Regulation of Krebs-TCA cycle

to save us some time I went ahead and drawn up a simplified version of the citric acid cycle here and if you remember it begins with with acetyl co aan Turing this cycle and it combines with this molecule oxaloacetate to form that trait and this citrate undergoes various conversions and oxidations which eventually cause the two carbons that entered with acetyl co away because remember acetyl co a is a two carbon molecule these two carbons exit as carbon dioxide and as its oxidized and loses its carbon dioxide acetyl co it also allows us to produce the electron carrier molecules fadh and nadh and with which if you recall go to the electron transfer 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 3 have as our reactants acetyl co am entering the cycle we also have them coenzymes like NAD+ and fh g and we also have a free gdp remember GTP is formed in the cycle as well and all of this eventually will produce carbon dioxide from the oxidation of a seal kawai we reduce our electron carrier molecules so nadh and fadh2 we also form a GTP now the reason I wanted to go ahead and bring out this entire overall reaction of the citric acid cycle is because when I was first learning cycle I kind of often got stuck in the individual reactions that we're taking place and this kind of a merry-go-round and getting confused with all these names like I citrate and sectional kawai 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 like pollicis 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 the 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 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 hard pressed to find a living individual who has a mutation in there 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 date instead the major form of regulation of the citric acid cycle is through a low steric regulation so i'll remind you that allosteric 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 your part of the enzyme that's not the active site and essentially by doing that that causes the enzyme to undergo a conformational change and they can either make the enzyme work better in which case we call it an allosteric activator or it can make the enzyme not work as good in which case we call it an allosteric inhibitor and the way that I remember that allosteric regulation is the major kind of form of regulation in the citric acid cycle as I remind myself that since the cycle is always on it's still kind of wants to be able to adjust on a minute to minute so rather fast way - the kind of energy needs of the cells and go ahead and write that here wants to respond to the energy needs of the fell and the way that it can figure this out is by looking at the molecules that has floating around and these molecules are often those that are involved in regulating this pathway allosteric Lee 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 co wave around for example remember this is one of the major kind of substrates for this pathway and 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 when high yield example of this is when it rate under conditions of high ETP generally shuttles a lot of its a seal co way into the cytoplasm for fatty acid synthesis and of course when this happens it's taking this straight out of the cycle and so it will slow down the overall cycle on the flip side left their body within 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 it along the citric acid cycle and one place they enter is they actually are converted into alpha keita glue to right here and device to say that the general idea here is that if you have more this substrate around its 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 any DJ and fadh2 to produce more ATP all right let's give a general overview of substrate availability but now i want to talk more in depth about this allosteric regulation and you would notice if i told you but it turns out that there are three reactions in mr. acid cycle that have a very large negative Delta G remember large negative Delta G means that these reactions are largely irreversible which means that they are good target 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 in the field go into sit rate as well as the conversion from Isis sit straight to alpha keita clue to rate and alpha ketoglutarate 2 sectional co a now to go ahead and keep this kind of diagram as clear as possible i'm gonna 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 acetylcholine is situated citrate synthase and I citrate to allocate glitter eight is isocitrate dehydrogenase some of the ID and that advocated glitter 82 sectional co a is alpha keita clue to rate dehydrogenase now the allosteric 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 you and to kind of justify why certain things are Alice seriously inhibiting or activating these enzymes so why don't we start off with the allosteric inhibitors and one kind of easy allosteric inhibitor to remember is nadh because it allosteric Lee 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 any DJ is a product of the overall citric acid cycle right so it's a product right here and so we're building up nadh is essentially assigned to the body that the citric acid cycle is going faster than the essentially the electron transport chain which is using up these nadh can consume those any th's and so it's time for the citric acids that go to slow down now another allosteric inhibitor that should make some sense to you is ATP so if we have a lot of ATP and the body it makes sense that this would be an allosteric 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 and only two of these enzymes have been shown to be inhibited by ETP and those are fit rate in faith and I so the trait dehydrogenase now the final allosteric 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 allosteric Lee inhibiting some of these enzymes and the two notable products that do that our first hit rate which can allosteric Lee negative feedback on its enzyme citrate synthase as well as sex in elko a which not only negatively allosteric Lee feedback on to the alpha keita glitter eight dehydrogenase but it also can actually negatively feedback on this citrate synthase enzyme as well in one way that I kind of remember why i sectional kawai might want to kind of feedback all the way back to the city rates in places to recognize the citrate synthase is that 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 allosteric inhibitors but what about the allosteric activators the first allosteric activator that always comes to my mind is a DP remember that ATP is hydrolyzed 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 running out of it ETP and it will therefore need to produce more ATP and so if he needs to produce more ATP it makes sense that 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 the traits in faith and isocitrate dehydrogenase all right we're heading the home stretch here and there's actually only one more allosteric activator that we need to talk about and that is calcium the 1i calcium be an allosteric activator will remember that our muscle cells require an influx of calcium to contract so presumably you know for exercising really hard of course our energy needs go up but our calcium levels inside of yourself are also going up because of all that muscle contraction so this is essentially 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 allosteric Lee activate isocitrate dehydrogenase as well as alpha keita glitter eight dehydrogenase