hello and welcome to the review of liping cot's biochemistry textbook in this chapter we're going over chapter eight which is an introduction to metabolism and then also touches on glycolysis which is the first breakdown portion of carbohydrates if you enjoy the video please don't forget to give it a like and if you haven't subscribed yet please consider doing so as it does help the channel out if you'd like to support the channel and get downloadable audio files of these chapters you can do so in the patreon link within the description so before jumping into metabolism we should talk about these metabolic pathways that occur we have two different types of metabolic pathways which is just really describing when you have one substance go through multiple reactions and then end up with one product or multiple products these Pathways can either be catabolic which means that they are degradative so you turn one larger molecule into multiple smaller pieces or they can be anabolic or synthetic meaning that you convert multiple small pieces pie into one product or just a couple products metabolism is just describing all of those chemical reactions in one so it's the sum of all those chemical reactions all those Pathways that occur in a Cell a tissue or the body and those can be described as a metabolic map as you can see in figure 8.2 here now this is obviously going to be quite overwhelming first time you see it but this is just the overall metabolic pathways that can occur we're going going to touch on just glycolysis today so just this one portion here and then eventually throughout the other chapters go through all these other regions as well so the crib cycle the TCA cycle Uria cycle the Pinos phosphate pathway Etc so all of these reactions they're all kind of linked together and they all occur for different reasons before jumping into glycolysis we still have some additional details to talk about when it comes to catabolic and anabolic pathways we talked about how catabolic Pathways turn one larger molecule into a smaller molecule and the reason behind that is that breakdown of that larger molecule releases that energy and you're trying to capture that energy somehow to be used in the body so this is where your food stuffs gets converted down into smaller waste products and along that pathway you are creating energy stores typically in ATP so catabolic Pathways create energy or utilizes the energy from that food stuff as ATP and it is a convergent process meaning that you have multiple molecules that can transformed into just a few common end products and there are three stages to these catabolic Pathways and you can see the example at the top here where the first stage is hydrolysis of these complex molecules into their building blocks so proteins to amino acids carbohydrates to monosaccharides fats down to glycerols and your fatty acids so hydrolysis of the complex molecules into building blocks these building blocks are then converted into esile COA estile COA is then oxidized to generate large amounts of ATP via the oxidated phosphorilation pathway which we talked about in previous chapters already so this is our main catabolic pathway converting our food stuffs ultimately down into estile COA so that's convergence which eventually gets oxidized to produce ATP carbon dioxide and water as well via the oxidative phosphorilation system anabolic Pathways however is a Divergent pathway so you're creating multiple products from a few precursors so the example is amino acids into multiple different proteins and then they also require energy to be put into the system in order to create those products so catabolism generates energy anabolism uses energy as a little shortened version of that now in terms of Regulation our metabolism is regulated heavily to maintain H homeostasis and it's done that through various communication Pathways so we've got intracellular communication which is for momentto moment regulation so very shortterm regulation and that's through the availability of our substrates or the products inhibiting through negative feedback or having alterations to our activators or inhib hibitors or our enzymes so either you don't have enough substrate you're inhibiting yourself with how much products you creating or the enzymes are getting altered we then had inter cellular communication so that's signaling between cells which may occur either through direct contact via Gap Junctions it may be through endocrine system so that's a hormone being released from a gland entering the circulatory system to then reach your target cell or a neuro crine or a nerve cell synaptic signaling so that's release of neurotransmitters from a nerve cell onto the target cell typically these signals will then induce a change in your gene expression within your nucleus so then you actually increase or decrease the production of your enzymes which then provides a longer term control of your metabolic processes it's able to do that through these secondary messenger systems which we're going to go into a little bit more detail on mainly just focusing on the adinal cycl system however there are multiple other secondary misinger systems out there we're going to focus on adinal Cycles however now adinal cyclas utilizes initially G protein receptors so these G protein receptors are labeled so because they're attached to either GDP when they are inactive or GTP when they are active and they will only stay active for a certain period of time because that g protein is a GTP a so it's going to break down that GTP into GDP and then become inactive again now there are two different types of G proteins you've got GS which means stimulatory and GI which is inhibitory that's just really saying what the ultimate outcome is from stimulating this receptor will be so GS will stimulate a response to then create a action within the cell whereas GI is inhibitory and activation of that receptor will inhibit a particular process so what happens is that your hormone or neurotransmitter will bind to this G protein receptor and let's just follow the pathway of a GS protein GTP binds to it which then results in the activation of adanal cyclas which is a enzyme that's able to convert ATP to cyclic or CM so the adanal cycl system is very common just to think it's involving the secondary messenger system of cyclic and then that's because it's produced from ATP so CM then goes into the cell and actually activates protein kinases once activated these protein kinases can then phosphorate various proteins which will either inhibit or activate those proteins so the ultimate end process for adinal Cycles is the activation of protein kise to then activate or inhibit various proteins with in the cell and then that will tell that cell to either increase its function or decrease its function depending on the type of hormone or neurotransmitter and the type of G Protein that's present so that is your adanal cycl system it's just describing how a signal outside of the Cell results in an action within the cell once cyclic has been produced and it's activated your kise and then gets hydrolized by phosphodiesterases to break it down so you don't have a constant signal those proteins that have been phosphorated and have subsequently been activated or inhibited they are reversed out of that state by an enzyme called phosphatases they just take off that phosphate group and remove that phosphorilation so you're able to reverse the influences of that original hormonal neurotransmitter so it's not an irreversible or permanent change so next we're going to talk about gly pois remember from this metabolism map here we're just focusing on the central