Metabolism | Regulation of Glycogen Metabolism

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iron engineers in this video we're going to continue off with the glycogen metabolism but we're going to end off in this video talking about the regulation of glycogen metabolism because understanding the pathway is significant you know that's important but specifically understanding what's controlling whether it's getting broken down or being synthesized is even more significant okay so let's say I take the two main enzymes that are being regulated in that glycogen metabolism process so let's say that I take this enzyme here and we're going to say that this enzyme was the glycogen synthase so glycogen synthase you'll remember he was the one that's forming those alpha 1-4 glycosidic bonds it along gating the actual glycogen polymer the other one that we're going to talk a lot about look at his bearded dude is going to be what's called glycogen phosphorylase if you remember this was the guy that was reaching into a satchel pulling out those phosphates and adding those phosphates into the actual glycogen to form glucose 1-phosphate these two enzymes are the main enzymes that are being regulated heavily in the glycogen metabolism video so if we were to kind of just make it as just a simple kind of concept here technically I'd say that I have glycogen here and I have glucose let's do glucose in a different color let's put glucose in red glucose if I'm going from glycogen to glucose that's called glycogenolysis so if I'm going this way I'm going from glycogen to glucose this process is called glycogenolysis but then if I'm going from glucose to glycogen this is called glycogen SS so again what is this air if I were to kind of write on this side here this side here is going to be glyco Genesis right glyco Genesis is going from glucose to glycogen and then over on this side you're going to have glyco journalist and this is going to be taking the glycogen of breaking it down to glucose if you'll remember this enzyme the glycogen phosphorylase is controlling this step he's one of the main enzymes involved in this step breaking the glycogen down at the glucose where as this enzyme the glycogen synthase he was involved in the building up of glycogen he was responsible for being able to synthesize glycogen now it's not enough just to know that we have to know what's controlling this enzyme and what's controlling this enzyme it's not too bad if we think about it logically glycogen synthase wants to make glycogen so what would be a stimulus of this reaction the main powerful stimulus allosteric because we're going to do two types of regulation so it can be two types of regulation one type of regulation is going to be with respect to allosteric regulation allo steric regulation in other words meaning that this molecule binds to some other site other than the active site and it changes the overall three-dimensional structure that molecule whether it either activates it or deactivates it it depends on the molecule the other type of regulation that we're going to focus on is hormonal and that will be the next one that we'll talk about after allosteric so hormonal how are hormones influencing these enzymes okay now glycogen synthase to think about this logically again let's say that I have a lot of glucose 6-phosphate what would a lot of glucose 6-phosphate indicate okay that would indicate that I have high blood glucose levels because if there's a lot of good with six philosophy that means that a lot of googles is getting brought into our cells and getting phosphorylated that means that the blood glucose levels are high if the blood glucose levels are high what hormones getting activated insulin and insulin loves to stimulate glyco genesis so wouldn't this be a stimulator of this enzyme because he wants to synthesize glycogen yes so this molecule will bind onto some allosteric site and stimulate this molecule but think about it logically let's come over here to this guy this glycogen phosphorylase think about this now what if I have really really high glucose 6-phosphate levels if it's stimulating in that enzyme we wouldn't want this enzyme to be stimulate at the same time so wouldn't we want this same stimulus to inhibit this enzyme yes so this is going to inhibit this enzyme from functioning that is one of the most powerful allosteric stimuli of the glycogen synthase okay and that is going to be what we're going to talk about mainly here now that's going to be the allosteric stimulator now let's talk about something that's going to inhibit this process but not specifically inhibit this enzyme we're going to talk about what's inhibiting this enzyme or what's stimulating this enzyme okay so we know glucose 6-phosphate inhibit this enzyme what else could inhibit this enzyme you know if you have a lot of glucose 6-phosphate you're making a lot of specifically a lot of ATP and if you're making a lot of ATP that means there's a lot of krebs cycle activity a lot of like glucose being broken down so in that case if we're already utilizing glucose through glycolysis and the Krebs cycle and electron transport chain we don't really need glycogen to be broken down into glucose because just going to make us make more ATP and if we have too much ATP that's going to stop this process how significantly large amounts of ATP is going to inhibit this enzyme and if ATP high amounts of ATP inhibit this enzyme he can no longer break glycogen down into glucose why is that a good thing because if he keeps breaking down glycogen down into glucose there'll be too much glucose too