Metabolism | Regulation of Gluconeogenesis

all right engineer in this video we're going to specifically talk about the regulation of gluconeogenesis so we've already talked about gluconeogenesis and the pathway that's involved in it in this part remember I told you guys that we were going to talk about what's called the glucose alanine cycle and the Cory cycle and how that's linking the muscles to the liver or vice versa we're going to do that first and then after that I want to talk about those enzymes that Pepsi K that pyruvate carboxilate and the fructose 16 bis phosphatase and what's regulating those enzymes okay but first off let's go into these two cycles so the first cycle that we're going to do first is the Corey cycle now if you guys remember I told you that in the muscle we had glycogen right and whenever we had that glycogen we could utilize that specific enzyme which was called glycogen phosphor within the muscles right to convert that into glucose 6 phosphate and again what enzyme was doing this inside the muscle this was the muscle let's put M glycogen phosphor so the muscle glycogen phosphor was stimulating this step to break down the glycogen into glucose uh specifically to Wi glucose one phosphate if we were to be really really particular it actually broke it down into glucose one phosphate and then there was another enzyme that converted that glucose one phosphate into glucose six phosphate if we were being very very specific this was the phosphoglucomutase so we'll put phospho gluco mutase enzyme now this glucose 6 phosphate we said it can't get out of the cell and the skeletal muscles or different types of muscle tissues do not have that enzyme called glucose 6 phosphatase that can rip off that phosphate remember it was in the endoplasmic reticulum this there's no enzyme like that in the muscles so we're gonna have to do something else to disguise that glucose in a different form so we can do two things okay so let's say I take off I take off this pathway right here so I come over here and I Branch into a different path because this is where we're going to Branch into the Corey cycle and then we'll come over back and talk about the glucose alanine cycle so you know glucose 6 phosphate can undergo glyc glycolisis and at the end of glycolysis you produce what's called pyruvate right and then throughout that process of glycolysis I can actually generate a total of two ATP So within this skeletal muscle I can actually generate two ATP if we take into consideration Anor robic processes but then in this glycolysis pathway we end up with pyruvate right pyruvate can't actually be put into the blood in this form we have to do it in a different form so what we're going to do is is if you guys remember there was a special uh molecule you guys probably remember that in enzyme it was called lactate dehydrogenase it was the guy that the solders soldiers were treating on right the bald guy what was he doing the lactate dehydrogenase was acting on pyruvate and what it was doing is it was unloading nadh's onto the pyruvate so it was unloading nadh's onto the pyruvate to convert into NAD positive and what was the molecule that was formed as a result of this this was lactic acid what happens to this lactic acid I'm going to take this lactic acid and I'm going to push it out of the muscle cell and into the blood okay so now I'm going to take this lactic acid and I'm going to put this into the blood all right then what I'm going to do with this lactic acid is I'm going to take it up in the liver so the liver is now going to take up this lactic acid so this lactic acid is going to go through the blood and it's going to get taken up by the liver when it gets taken up by the liver there's another pathway here so now look what happens in here I'm going to bring this lactic acid in into the liver when I bring it into the liver so here's my lactic acid I can reconvert that back into what I can reconvert this back into pyruvate how because you know that and let's actually keep this consistent what color was this over there it was actually a pink Arrow right so now let's have a pink Arrow here coming up so lactic acid to pyruvate now if you remember there was a specific enzyme catalyzing this step this enzyme was called lactate dehydrogenase this is also present within the liver present in many tissues what it's doing is it's stimulating this enzyme but now the pathway is opposite so now in this pathway I'm going to take NAD positives and generate Na dh's and then look what I'm gonna do with this pyruvate I can now take this pyruvate and guess what I can do to him in the liver I can take this pyruvate and go backwards up to glucose 6 phosphate what can I do with that glucose 6 phosphate I can take this glucose 6 phosphate now I have in the liver what is that structure in the liver that's really really special if you guys remember the endoplasmic reticulum and in the endoplasmic reticulum there was a special enzyme what was that enzyme that was inside of the endoplasmic reticulum that enzyme inside here was called glucose 6 phosphatase and what happens we could take that glucose 6 phosphate off of this glucose so we're going to bring this in through a specific type of Transporter like T1 bring it in have it acted on by this enzyme and when it's acted on by that enzyme now you get free glucose and then what did it release off of it it released off a phosphate what