to save us some time I've went ahead and drawn out a simplified version of the citric acid cycle here and if you remember it begins with with acetal COA entering the cycle and it combines with this molecule oxaloacetate to form citrate and this citrate undergos various conversions and oxidations which eventually cause the two carbons that entered with acetal COA because remember acetyl COA is a two carbon molecule these two carbons exit as carbon dioxide and as it's oxidized and loses its carbon dioxide acetyl COA also allows us to produce the electron carrier molecules fadh and nadh which if you recall go to the electron transport chain to allow us to produce ATP so to summarize let's go ahead and write out the kind of overall chemical reaction of the citric acid cycle so we have as our reactants acetyl COA entering the cycle we also have some co-enzymes like nad+ and fad and we also have a free GDP remember GTP is formed in this cycle as well and all of this eventually will produce carbon dioxide from the oxidation of a c COA we reduce our electron carrier molecules so nadh and fadh2 we also form a GTP now the reason I wanted to go ahead and write out this entire overall reaction of the citric acid cycle is because when I was first learning this cycle I kind of often got stuck in the individual reactions that were taking place in this kind of merry go and getting confused by all these names like isocitrate and sual COA and I think that when we're trying to understand in particular how this cycle is regulated that is trying to figure out when essentially this cycle is in full speed and when it's kind of slowing down it's actually nice to kind of step back and look at the big picture now the first point I want to make is that in contrast is something like glycolysis which we usually think about as a metabolic pathway that we really consider to be either on or off the citric acid cycle is something that we usually consider always to be on but to various degrees depending on kind of the energy needs of the cell and the reason it always has to be on right is because it needs to be delivering these high energy electron carriers the electron transport chain to allow at least some constant flow of ATP production which is vital to a lot of the tissues in our body in contrast you can probably think of a case when you know a theoretical case perhaps where someone might not have any glucose in their diet and of course glycolysis then could be off but the body might be able to use fatty acids and other kind of sources of kind of fuel to enter the citric acid cycle and indeed kind of a clinical proof Pro of this is that you know there are kind of disease states that involve mutations of enzymes in glycolysis for example but you would be hardpressed to find a living individual who has a mutation in their citric acid cycle because this cycle is so vital to life so that brings me to my first point which is that there is no hormonal control in the citric acid cycle because it's on regardless of whether we're in the FED State or the fast state instead the major form of regulation of the citric acid cycle is through allosteric regulation so I'll remind you that alisic regulation is simply the ability of a molecule floating around in the cell to bind to a specific enzyme that's part of this pathway and it binds to a part of the enzyme that's not the active site and essentially by doing this it causes the enzyme to undergo a confirmational change and it can either make the enzyme work better in which case we call it an alisic activator or it can make the enzyme not work as good in which case we call it an alisic inhibitor and the way that I remember that allosteric regulation is the major kind of form of regulation in the citric acid cycle is I remind myself that since the cycle is always on it still kind of wants to be able to adjust on a minute to minute so rather fast way to the kind of energy needs of the cell so I'm going to go ahead and write that here it wants to respond to the energy needs of the cell and the way that it can figure this out is by looking at the molecules it has floating around and these molecules are often those that are involved in regulating this pathway allosterically and finally a third way that this cycle is regulated is by looking at substrate availability and this is exactly what it sounds like essentially if the body doesn't have a lot of acetyl COA around for example remember this is one of the mjor major kind of substrates for this pathway then it makes sense of course that the speed by which this nadh and fadh2 is produced is going to slow down because there's just not enough to enter the cycle now one high yield example of this is when citrate under conditions of high ATP generally shuttles a lot of its acetal COA into the cytoplasm for fatty acid synthesis and of course when this happens it's taking the citrate out of the cycle and so it will slow down the overall cycle on the flip side let's say our body was in a very starving State we haven't had food for quite some while and in some cases amino acids can actually begin to break down from our muscles and enter in various places along the citric acid cycle and one place they enter is they actually are converted into Alpha ketoglutarate here and suffice