much glycolysis too much Krebs cycle and then too much ATP and too much ATP our cell can only store so much ATP in the cells so ATP will inhibit this enzyme another thing free glucose but we have to be very careful when I mention this one so high amounts of free glucose can also inhibit this enzyme and it should make sense because if there's a lot of glucose that means that there's going to be a lot of Google's coming into the cell the blood glucose levels are high if our blood glucose levels are high we're not going to want glycogen to break it down to glucose and make them even higher that's going to make it worse so we want to inhibit this guy but this is only happening in the liver glucose is only inhibiting this like agem phosphorylation the liver in the muscles this is not inhibiting it okay so we need to make sure that we're very careful with that glucose is only inhibiting glycogen phosphorylase in the liver not in the muscles okay now we need to do something else now there's a weird component to this glycogen phosphorylase there's something else that we can do to this guy okay well before we do that one other thing before we do this one there's another stimulus there's a stimuli to this if you have high amounts of ATP right that means that you have low amounts of ADP okay so remember if you guys remember this concept high amounts of ATP means low amounts of ADP right because what's happening is we're forming a lot of ATP's and a lot of ATP is getting broken down into adenosine diphosphate and inorganic phosphate but if your ATP levels are low a lot of ATP can be getting broken down into a lot of ADP in an inorganic phosphate so what if our ATP levels are low if our ATP levels are really really low what is that significant about that that means that we're not having a lot of glycolysis we might not have a lot enough glucose in the bloodstream there might not be enough krebs cycle activity not enough activity the electron transport chain we need to make more ATP okay well this enzyme should be stimulated break down glycogen to glucose get that glucose into glycolysis kreb cycle and make more ATP how does it do that now it's not adp that does this it's something very very special that does this it's another breakdown product into ADP you can actually take ATP and ATP and your muscles can actually get broken down even further than adp they can get broken down into a MP and pyrophosphate which just means you're having pyrophosphate is just two inorganic phosphates linked together now if I have this a.m. P getting birth being formed because of excessive ATP breakdown in the muscles this will stimulate this guy and let him know to start becoming active so if there's high amounts of a em P that will stimulate this enzyme but this is only coming from the muscles this is only coming from the muscles it's a breakdown products whenever we had that cross bridge formation and whenever the muscles contract they actually build up a lot of a MP and a MP can stimulate this enzyme to break down more glycogen into glucose so that glucose can undergo that cellular respiration process to make more ATP for muscle contraction okay now again that's only happening in the muscles now there's another weird thing about this there's a enzyme that controls this time times activity okay so let's come down here now we have an enzyme this enzyme is called phosphorylase kinase but there's two forms of this enzyme one form is inactive and this inactive form is type B so phosphorylase kinase B is the inactive form of this enzyme but whenever he is active he can get converted into what do you think guys phosphorylase kinase a and a is the active form of this enzyme so whenever it's in phosphorylase kinase B it's actually going to be inactive but whenever it's in the form of phosphorylase kinase a it will be active what triggers that process to occur so what triggers this conversion of phosphorylase kinase B to phosphorylase kinase a and why is that relevant to glycogen phosphorylase okay now we're going to get into another process now we have to get into little too little the hormones so we'll come back to this and see how this is affecting it so inside on your liver cells you know you have these things called g-protein coupled receptors so these g-protein coupled receptors are going to be special because they're responding to a specific types of molecules what are these molecules that is responding to remember I told you that glycogenolysis is primarily stimulated by glucagon and norepinephrine and epinephrine I told you that we would come back that now it's time so now who are the molecules that combine here so what is this molecule looking to be it could be a plaform molecules what molecules this could be glucagon this could be epinephrine this could be norepinephrine any of these molecules and it's binding onto these receptors these g-protein coupled receptors when it binds on to this g-protein coupled receptor you know you can activate G stimulatory protein you know G stimulatory protein can then do what if you have G stimulatory protein he combined to gtp which makes him active when he becomes active what can he do he can then go and stimulate a a factor enzyme so there can be some type of effector enzyme embedded into the cell membrane let's say here is our effector enzyme you guys already know this enzyme this is called adenylate cyclase what does this enzyme do it takes ATP and converts it into cyclic a and P and then cyclic AMP e activates protein kinase a okay so now we'll come back to this protein kinase a in a second okay this protein kinase a is going