was the name of this enzyme this enzyme is specifically called GL glucose 6 phosphatase that enzyme right there is called glucose 6 phospha tase and this enzyme is only present in the liver or the kidney or also even certain types of tissues within the GI tract particularly the dadum but now we have this free glucose now we can take that free glucose and transport it out of this endoplasmic reticulum through t two Transporters and bring that glucose out where can that glucose go it can be contributed into the blood so now we can take this glucose that we have here and put that glucose specifically into the bloodstream so here's our F free glucose so now look what happened you see how I told you that the muscle specifically could break down glycogen but could only break it up to this point and then it stops because it doesn't have the enzyme we got the actual what we got it in the form of we took this glucose in the form of lactic acid we just hit the glucose 6 phosphate in the form of lactic acid and then what did we do we took that lactic acid to the liver and then reconverted it into glucose free glucose that could get put into the blood but you know what a cycle doesn't just end right there it has to go back so what can happen then I can take this glucose and to end the cycle I bring the glucose where I bring the glucose back in to this cell and I'll convert it into glucose 6 phosphate right cuz you know that there's an enzyme that does this step too what is the enzyme that catalyzes this conversion this is called in the liver hexo kinas so what is this cycle here called that we just did this whole cycle that we just did is specifically called the let's write it over here this is specifically the Corey cycle and it's just basically how we're getting the actual glucose from the muscle to the liver to be converted actually into free glucose cuz really the muscle can only get to glucose 6 phosphate and then it stops because it doesn't have that enzyme now there's another thing that we can do and again what is this process here called whenever we're taking this lactic acid remember when we did glucogenesis when we take this lactic acid into the liver and we convert that lactic acid into glucose what is this process here called gluconeogenesis so this is the process of gluconeogenesis where we're taking the lactic acid and then converting it into glucose in the liver but you know what else the muscle can do it can take and divert so now let's actually do this in blue and look what else it can do it can convert this glucose 6 phosphate into pyruvate again right so I say here's our pyruvate but then it can take this pyruvate and it can combine it with a specific type of amino acid you know what that amino acid is called that amino acid is called glutamate so now what I'm going to do is I'm going to take this pyruvate and I'm going to react it with an amino acid called glutamate and what I'm going to do is the glutamate is an amino acid right so it has an amine group on it it's going to transfer his am group onto pyruvate and then glutamate will actually get converted into Alpha ketoglutarate so now what is the result of these two reacting the result is I'm going to get two molecules one molecule I'm going to draw coming off of this reaction that we're not going to be really caring too much about that is called Alpha keto glut that is coming from glutamate the other product is when the amine group gets transferred onto the pyruvate and it gets transferred onto the pyruvate and gets converted into alanine you know alanine is an amino acid so what did I just do I took glucose 6 phosphate turned it into pyruvate and oh what do you generate out of this process right here what do you generate from this 2 ATP by anerobic mechanisms right assuming anerobic mechanisms I hid the glucos 6 phosphate in the form of pyruvate but then that wasn't good enough then I have to take the glutamate I have to give the glutamate that has you know the am group on the glutamate I give it to the pyruvate when I give the Amin group from glutamate to pyruvate glutamate turns into Alpha ketoglutarate which is a keto acid in the KB cycle and then pyu gains the amine group and it gets converted into alanine where can this alanine go so now this alanine can get transported in the blood so now look at this this alanine is going to come where this alanine is going to come through the blood right it's going to come through the blood and then where it going to go it can go into the liver what is it going to do in the liver all right so look at this we bring this guy in to the liver so here's our alanine here's our alanine right there alanine oh butcher that spelling let's put alanine alanine specifically alanine now that I have this alanine what I'm G to do is is I'm going to try to get rid of that amine group so I'm going to get rid of that amine group so what I'm going to do is I'm going to take the alanine and you know that there's enzymes inside of the liver that I can actually have here you know I can take this alanine I can combine it with another type of molecule I can combine this with maybe let's say I combine it with Alpha keto glutarate let's say I combine it with Alpha ketoglutarate so I take alanine I combine it with Alpha ketoglutarate alanine is amino acid he transfers his amine group onto Alpha ketoglutarate as a result let's draw this in pink here look at this as a result of