attracted very strongly to that enzyme it will bind on to that enzyme forming this product this enzyme inhibitor complex and notice the arrow is much longer going this way than this way and what that means is the binding is essentially irreversible the equilibrium lies very far to the right side of this chemical reaction now the majority of the time when this binding takes place between the irreversible inhibitor and the enzyme the binding is vehicle valent bonds but sometimes we can also have non covalent bonds so some inhibitors will bind to enzymes very tightly either by covalent or non covalent means and once bound they will not dissociate very easily from the enzyme and these inhibitors are known as irreversible inhibitors they have a very high affinity for the enzyme so one very common misconception about irreversible inhibition is that these inhibitors always bind covalently by forming covalent bonds between the enzyme and the inhibitor and that is simply not true there are examples of molecules that inhibit irreversibly and yet they only form non covalent bonds so remember that the underlining the defining point about irreversible inhibitors is that they bind very strongly and so they will not let go of that enzyme very easily that is what defines irreversible inhibition and once they bind they change the conformation and so they essentially inhibit or block the activity of that enzyme now there are many different examples of irreversible inhibitors and three examples are listed on the board so we have nerve gas we have penicillin and we have aspirin and each one of these molecules basically binds to inhibits a specific type of enzyme found inside our body so let's begin with nerve gas nerve gas is a very dangerous very potent reversible inhibitor and it forms covalent bonds it binds unto a special enzyme found inside the nervous system known as acetylcholinesterase so remember acetylcholinesterase is an enzyme that breaks down the neurotransmitter acetylcholine that is used to basically communicate between nerve cells and so by binding onto that enzyme onto the acetylcholinesterase it inhibits that enzyme from breaking down that neurotransmitter and that essentially leads to the breakdown of the nervous system and that leads to death of that particular individual now what about penicillin so nerve gas kills off that individual but penicillin actually saves that individual because for example if an individual has an infection by sunked some type of bacterial agent if we add penicillin into that individual what penicillin does is it binds unto special enzyme found in that bacterial cell that essentially is used by the bacterial cell to form the bacterial cell wall so that enzyme is known as transpeptidase so transpeptidase is an enzyme used by the bacterial cell to form the wall the cell wall around that bacterial cell and penicillin binds unto transpeptidase and prevents it in activates it inhibits it and prevented from making that cell wall and so the bacterial cell eventually dies off now what about aspirin well aspirin is once again an irreversible inhibitor that binds unto special enzyme known as cyclo oxy cyclooxygenase so aspirin binds onto cyclooxygenase and it prevents that molecule from essentially stimulating the process of inflammation and so that decreases pain it basically makes headaches go away and so forth and each one of these are irreversible inhibitors that modify the enzyme by binding covalently to that enzyme now let's move on so reversible inhibitors so in reversible inhibition we have these inhibitors that bind unto the enzyme but they bind relatively weakly and that means reversibly so we can easily change the conditions in the environment and that will essentially cause the dissociation of that inhibitor from that particular enzyme so the defining property of reversible inhibition is the ease with which the inhibitors can actually dissociate and break away from the enzyme under certain condition and this is in contrast to irreversible inhibitors that basically bind onto the enzyme and once bound they will not associate very easily now we can subdivide subcategorize reversible inhibition into three different types and actually there are four but in this lecture we're going to focus on three so we have competitive inhibition we have uncompetitive inhibition and we have non-competitive inhibition we also have something called mixed inhibition but we're not going to focus on that in this lecture so let's begin with competitive inhibition so what exactly do we mean by competitive inhibition well in some cases we have an inhibitor that actually resembles the substrate that binds on to the active side and so what that means is the structure of that inhibitor is similar to the structure of that particular substrate and because the structure resembles what that means is that inhibitor will bind to the same location where the substrate actually binds to and so that's exactly why that inhibitor will compete with the substrate for that active site and we see in competitive inhibition that inhibitor binds on to that same active site that the substrate actually binds to so in this inhibition the inhibitor molecule typically resembles that substrate and can therefore bind into the active site of that enzyme and once bound the inhibitor prevents that substrate from actually occupying that active side now what competitive inhibition does and we'll discuss this in much more detail in a next lecture is it keeps the v-max the same so it keeps the maximum velocity of that enzyme the same but it increases the apparent km value increases the Michaelis constant and we'll see exactly what that means and why is that and why that's the case in the next lecture so let's take a look at the following diagram so we have the enzyme shown