to be occurring whenever what whenever glucagon epinephrine and norepinephrine are being released when with these hormones be released they would be released whenever our blood glucose levels are low if our blood glucose levels are low we're going to want to stimulate glycogen breakdown into glucose glucose specifically called glycogenolysis now how does that happen you see this protein kinase a he's going to come over here and he's going to phosphorylate this kinase so look at what happens here here's our protein kinase a this protein kinase a can come over here and it can phosphorylate this molecule so now look he's going to phosphorylate him if he phosphorylates this phosphorylase kinase B it activates this enzyme when this enzyme is activated then what is he going to be phosphorylase kinase a so the phosphorylated version of this enzyme is active so now he is active okay and again who is doing this specifically protein kinase a so protein kinase a which is coming from what coming from glucagon stimulus or norepinephrine stimulus or from epinephrine stimulus is going to activate phosphorylase kinase B and turn them into phosphorylase kinase a now what is going to happen phosphorylase kinase a is going to kick this guy into gear he's going to come over here and he's going to put phosphates right on this guy look he's putting phosphates on his armpits alright when he puts phosphates onto this actual enzyme he's going to become activated okay when he becomes activated he's then going to do what stimulate this step converting glycogen back into glucose so now that should happen but again what is happening specifically glucagon epinephrine norepinephrine are being released when our blood glucose levels are really low or when we're in a stressful situation binding onto g-protein coupled receptors activating the G stimulatory binding with gtp to become active activating adenylate cyclase adenylate cyclase converting ATP into cyclic GMP cyclic GMP activating protein kinase a and then protein kinase a is doing what it's phosphorylating phosphorylase kinase be turning them into phosphorylase kinase a and then phosphorylase kinase a phosphorylates glycogen phosphorylase which stimulates this enzyme who then converts glycogen into glucose there's one more mechanism that can do this also you know Gugu on epinephrine norepinephrine they have different types of adrenergic receptors like alpha adrenergic receptors and beta adrenergic receptors let's say over here I have another receptor specifically another type of receptor and this receptor is another g-protein coupled receptor but whenever epinephrine and norepinephrine bind on to this g-protein coupled receptor it activates a different type of g-protein let's say this specific g-protein is going to be G Q what G Q does is it's still going to bind on to gtp and become active when he becomes active he goes and activates a different enzyme so let's say here is this different enzyme this enzyme special because it's a phosphodiesterase enzyme this enzyme is called phospholipase C and what happens is when this GQ stimulates him phospholipase C does something really cool he takes and breaks down a molecule which is called pip2 he breaks him and he breaks them into two components one is called die a seal glycerol the other one is called ip3 you know that there's certain types of storages that have what's called the endoplasmic reticulum in these cells and then these endoplasmic reticulum czar rich in calcium you know what it's going to do it's going to pump out calcium ions this calcium is then going to bind to a protein called calmodulin calmodulin and when calcium binds to calmodulin this can stimulate the conversion of phosphorylase kinase B to phosphorylase kinase a so again let's review this one more time epinephrine and norepinephrine can also buy them out to different types of g-protein coupled receptors on the liver right and when it does that it activates GQ GQ activates phospholipase c which cleaves phospho and entitled diphosphate into diacylglycerol and inositol triphosphate in lesotho triphosphate binds on to receptors on the endoplasmic reticulum and pushes out calcium calcium binds onto a molecule called calmodulin and then that calcium calmodulin complex will stimulate the conversion of phosphorylase kinase B to phosphorylase kinase a if phosphorylase kinase a is activated he'll phosphorylate glycogen phosphorylase if glycogen phosphorylase is activated he'll convert glycogen into glucose holy crap that was a lot right but it should make sense but those protein kinase a he's not selective he doesn't just say I'm going to phosphorylate this guy not this guy he also phosphorylate this guy it's our glycogen synthase so you need a protein kinase a look what can happen you know glycogen synthase actually exists in two forms also he can exist in two forms it's the same thing as the phosphorylase kinase B so say I have here glycogen synthase but specifically this is the B type and then over here I have another one and this is called glycogen synthase and this is type A if I have that protein kinase egg come into play so saying here's my protein kinase a if that protein kinase a phosphorylate this G stimulus I'm sorry this glutton synthase and it's in the B form and converts it into the a form sorry this is not gonna happen it should actually be the opposite if this glycogen synthase is in the active form and he gets phosphorylated and he gets phosphorylated by protein kinase a when this lot of protein kinase a phosphorylate the G stimuli I'm sorry the glycogen synthase protein it converts them