I ninja nerds in this video we're going to talk about the krebs cycle so you can also call it you know the tricarboxylic acid cycle you can call it the citric acid cycle so there is other names for it was actually founded and developed by the guy named hans krebs that's that's where it came from okay so now when we go through the Krebs cycle we've already gone over in great detail we've already gone over the glycolysis pathway and then we have actually gone over all the glut transporters we've gone over the glycolysis pathway of converting what is this molecule here this is glucose right here we've converted glucose into pyruvate and how many pyruvates have we actually made technically we made two of these right because we split the six carbon fragment into two three carbon fragments so we've actually made two pyruvates and during that process you guys already know that we generated two NADH s and two net ATP and then you know that we've already gone into detail whenever there's oxygen present we can take this pyruvate bring it into the mitochondria and we can transition it right we can get ready to transition to the Krebs cycle and in that transition step or that preparation step what do we do we added a coenzyme a into this reaction right and then what else did we do we generated two NADH s and we produced two co 2 s by decarboxylation and I was done through this whole pyruvate dehydrogenase complex with the e1 e2 and e3 we already gone up we already went over that in great detail and all the mechanisms now we're going into this next thing which is the Krebs cycle so we formed this Utica way from the transition step right this molecule ER here's our acetyl co a now what we're going to do is we're going to convert this acetyl co way we're going to fuse it with this four carbon fragment right here this four carbon fragment is actually referred to as oxaloacetate so again this guy right here is called I'm going to denote it I'm going to abbreviate it Oh a a oxaloacetate is going to combine with the acetyl co a when these two substrates combine they use together and the presence of this enzyme we'll talk about this enzyme in a second but oaa is a four carbon structure combining with a two carbon structure and again what is this this red structure coming off of the acetic oi that's the coenzyme a when this acetyl co a and win this Oh a a combine with this enzyme they form a six carbon molecule look one two three four five six what is this molecule called this is called citrate it looks really interesting yes citrate is Krebs starting substrate for making oxaloacetate what'd I just do I gave you guys a little quick mnemonic to be able to remember all of this so it's an easier one to be able to do okay so how do I remember I'd be again oxaloacetate and acetyl co a come together in the presence of this enzyme to form citrate and I like to remember that citrate is Krebs starting substrate substrate for making oxaloacetate what is is for is is for I so citrate let's get all these intermediates all the way just an easy way to be able to remember them because that's what we longed for all right sometimes things just get it out of the way the memorization ray Krebbs is for alpha keto Glitter 8 I might refer to it as a kg whenever you guys see it like that starting is for succinylcholine all Co a substrate is for sockson 8 this is succinate for is few married and then the last one is making which is going to be malate and the last one is oxaloacetate so again it goes citrate is Krebs starting substrate for making oxaloacetate just a little quick mnemonic I thought that would help out to just memorize you know the basic intermediates now that we've done that really there's nothing crazy else that we have to know other than just regulatory steps and what's happening in between okay cool let's do that now that we know the intermediates let's focus on the enzymes and what's produced in what's happening in each step so acetic away in OAA or oxaloacetate when these two are fusing there's a special enzyme and what does this enzyme doing it's forming centrate it's synthesizing citrate so what would that enzyme be called you call it citrate synthase so there's a citrate synthase enzyme this citrate synthase what is he doing he's taking the oxaloacetate in one part taking the acetyl clay on the other part using them together and making citrate now the question is this enzyme is extremely very highly regulated so it's going to control this step so a CoA going into citrate with oxaloacetate this is not a reversible step this is a one-way reaction so what does citrate synthase have to be regulated by okay it's going to go on and on what you guys are going to see throughout a series of these biochem videos think about this if our body is having a lot of metabolism so it's occurring a lot a lot of metabolism are a lot of Krebs cycle a lot of electron transport chain activity I'm making a lot of ATP if I'm making a lot of ATP do you think I'm going to want to keep having the Krebs cycle going on making more nadh and fadh2 s no because I already have too much of it this is going to inhibit it that's going to do allosteric ly inhibit this enzyme same thing in the Krebs cycle you'll see that will generate a lot of what's called NADH s that you see here NADH is if there's too many of them it's also basically telling this enzyme there's a lot of energy supply within the cell we don't need anymore shut down don't do this anymore okay then we have another one citrate himself you know whenever there is actually too much citrate citrate can actually come back and inhibit this enzyme so citrate himself can come back and inhibit this enzyme so citrate can say okay there's way too much of me because generally what's going to happen when you mix it rate you automatically get covered in to isocitrate generally some of the citrate can also get converted into the