to say that the general idea here is that if you have more of this substrate around it's it's going to push the cycle to go faster which makes sense in this case right because the body is alerted to the fact that it's starving and so it wants to be able to produce more nadh and fadh2 to produce more ATP all right so that's kind of a general overview of substrate availability but now I want to talk more in depth about this allosteric regulation now you wouldn't know this if I told you but it turns out that there are three reactions in the citric acid cycle that have a very large negative Delta G and remember large negative Delta g means that these reactions are largely irreversible which means that they are good targets for regulation because once these reactions essentially occur it's usually like a ball rolling down a hill and will allow everything else to occur and these three reactions are the conversion of oxaloacetate and AAL coate into citrate as well as the conversion from isocitrate to alphaet glutarate and alphaet glutarate to Sul Cod O A now to go ahead and keep this kind of diagram as clear as possible I'm going to go ahead and kind of abbreviate the names of these enzymes but of course you can always go to Wikipedia or a textbook and remind yourself what these enzymes are called but of course this enzyme from oxaloacetate and acetal COA citrate is citrate synthase and isocitrate to alphaet glutarate is isocitrate dehydrogenase so I'm going to say ID and then Alpha ketoglutarate to seal COA is Alpha ketoglutarate d hydrogen Now The alisic Regulators of these three enzymes can end up being kind of a long list but my hope in this video is to just be a resource for you to come back to and to kind of justify why certain things are alisic inhibiting or activating these enzymes so why don't we start off with the alisic Inhibitors and one kind of easy alisic inhibitor to remember is nadh because it alisic inhibits all three of these enzymes and the reason it does this and it should be apparent to you why this is so is that notice that nadh is a product of the overall citric acid cycle right so it's a product right here and so if we're building up nadh it's essentially a sign to the body that the citric acid cycle is going faster than the essentially the electron transfer chain which is using up these nadh can consume those nades and so it's time for the citric acid cycle to slow down now another aliser can ior that should make some sense to you is ATP so if we have a lot of ATP in the body it makes sense that this would be an alisic inhibitor of processes that produce energy right because we want to conserve energy and not kind of make more energy than our body needs so in this case turns out experimentally for some reason um only two of these enzymes have been shown to be inhibited by ATP and those are citrate synthese and isoc citrate dehydrogenate now the final alisic Inhibitors to talk about are actually products that form in the citric acid cycle and these products that they accumulate in excess amounts can actually negatively feedback by allosterically inhibiting some of these enzymes and the two notable products that do that are first citrate which can allosterically negative feedback on its enzyme citrate synthase as well as sexl COA which not only negatively alisic feedbacks onto the alpha ketoglutarate dehydrogenase but it also can actually negatively feedback on the citrate synthase enzyme as well in one way that I kind of remember why sexal COA might want to kind of feedback all the way back to the citrate synthes is to recognize that the citrate synthase is the kind of first kind of point of entry into the citric acid cycle and so you know if it can stop the citric acid cycle sooner it will essentially waste less energy so to say all right so that kind of sums up the alisic Inhibitors but what about the alisic activators the first alisic activator that always comes to my mind is ADP remember that ATP is hydrolized by a water molecule into ADP and a free phosphate group so if ATP levels accumulate in excess of ATP then it's a basically a sign that the cell is running out of its power it's it's running out of its ATP and it will therefore need to produce more ATP and so if it needs to produce more ATP it makes sense that it would want to activate the enzymes in the citric acid cycle and it's easy to remember because it activates the same enzymes that ATP inhibits so those are citrate synthase and isocitrate dehydrogenase all right so we're hitting the home stretch here and there's actually only one more alisic activator that we need to talk about and that is calcium so why might calcium be an alisic activator well remember that our muscle cells require an influx of calcium to contract so presumably you know if we're exercising really hard of course our energy needs go up but our calcium levels inside of our cell are also going up because of all that muscle contraction so this is essentially a way for the body especially in skeletal muscles to essentially couple muscle contraction with producing more ATP to meet the needs of those Contracting muscles and again this is experimental evidence but calcium has been shown to alisic activate isocitrate dehydrogenase as well as Alpha ketoglutarate dehydrogenase