into the inactive form so this is the active form and this is the in active form so again what does protein kinase a doing protein kinase a is adding phosphates onto glycogen synthase when he adds the phosphates onto glycogen synthase which is in the active form he'll then be converted into thee in active form so that should make sense and what would that do to this enzyme he'll then be inhibited and if protein kinase a phosphorylates glycogen synthase which converts him from the active to the inactive form can he take glucose and converted into glycogen no and so this process will be inhibited so we can say in a weird way that protein kinase a is inhibiting this enzyme because he's doing what he's putting phosphates on him and putting phosphates on this enzyme inhibits this enzyme now we come to the hero the hero who's going to save them all this is called insulin let's say over here have another receptor so here's another receptor and this receptor is specifically for insulin so here's my receptor and this is different this is a tyrosine kinase receptor right and we're not going to go over the pathway in this what we're just going to say specifically what's happening here is that insulin is going to be released whenever your blood glucose levels are high so whenever you have high blood glucose levels insulin is going to be released insulin is going to activate this receptor when he activates this receptor this receptor leads to the activation of very specific proteins and these proteins are called phospho protein phosphatases so who's activating these proteins these phospho protein phosphatases this is going to be the presence of insulin so insulin is stimulating the formation of these phospho protein phosphatases okay now these fossil protein phosphatases when they're formed by due to insulin do the high blood glucose levels these fossil protein phosphatases are going to do something special so you see these phosphates that were put on by the gloves specifically the protein kinase a because of glucagon and norepinephrine epinephrine well look what happens here I can do this exact opposite reaction I can take glycogen synthase from the B form which is the inactive form and put him back into the active form how can I do that with these fossil protein phosphatases I'm just going to denote them PPP right so phospho protein phosphatases these phospho protein phosphatases are going to do what they're going to remove phosphates from the glycogen synthase which is in the inactive form the B form so now look this philosophers are going to be removed from the glycogen synthase if the phosphates are removed from the glycogen synthase now the glycogen synthase goes from the inactive form to the active form who is doing that specifically these philosopher protein phosphatase which are coming from insulin so again one more time insulin is released whenever there's high blood glucose levels he's stimulating these actual specific tyrosine kinase receptors activating phospho protein phosphatases phosphor for protein phosphatases will rip the phosphates off of this glycogen synthase so you can actually show like this look he's going to come into play and what is going to release off all will he pull off of this Judgment Day so pull off phosphates when he pulls off the phosphate that stimulates this enzyme so again how is it happening let's say to this glycogen synthesis in the inactive form due to protein kinase a then what happens is we can take it from the inactive form to the active form type a whenever we have phospho protein phosphatases ripping those phosphates off of the inactive glycogen synthase turning em into the active form if this happened then what happens in this enzyme he is activated and if he is activated he can take glucose and converted into glycogen last but not least these fossil protein phosphatases are not specific also so you know what they can do you know how we were adding phosphates onto this phosphorylase kinase B to convert them into phosphorylase kinase a these phospho protein phosphatases can also come over here and look what they can do they can remove what they'll remove the phosphates off of this phosphorylase kinase a when they remove these phosphates off of the phosphorylase kinase a then what will happen this still one did couldn't convert her back into d inactive form so again what happens fossil protein phosphatases act on the phosphorylase kinase a rip off the phosphates and he'll go from the active form back to the inactive form but he's not done she needs phosphates that this guy put onto this guy's armpit these phospho protein phosphatases are going to come over here and what are they going to rip off of this glycogen phosphorylase they're going to rip off phosphates when they rip off the phosphates then what's going to happen this glycogen phosphorylase is no longer going to have phosphates on them so will he be inhibited or will he be stimulated he will now be inhibited because he was activated by phosphate groups when you pull those phosphate groups off of him he is then inhibited so if you rip these phosphate groups off of the glycogen phosphorylase via the activity of these fossil protein phosphatases it'll inhibit this enzyme if this enzyme is inhibited he can no longer break down glycogen into glucose so that's why insulin stimulates glyco genesis and epinephrine norepinephrine and glucagon stimulate glycogenolysis if you phosphorylate this enzyme he's activated if you D phosphorylate him he is inactivated if he phosphorylate this enzyme he's inactivated if you d flat for late this enzyme he's active