basic units for fatty acids called Malin yoko and we'll see that but generally it should be progressing somewhere it's showing to be building up when it's building up it's letting the citrate synthase know don't make any more of me stop working and then there's another one he's all the way down there though it's called succinylcholine so sucks and all co is also an allosteric inhibitor he's just a little bit more downstream and he's just telling this enzyme hey before you even think about making citrate there's already too much of me so shut down and stop making more citrate and making more of me making more nadh is more ATP just stop doing that and these are generally the main allosteric regulators of this citrate synthase now what would be a stimulator we've already talked about there's so many times but it's a good good way to keep continuously reviewing ATP gets broken down into what guys it gets broken down into ADP and inorganic phosphate if you're breaking down a lot of ATP you're going to build up a lot of ADP and this is going to signify that you are actually not having a lot of ATP within the cell if there's not a lot of ATP in the cell that's not good because ATP is needed for transport mechanisms for metabolic pathways for DNA synthesis so many different things ion channels so ADP would be a very powerful allosteric stimulator of this enzyme it would let this enzyme know hey there's not a lot of ATP you need to continue to keep going through the Krebs cycle making more nadh and fadh2 and make more ATP so that would be that guy so generally this is how we're going to allosteric ly regulate this googly-eyed enzyme okay because this googly-eyed enzyme is involved in this step right here converting me a seed go into surgery very very highly regulated step okay so we're done with that one okay so now we got this Betty White enzyme okay there's Betty White Ensign with the perm going on it's converting citrate which is a six carbon molecule into what okay one two three four five six it's still six carbons so what's really happening it's just an isomerization reaction and isomerization reactions all you're doing is you're just shuffling around the hydrogens on the carbons but there should still be the same number of carbons and hydrogen's and oxygens in this guy as there is carbon two hydrogens and oxygens in this guy so it's just shuffling things around not a crazy crucial step but the enzyme controlling this step as you guys can see it's doing what it's able to move in the reverse direction so whenever there is too much isocitrate you can convert it back into citrate it is possible and it actually does happen and you'll see this whenever we talk about this in fatty acid synthesis but the enzyme is controlling this is called a connotates ACON ITA se okay a connotations I'm so there's you know just because it's not controlling it's not highly regulated is reversible doesn't mean that this enzyme is an important you know there's a rat poison in rat poison there's a chemical that's present called floral acetate and what happens with this floral acetate is kind of acting like a seed okole you know acetate is just basically another fancy word for saying it's a two carbon structure I don't have to just a fluorine attached to it so it's going to get actually converted it can act like floral acetate so you know how you're going to have a fetal Co a here you're going to have this floral acetyl co a which gets converted into fluoro citrate and that flora citrate binds on to the Econo taste enzyme and what is it eventually going to do it's going to inhibit this enzyme in this enzyme once it's inhibited it can't convert the Train isocitrate so you can't you won't be able to generate eventually NADH is fadh2s and ATP and that is a very very bad thing so floral acetate can actually cause inhibition of this accommodation time and again it's within rat poison so if you you know somehow terribly take on too much rat poison for what a reason it can inhibit this enzyme alright cool nobody come into this next one so we're going to convert isocitrate into alpha Q to glue rating alright cool how many carbons is this guys six carbons how many is this guy one two three four five okay cool five carbons that means I lost a carbon somewhere whenever you guys hear that whenever you see a carbon missing automatically assume that you lost that carbon in the form of co2 what does that call I know we talked about it but what does it call whenever you lose a carbon in the form of co2 what do they call that they call it D carboxylation okay so decarboxylation is the the actual reaction in which you're removing a carbon in the form of co2 primarily a carboxyl and carbon when we're losing them okay now in this reaction we have a very very important enzyme this enzyme is called ISO citrate dehydrogenase right away Bell should start ringing in your head once you hear dehydrogenase automatically know that you are going to be converting nad positives into NADH s okay automatically once you guys see that automatically think oh I'm going to make any of the H's in this step so what happens in this reaction in a D+ is reacting in this step to generate in a d h okay that's what's happening in this step I'm taking any deposit and converting it into NADH cool now you see how this step is one direction is not bi-directional so this is not a reversible enzyme it can only be moving in one direction usually any enzyme that forms co2 is generally usually irreversible isocitrate dehydrogenase has three pockets look it's got this pocket this pocket this pocket what is going to happen here okay again realize that whenever we're actually having high amounts of a teepee you guys can all automatically think that whenever there's high amounts of ATP this little sneaky dog has three binding sites okay three binding sites what's going to happen to this little Snoopy dog or