this reaction these two reacting look what I get coming off of this reaction is going to be the insignificant part you know Alpha deuterate he gains the amine group from the alanine when he gains the amine group from the alanine he gets reconverted back into glutamate and then we'll talk in another video that this glutamate undergoes what's called oxidative deamination so in other words he'll get rid of his amine group in the form of ammonia and and he'll get regenerated into Alpha keto glutarate and then this will go into the Ura cycle and we'll talk about this in amino acid metabolism but for right now we don't care about that we care about what happened to this alanine alanine transfers his Aman group on alpha ketoglutarate alpha ketoglutarate transfers his oxygen onto alanine and alanine now becomes something different he becomes pyruvate what can happen with that pyruvate that pyruvate can get converted into what glucose 6 phosphate and then from that glucose 6 phosphate what can happen he can get converted back into free glucose and then that glucose thing what can happen with that glucose he can then be taken back to the muscle so then let's actually show this step here that this pyruvate can then get converted into glucose 6 phosphate then from that glucose 6 phosphate what can happen I can take that glucose 6 phosphate have it be acted on by glucose 6 phosphatase and then that glucose 6 phosphatase what can happen to him that glucose 6 phosphatase can convert the glucose 6 phosphate into free glucose and then put that glucose into the bloodstream what is this process here called when I take this alanine and I basically help to convert it into free glucose glucose then goes to the liver comes back out as alanine it's called the glucose alanine cycle it's simple all right so again what is this process here called glucose alanine cycle now we talked about the Corey cycle we talked about the glucose alanine cycle now I need to talk about one more thing to finish off you remember those enzymes those specific enzymes that we uh we talked about a lot in gluconeogenesis specifically the three ones specifically Pepsi K which stood for phospho enol pyruvate carboxy cyas and then we had another enzyme this one was called pyruvate carboxylase and then there is one it's not as significant but we should mention it regardless is going to be fructose six bisphosphatase so again this is called fructose one six bis phosphatase the question at hand is what is regulating these enzymes because we talked about how these enzymes are working we told you what they we know what they do we know that pyruvate carboxilate does what it converts specifically pyruvate into oxaloacetate we know that we know that specifically this pyruvate carox is taking what it's taking the pyruvate and converting it out into oxaloacetate but the next question is what's regulating this enzyme what's stimulating this enzyme you know this enzyme is specifically stimulated by acetylcoa so acetylcoa can actually allosterically stimulate this enzyme because you know whenever there's too much aceto COA that means that there's a lot of KB cycle activity and that means that we don't need to keep breaking down the glucose we can actually take and get those GL we can make make glucose now so now whenever there's excessive amounts of acetylate it'll stimulate the pyruvate carboxilate which will convert pyruvate into oxaloacetate and then you could also have certain things that could actually inhibit this enzyme what would inhibit this enzyme well there would be the opposite of aceto COA maybe COA could stimulate this enzyme or you could even say low energy signals so maybe certain type of situations in which there is high amounts of ADP so maybe high amounts of ADP which is signaling that there's low energy signals this could stimulate I'm sorry inhibit this enzyme because if you want you're going to want to inhibit this enzyme if there's low energy signals you're going to want to divert this from making glucose and start breaking down glucose to make ATP so this should inhibit this enzyme okay what about Pepsi k Pepsi K is a whole different animal he's actually regulated based upon synthesis you know there's a ma very very important hormone in our body that's released during very very long-term stress or in situations when our blood glucose levels are low or maybe even when have a fever it's specifically called cortisol cortisol is a steroid hormone and what cortisol can do is you know he's actually a steroid hormone so he can activate specific genes and he'll activate specific genes that'll synthesize all of these enzymes so look at this upon the presence of cortisol and when is cortisol released cortisol is released whenever your blood glucose levels are really low hypoglycemia and also during stress but more of like the chronic stress okay and what is he going to want to do he's going to want to be able to promote gluconeogenesis so what does he do he synthesizes more Pepsi K more pyu carboxilate and more fructose 16 phosphatase so that we can actually have these enzymes break down all these molecules to make glucose cuz these enzymes are what are facilitating the making of glucose now we know that specifically cortisol is regulating Pepsi by stimulating him you know there's other um hormones that are also doing this too not just cortisol but even glucagon glucagon is another hormone that is also going