okay now last thing I want to tell you guys out of this whole video is that you know glycogen phosphorylase in the debranching enzyme are not the only enzymes that are involved in that glycogen glycogen glycogen Alice's pathway there's one other enzyme that I want to mention with you because I'm going to tell you guys what can happen when some of these enzymes are dysfunctional there's one other enzyme that it can account for about one to two percent of glycogen alysus most of them is going to be if you guys remember from the glycogenolysis video it was primarily just the glycogen phosphorylase in the debranching enzyme one to two percent can be done by specifically lysosomes in these lysosomes we have what's called this acid we can actually call it acid maltese or alpha 1-4 glucoside a so acid maltase or alpha 1-4 gluco sia days why am I telling you this because there is a disease that can occur whenever these lysosomes are having a deficiency or mutation within this acid maltase or this alpha 1-4 glucose I days whenever these people are deficient in this actual enzyme it can cause significant types of problems primarily it can cause a lot of damage to their heart and if that is occurring they call this disease very very dangerous disease they call it Pompey's disease and this is specifically a glycogen storage disease type 2 okay now conversely there you and I had this enzyme this glycogen phosphorylase enzyme he's extremely important also if this glycogen phosphorylase enzyme is deficient he can also have a mutation this guy too and here's the way I like to remember these types of I kind of go down like a weird order so I go like this okay so I go down like this so I kind of remember these guys in a specific way so I'm going to have a different type of glycogen storage disease for each one of these guys so this is going to be my glycogen storage disease I'm just going to give you a couple often the more significant ones one of them is actually going to be Vaughn jerky disease and Vaughn Gurkhas disease is actually type 1 glycogen storage disease and what happens is in this glycogen storage disease type 1 you're lacking a specific enzyme that enzyme is called glucose-6-phosphatase then we already know this one if you have P 2 stands for pompes disease and then pompes disease you're lacking a acid maltase enzyme then if you go down again to c c standing for Corey's disease okay let's just work clarice disease and then you can keep going down okay so let's keep going down so Anderson's disease and then you can also have another one which is going to be McArdle's disease and the last one is actually called hers disease so here's how I like to remember how they how you can R what enzymes are dysfunctional so you see this see what comes after C D and you know what actual enzyme is actually going to start with D this is debranching enzyme if there's some type of deficiency in the debranching enzyme this can cause Corey's disease what comes after a B this is the deficiency in branching an enzyme so if you have a deficiency in the branching enzyme this can also cause a glycogen storage disease then the M and McArdle's disease if you kind of look at the end they're not em in the McArdle disease this is the deficiency in the glycogen phosphorylase but specifically in the muscles because they behave differently so this is like you're going to put GP glycogen phosphorylase but specifically in the muscles then if you see hers disease hers disease there's an H you know it's the glycogen phosphorylase enzyme it's also deficient in this one but the glycogen phosphorylase what is H stand for hepatic liver this is the liver glycogen phosphorylase so here's I like to remember these guys now that we have all this I can go down in an order this is glycogen storage disease type one this is like a Jen storage disease type 2 type 3 type 4 type 5 and type 6 so if you have glycogen storage disease in any deficiency in these enzymes that we've mentioned throughout all of these series of videos can cause significant damage on the heart on the liver on even the spleen different types of tissues can be extremely damaged due to these glycogen storage disease if you wanted to remember any of these the most significant the most damaging the most dangerous one is von Gierke disease usually children never live past the age of 1 year old so it's extremely dangerous disease so again von Gierke says the deficiency in glucose-6-phosphatase pompey's the deficiency in acid maltase Cori's diseases remember see well it comes after that DD branching enzyme anderson's is what comes after a B branching enzyme McArdle's remember the M it's for muscle glycogen phosphorylase and then H for hers disease remember that's hepatic or liver the liver glycogen phosphorylase any deficiency in these enzymes can cause significant catastrophic effects on the body iron engineers in this video we covered a lot about the regulation of glycogen metabolism and what can happen whenever these breakdown prot breakdown process in this glycogen metabolism occur I hope it all made sense I hope you guys enjoyed it if you guys did hit that like button subscribe please and leave some comments on the comments section we look forward hearing from you guys all right ninja nerds until next time
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Channel: Ninja Nerd
Views: 169,762
Rating: 4.9816785 out of 5
Keywords: metabolism, regulation of glycogen metabolism
Id: NL6ETs9k3Wk
Channel Id: undefined
Length: 30min 45sec (1845 seconds)
Published: Tue Jun 13 2017
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