the isocitrate dehydrogenase enzyme if there's too much ATP ATP will inhibit this enzyme and that should already make sense because there's too much energy production we want to slow it down whereas think about the opposite effect if I'm breaking down a lot of ADP ATP and generating a lot of ADP that should stimulate this enzyme in that it does my friends okay and for the last one this one's kind of gonna be like what the heck where'd that come from calcium is another strong stimulator of this enzyme and this should actually make sense think about this in the muscles in muscles calcium is acting as a nice important type of signaling molecule to activate the the cross bridge formation within the skeletal muscles even cardiac muscle right he's important for that because we need calcium in order for our muscles to contract but another thing that we need for our muscles to contract is ATP if this enzyme is stimulated he's going to help to generate any DHS which will take those high drives to the electron transport chain and generate ATP so calcium is helping to stimulate this enzyme so we can make more ATP so we can have more contractions because he knows ATP is needed to detach the myosin from the actin for the cross bridge formation right so calcium is kind of letting this enzyme know make more ATP ADP we're not we don't have enough ATP in a cell we need to make more ATP is an inhibitor because it's saying we have too much stop making more simple nothing crazy about that okay now we're going to move on to this next enzyme this next enzyme is extremely important we really need to remember this in but this enzyme right here look at this she's got you know locks here this is called alpha I'm going to do that key to glitter 8kg D hydrogenation v this is an extremely extremely crucial in bond okay count how many carbons we have again 1 2 3 4 5 4 alpha cute blue ray for suction okay how many do I have one two three four okay that means I must have lost the carbon oh yeah cool so there must have been decarboxylation I must have lost a carbon in the form of co2 so there must have been another decarboxylation reaction oh wait Zach so whenever I have a dehydrogenate e+ to NADH okay so that's not bad this reaction is kaput it's done that's it it's not that bad because all you got to remember is okay five to four loss of co2 decarboxylation any deposit to NADH because there's a dehydrogenase enzyme that's it now we have to remember look this she's got three pockets here and her dreads okay what's going to happen same thing now think about this one it's going to be a little tricky nothing crazy you see succinylcholine he's just sitting here he's going to tell this enzyme if there's too much of him and if this enzyme needs to stop so look look like sucks in Ocoee I can come over here and do it can come and bind onto this enzyme and it will inhibit this enzyme and tell this enzyme don't keep converting allocute obliterate to suck sonic away we don't need to do that anymore there's either too much ATP there's too much any DHS there's too much energy produced in the cell stop okay now the next ones are the next ones a little weird but it's not crazy see these NADH es if you start generating too much NADH s that can also tell this enzyme to shut down so this NADH can actually come over here and what can they do look here's our NADH if there's too much NADH s what will it do to this enzyme it will inhibit this enzyme tell the same time don't keep converting me alpha-keto great into socks antiquate because there's already too much NADH s we need to stop making as much and that will inhibit this enzyme and the last thing is super simple because we already talked about him calcium right calcium is also going to work in this step - so you're going to have nadh who is going to be inhibiting this enzyme suck cynical a which is going to be inhibiting this enzyme and then what else is going to be working in this stuff calcium calcium's going to be doing what in this step calcium is going to be stimulating this enzyme here okay so now that should make sense now right because we generated co2 by decarboxylation we generated some NADH s out of this reaction because we have the alpha Q tubular hydrogenase but then we need to be able to correct you late this enzyme to control how much activity is going on if there's too much sucks in Ocoee from too much krebs cycle activity it's going to inhibit this enzyme to stop this Candace Krebs cycle from continuing to occur if there's too much NADH s that are being generated it'll also inhibit this enzyme tell it not to continue to give her because we already have too much any DHS and too much ATP but then again calcium think of the muscles calcium is going to try to do what helps to be able to form that you know to allow for the muscle contraction but we need ATP in order for the muscles to contract so without the ATP the muscles won't be able to contract so calcium is helping to activate this enzyme so we can speed up the ATP production all right cool now why do I want to mention this enzyme and say it's extremely important okay in your body alpha key to glue the rate is an interval component of an enzyme called histone demethylase and this histone demethylase basically what histone demethylases do let's say here's the DNA because I have a sequence of DNA or something like that right and you know DNA is wrapped around histone proteins and histone proteins are basically very important for being able to control the organization of these DNA the gene expression and stuff like that so these histone proteins are actually going to be having the DNA wrapped around them what histone demethylases do is you might have methyl groups on these guys here which are basically controlling you know gene modification epigenetics and stuff like that the system the matheletes will come over and remove those methyl groups I also