in blue this is the active side of the enzyme this is the inhibitor and this is the substrate and notice that they are very similar in their structure and that's precisely why when we mix these three molecules that inhibitor will bind onto the active site forming the enzyme inhibitor mixture and so this substrate will not bind unto that active site simply because there is no space to actually go into that active site now the question that you might ask is why is it that the red molecule inhibitor binds into the active side and not the green molecule the substrate well because normally the affinity of that inhibitor for that active site is much higher than the affinity of that substrate and that's exactly why if given the chance to if we mix these three molecules because this has a much higher affinity for the active side in the substrate this will be much more likely to actually bind into that active site to form that enzyme inhibitor mixture enzyme inhibitor complex now the defining point about competitive inhibition that you should know is because that inhibitor binds inside the active side the same region where the substrate actually binds to we can actually kick off that inhibitor from the active side by increasing the concentration of the substrate and that's because when we increase the number of the green substrate molecules there's much higher math radical probability chance that the substrate will essentially collide with the active side and go into that active side so by increasing the concentration of the green molecules we increase the likelihood that the green molecules will collide with the active site to form the enzyme substrate complex and that's exactly why if we increase the concentration of the substrate those green molecules will eventually outcompetes these red inhibitor molecules and that will bring back the velocity of that the velocity or the rate of that enzyme back to its normal value so once again competitive in he compared inhibitors typically have a much higher affinity for the active side then natural substrate molecules however if we increase the concentration of the substrate the additional substrate can out-compete the inhibitor for the active site therefore increasing the substrate concentration can remove the effect of that competitive inhibitor that it has on that enzyme and this is only true in competitive inhibition it is not true in uncompetitive and it is not true in non-competitive so if you're given a problem and you are told that by increasing the concentration you essentially remove that effect you should know that that is competitive inhibition now what's one example of a molecule that acts as an inhibitor in the competitive inhibition fashion well inside our body the cells have to be able to synthesize purine molecules and pyrimidine molecules because these are the molecules that are basically used to produce DNA molecules now one important enzyme in the biosynthesis of purines and pyrimidines is known as dihydrofolate reductase and the substrate to this enzyme is dihydrofolate now we also have this molecule known as methotrexate and methyl Trax 8 is a competitive inhibitor to this substrate to this enzyme here in fact methotrexate is about 1,000 times more likely to actually bind on to the active side of dihydrofolate reductase then die hydra foley itself and so that's exactly why it will be much more likely to bind to the active side than the substrate but if we increase the concentration of the substrate that will essentially out-compete that inhibitor for the active side and that will bring back the rate of the enzyme back to normal now let's move on to uncompetitive inhibition well in some cases we see that when that substrate actually binds on to the active site of the enzyme once the binding takes place it creates conformational changes and sometimes in some enzymes that conformational change actually creates a brand-new pocket a brand new region of space that can now bind some type of inhibitor molecule and that inhibitor molecule can now bind into the space to form the enzyme substrate inhibitor complex and once this complex is formed that will essentially inhibit or block the activity of that enzyme and this type of inhibition is known as uncompetitive inhibition so in some cases the binding of the substrate to the active site changes the conformation of the enzyme and creates a brand new pocket we call an allosteric site that was not previously there and this pocket is only created when the green substrate binds into the pocket of this blue enzyme so before the binding took place we did not have that allosteric site but once the binding takes place we create this pocket the crevice that can now bind some type of inhibitor molecule and if that red inhibitor molecule is in crota is in close proximity it can bind onto that pocket and once it binds it forms the enzyme substrate inhibitor complex and notice that once the bound once the inhibitor is found it will basically prevent that green structure from exiting that active site and that will ultimately prevent that product from actually being formed now as we'll see in the next lecture and again we'll discuss this in much more detail and we'll see why this is the case in uncompetitive inhibition the V

Channel: Andrey K

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Keywords: irreversible inhibition, irreversible inhibitors, reversible inhibition, reversible inhibitors, competitive inhibition, uncompetitive inhibition, noncompetitive inhibition, non-competitive inhibition, mixed inhibition, types of enzyme inhibition, enzyme inhibition, enzyme inhibitors, inhibition of enzyme, biochemistry, enzyme kinetics, aspirin, nerve gas, penicillin, methotrexate

Id: 0ZiCqwtFMTs

Length: 16min 5sec (965 seconds)

Published: Fri Mar 13 2015