to be helping in this process but specifically the stimulation of Pepsi K or even the stimulation of pyruvate carox via phosphorilation reactions and we can even say technically phosphorilation of fru one sigus phosphites right but specifically how is glucagon regulating it glucagon is helping within the synthesis of Pepsi K he's helping in the synthesis of pyu carboxilate and he's helping in the synthesis of fructose 1 Six B phosphatase but if you had to remember the more important one the significant one you need to remember cortisol cortisol is the primary one that's leading to the synthesis of Pepsi K pyruvic carboxilic and fructose 16 bis phosphotase if we have more of these then we can have more of these enzymes available for gluc Genesis one more thing this enzyme he's also heavily regulated you know how he's actually regulated so let's actually get rid of this glucagon one here because glucagon does it in a weird way he regulates this enzyme in a very very weird way okay you remember this molecule called fructose 26 bis phosphate this molecule is a very strong inhibitor of this enzyme now we have to go back for just a second not too long and explain how this fructose 26 bis phosphate is made you guys remember we had that bclear uh dimer that component of this actual molecule here we had this guy right here and this guy right here and it was actually broken into two components but it was one enzyme one component of the enzyme was phospho fructo cyas 2 and the other one was fructose 2 six bis phosphatase and this was one whole enzyme if you remember the phosphor fructokinase 2 was taking fructose what six phosphate and converting it into fructose 2 six bis phosphate then this enzyme here fructose 26 bisphosphatase was actually being ripped away so then look here I'm going to do it with a different Arrow fructose 26 bis phosphatase can rip off the phosphate off of fructose 26 B phosphate and convert it back into fructose six phosphate now if you guys remember that there was actually hormones that were activating these guys so what was actually activating well first off before I do that what was this fructose 26 phosphate really good for besides saying absolutely nothing you know fructose 26 bis phosphate what was he doing remember that specific molecule phospho fructo cyas one remember that fructose 26 bis phosphate is the strongest stimulator of phosphofructokinase 1 if you have a lot of this enzyme I'm sorry if you have a lot of this fructose to6 Biz phosphate it'll stimulate pfk1 which will trigger glycolysis but if you want to do the opposite you're going to want to rip off the fructose 26 Biz phosphate so now the question is how would glucagon or epinephrine or norepinephrine regulate this enzyme okay so let's think about this logically this molecule wants to stimulate pfk1 so I need to get rid of him so these molecules glucagon epinephrine and norepinephrine are going to activate protein cyas a protein kyese a is going to phosphorate what is he going to phosphorate he's going to phosphorate this whole enzyme when he phosphorites this whole enzyme two things happen when this component of the enzyme is phosphorated this one the pfk2 right when this enzyme is phosphorated what happens he is actually going to be what inhibited if he is inhibited this part if it's inhibited if this is phosphorated this whole enzyme this part is inhibited and this part is stimulated why what would that do okay if this part is stimulated it'll convert fructose 26 bis phosphate into fructose 6 phosphate what does that mean for the fructose 26 bis phosphate concentration his concentration is going to do what it's going to go down if his concentration goes down is he going to be able to stimulate pfk1 no so he will no longer be able to stimulate pfk1 another thing is fructose 26 phosphate it is inhibiting this enzyme if there is decreased concentration of this fructose 26 bis phosphate then what will happen there won't be as much of this guy and what will happen this will stimulate this enzyme okay so again let's do this one more time there's a bclear enzyme consisting of phosphor fructokinase 2 and fructose 26 B phosphatase if you have glucagon epinephrine and norepinephrine they'll activate protein cyas a who will phosphorate this whole dimer but whole nuclear B protein when it does that it phosphates the whole thing when it phosphates it it inhibits the pfk2 portion so he can't convert fructose fructose 6 phosphate into fructose 26 B phosphate that part's inhibited but whenever it's phosphorated activates the fructose 26 bis phosphotase which cleaves the phosphate off of what the second carbon and converts it into fructose 2 uh fructose 6 phosphate when fructose 26 Biz phosphates concentration decreases he can no longer stimulate pfk1 so glycolysis is inhibited also when his concentration decreases he no longer is able to inhibit this fructose 16 bis phosphatase and now this fructose 16 bis phosphatase is released from inhibition and then he can do what he can cleave fructose 16 bis phosphate into fructose 6 phosphate which will then help to go and make glucose okay Niners we covered basically the regulation of gluconeogenesis we covered the Cory cycle and the glucose alanine cycle in this video I hope it all made sense I hope you guys enjoy enjo it if you did hit that like button subscribe and comment down in the comment section all right Engineers until next time