keep the glute array is a cofactor it's a cofactor that this histone demethylase right in our body we have that enzyme right so what was making the alpha ketoglutarate if you guys remember we were taking what we were having this alpha Q to glue to rate was going to be an important component of this step right here right helping to synthesize you know being a component to histone demethylase if this alpha keto glued array right so remember we had the isocitrate isocitrate was actually being converted what isocitrate was being converted into alpha ketoglutarate right and that was done by the isocitrate dehydrogenase enzyme but then alpha ketoglutarate is getting converted into what it's getting converted into Sox in ocala through what alpha ketoglutarate dehydrogenase in a condition in which there is a mutant form of that alpha key to glue rate dehydrogenase specifically the one which is having a NADPH is involved with the not na DS NADPH is in a condition in which there is some type of mutation in this enzyme with the NADPH is it can actually convert instead of converting it at the succinylcholine a lot of this alpha Q to Glitter rate you can get another molecule here and it's called two hydroxy Glu rate why am I tell you this because two hydroxy gluta rate will come in and do what it'll bind and prevent this alpha keto GU turret from being able to bind if alpha ketoglutarate can't bind onto the histone demethylases can you control the gene expression no if gene expression isn't controlled it can lead to tumors it can lead to uncontrolled cell growth primarily super-dangerous one because a priori of it called bleona's gliomas are basically tumors that are occurring within the glial cells in the brain one of the really really dangerous ones is the astrocytomas or the glioblastoma multiforme so gbm's which are very very dangerous can you really have an 80% metastatic rate and they're usually malignant can cause you know unfortunate death but again understanding how something so small that you would think you know there's just metabolism it can have such an amazing effect on your body so again any type of mutation is alpha ketoglutarate dehydrogenase particularly with the NADPH one and instead of na dh1 can lead to the formation of a byproduct called two hydroxy butyrate which can inhibit the alpha ketoglutarate from binding to the histone demethylase inhibiting this enzyme inhibiting gene expression and leading to uncontrolled cell growth and tumor formation okay now that got that out of the way let's move into the next one now we got to take this sucks in Ocoee and i'm going to convert it into succinate okay what happened you're okay somewhere in this reaction oh look at that alpha keto glue to rate going to suck Seneca wait what did we miss over here we had that koay I should have a coating on this guy what does that mean that means I added a co a onto this step let's add that in there so there must have been a coenzyme a being added into this stuff you know there's alpha ketoglutarate dehydrogenase if you guys remember the pyruvate dehydrogenase complex this enzyme functions in the exact same mechanism so if you guys remember that enzyme you remember how this enzyme functions anyway we add the co am then look what happens we we get rid of the co a so then we lose the co-ed in this step but it's all for good reason it's sometimes we might not like why it does this well what's happening here something really funky is happening when we release the co a it generates a little bit of energy a little bit of potential energy another body uses to take GDP and an inorganic phosphate and use that to form gtp okay it's cool but then you know who comes in ADP ATP is like oh man I'm going to Pitt pocket this guy so hard so what did you do adb comes over here and steals the faucet from the GTP adp when he gains the phosphate what if he turned into he gains another phosphate so he turns into ATP okay that's cool well what happens to the gtp the gtp unfortunately goes back to GDP okay so it's a cool way of our body being able to generate ATP through what's called substrate level phosphorylation so again what is that called it's called substrate phosphorylation which is completely different as compared to oxidative phosphorylation so substrate phosphorylation doesn't generate as much ATP as compared to oxidative phosphorylation okay so that's happening in this step so we're developing ATP and that's coming because of releasing out the coenzyme a which creates a little bit of energy to take GDP and inorganic phosphate fuse them together to make GTP but then adp comes over here pit pockets that phosphate from the GTP it makes ATP which converts the GTP back into gdp what enzyme is helping in this step okay this enzyme here converting sucks in Ocoee into sockson eight it's got pretty cool enzyme this is cold specifically sucks in all co a synthesis okay so you have the sucks tentacle a sent to taste enzyme and what this enzyme is doing is it's being involved in this step to stimulate the conversion of succinylcholine to succinate now when we get that succinate nothing crazy happens in this next step but let's see what's happening here nonetheless okay look we're taking sockson eight we're converting it into two married when we take Sox amine convert it into a few marry we have another enzyme look at this look at this freak okay this enzyme right here is special you don't know why look where he's actually anchored he's anchored on the mitochondrial membrane specifically the inner mitochondrial membrane the cristae is is actually called complex 2 enzyme complex that's a part of the electron transport chain but we like to call it something else we call it succinate dehydrogenase boom light bulb what does that mean automatically if you think F ad in this case that's a th - but you guys are probably like oh do what you told me it was nad any type of coenzyme usually f ad or nad is usually involved whenever you hear dehydrogenase okay now because i'm forming fadh2 this is going to be how energy production but you know what else is also helpful for this you know in certain condition that's called pheochromocytoma so called pheochromocytoma there's some type of mutation in this end vine an alteration or mutation this enzyme can cause a situation where you form a neuroblastoma it's usually benign meaning it's not metastatic it doesn't spread but the spiel chromis i total is usually a tumor that develops within the adrenal medulla and it causes an excessive amounts of epinephrine and norepinephrine to be produced which causes an extreme hypertensive crisis so a very very dangerous condition but just seeing any type of mutation this enzyme can lead to this condition pheochromocytoma all right cool so again remember that this is an enzyme complex - it's a part of the electron transport chain and it's converting fadd fadh2 but it's also reversible so this reaction can be reversible alright cool so that's that step now we're going to take the fumarate and we're going to convert that into the Mallee okay this enzyme is really really simple nothing crazy about this enzyme this enzyme is called humerus and look we got Humpty Dumpty he's sitting on this reaction Humpty Dumpty is actually going to do what he's going to throw some water into this reaction he's like a let me help out in this reaction to the best of my abilities and he throws water into this reaction but again remember that this reaction is reversible so what does he do in this reaction Humpty Dumpty takes and throws water into this reaction to convert few Mary into malee name--but might be like okay simple must not be an important of an enzyme he is very important you know in the condition which there's a deficiency in this enzyme it can lead to the formation of what's called li Alma's or leiomyomas 2 and the Oma's are usually going to be tumors that develop within smooth muscle tissue usually they're benign perfect example this one is they also call them fibroids but it's some type of you turrents very very common in the uterine smooth muscle and even in the kidneys okay so this can happen in the uterine smooth muscle and it can happen in kidneys but usually there's some type of glioma and again just a deficiency in this enzyme can cause that significant change unbelievable okay so now we got malate malate has this Haiti's looking enzyme look at this look at this frame hi this guy right here is the cool enzyme I like him he's called malate dehydrogenase be you guys should automatically think again NAD+ to NADH so what's happening I'm taking NAD+ and I'm converting it into and ADH why because there is a dehydrogenase enzyme present when there's a dehydrogenase enzyme present its converting NAD+ to NADH in this step this enzyme is also reversible so this reverse reaction can occur Oh a to malli and we'll see that and throughout more videos where we cover a little bit on gluconeogenesis and even electron transport chain okay now that we've done that we've covered all of these different enzymes that are involved in this in these steps here now one other thing I want to do I want to tell you guys is is that when I'm taking this acetyl co a what am i doing right I'm taking this acetyl clay I'm combining with the oxalic acid and having it react with citrate synthase to form citrate citrate is reacting with a con taste to make isocitrate isocitrate is going to be acted on by isocitrate dehydrogenase to make alpha ketoglutarate alpha ketoglutarate gets converted to sucks in Ocoee when acted on by alpha key to obliterate dehydrogenase the suck suck suck Seneca wave sent to taste is going to be taking succinylcholine and converting it into succinate to generate a little bit ATP in that step and then succinate is converting it into a few merry and then if you married it's being converted into Malley and malate back to LA how many ask eunuch away should I really be having going through this cycle this is crucial I have two pyruvates well two pyruvates get converted into two acetyl coins I need to make two turns if I make two turns don't I really develop two fadh2s don't I really develop to nad ages and don't I develop another two NADH is right here and another two NADH is right here and technically two ATP and two Koei's right and to Koei's being added okay so how many co2 is that we generate out of this we generated chewing this step and we generated two in this step so two plus two is four so we got four co2 is out of this okay what about any DHS I generated 6 nadh --is how I generate sixteen eighty ages let's look we generated to any DHS in this step going from malli to oxaloacetate right so that's two I generated two NADH is in this step going from isocitrate to alpha ketoglutarate that's four and i generated two more nadh is going from alpha q to glue two right to suck Sunoco a that's six then what was the last thing that we generated to fadh2 s okay cool so I got two fadh2s last thing how many ATP did I generate two ATP and by what type of phosphorylation substrate phosphorylation so again I'm generating by substrate phosphorylation and where is that happening that's happening when I'm going from succinylcholine eight remember I'm taking the gdp to GTP and having the adp pick off that phosphate to form ATP two of them by substrate level phosphorylation so out of this this is going to be the main products that you'll get out of this and these nadh and fadh2 s will go and take these hydride ions to the electron transport chain will they'll be used to make ATP by oxidative phosphorylation ideas here so we went over a lot of information in this video I hope it all made sense I hope you guys did enjoy it if you did please hit the like button subscribe put a comment down in the comment section I ninja nerds until next time