portion the central portion involves all of these reactions which ultimately is glucose getting converted to pyruvate now along the way there we're having the production of two atps in total so there's two inputed four that gets produced so there is a total of two atps from this entire process and then depending if there's oxygen present we are going to either have the production of nadh molecules or the production of lactate so if oxygen is present then nadh can go into the mitochondria and then actually go through the oxidated phosphorilation system release its electron once it gets in through those shuttle systems remember that we talked about and then that electron gets given up to oxygen if the oxygen is not present or we don't have mitochondria so either a cell isn't going to have mitochondria like a red blood cell or you're going to have a hypoxic environment so you may not have blood supply to a certain limb you may be anemic one of those situations then there's no Oxygen to accept the electron from the nadh so then nadh is going to accumulate within the cell unless you're able to actually remove that electron again and give it up to pyruvate and create lactate so lact gets formed in the absence of oxygen because you're trying to get rid of the accumulated nadh molecules and that allows glycolysis to continue if you have an accumulation of nadh and you have an accumulation of pyruvate then you're going to stop glycolysis and remember you do get some production of ATP with glycolysis so you want it to occur so when there is no oxygen you get rid of the nadh molecules and you get rid of pyruvate by creating lactate that allows glycolysis to continue and you allow the production of just a couple ATP molecules which provides a little bit of energy to that hypoxic cell or that red blood cell which doesn't have mitochondria so that is the main difference between aerobic and anerobic Metabolism or aerobic and anerobic glycolysis is that the absence of oxygen means that we create lactate so then we remove some of these products which are going to inhib glycolysis so then it can continue so that's a little point we'll make first otherwise we're going to talk about aerobic glycolysis and presume that we're able to continue through this pathway as normal before getting into that though we have to get glucose into the cell now glucose is going to be flowing through the blood predominantly after a meal and it needs to get into each cell once it gets into the cell it gets instantly converted into this glucose 6 phosphate which almost locks it into the cell locks it into the glycolysis process but in order to actually get the glucose molecule into the cell it has to stay as regular glucose because glucose 6 phosphate can't cross the membrane so glucose traveling through the blood will get transported into the cell either due to a glut transporter which is a sodium independent transport system so it allows glucose to travel down its concentration gradient via facilit ated diffusion through this protein carrier molecule there's two processes or two states where first it enters there's a confirmational change and then it exits so glute there are multiple different types glute 1 3 and four involved with glucose uptake from the blood glute two is in the liver and kidneys and they can transport glucose either into the cell with high blood glucose or out of the cell with low blood glucose and then lastly glute 5 which which is slightly different because it's not involving glucose this is the primary transporter for fructose within the small intestine in teses so that is glute that uses facilitated diffusion down glucose's concentration gradient we then have this other one called sglt now this is sodium dependent transporter so this involves sodium traveling down its concentration gradient to then push glucose against its conc ation gradients predominantly used in the epithelial cells of the intestines renal tubules and the choroid plexus within the central nervous system so sglt pushes glucose against its concentration gradient glute is just a protein that facilitates glucose going down as concentration gradient so now getting into glycolysis now if you need to remember each individual little product here then that just takes rot learning you're just going to have to memorize every single one otherwise we're just going to touch on the main reactions that occur within glycolysis and make sure we hit the key points here so there are two different stages of glycolysis the first phase is an energy investment phase meaning that we actually invest two ATP molecules into the system to help to convert glucose down this reaction pathway and then eventually at the second stage we generate some energy by producing four ATP molecules which gives us the net 2 ATP production and we also generate two nadh molecules which is going to go on to the oxidative phosphorilation pathway in the presence of oxygen we also generate two pyruvates which isn't done now you know that's not going to be the end of this process that then goes on to be converted into atile coenzyme a which then has other roles that we're going to talk about in future chapter so getting into each glycolysis reaction or at least the main ones the first step is to turn glucose into glucose 6 phosphate remember that locks it within the cell because glucose 6 phosphate cannot cross the membrane it does that through this enzyme called hexokinase there are four hexokinases hexokinase 1 to3 uh hexokinase 1 to three and these guys are in most tissues they have a high affinity for glucose but a very low maximum velocity and they're inhibited by the product of glucose 6 phosphate so they're able to convert high concentrations of glucose into glucose phosphate now hexokinase 4 is a little bit more confusing because it's actually called glucokinase so we're going to refer to it as glucokinase here this is found in your liver and your pancreatic beta cells and it functions more as a glucose sensor to then actually stim ulate insulin secretion in the pancreas and in the liver has the same role of locking it up as glucose 6 phosphate but that's more to convert it into glycogen for storage now the difference between glucokinase and hexokinase is that glucokinase in the liver and the pancreas has a relatively lower km or lower Affinity so it's only able to really work when there are very high concentrations of glucose because remember they're functioning when there are high blood glucose levels or high blood sugar levels because we're functioning in the pancreas to then secrete insulin to reduce those high blood sugar levels or in the liver to convert all that high glucose into glycogen and lock it up so it has a lower Affinity but a very high Vmax so that allows that reaction to occur quite efficiently and quite effectively whereas hexokinase remember we said that it has a high Affinity so although it works with a high concentration of glucose it's able to just continuously convert glucose into glucose 6 phosphate and it does it at its own pace it's just able to lock it up as soon as it gets into the cell the last difference is that glucokinase is not actually inhibited by glucose 6 phosphate it's actually inhibited indirectly by fructose 6 phosphate so slight differences there but they both function to phosphorate glucose lock it up within the cell and this is the first irreversible step in gsis there are three total irreversible steps and this is the first one the next step converts glucose 6 phosphate into fructose 6 phosphate it's not rate limiting it's reversible we're going to move on the next step is the second irreversible step this is using phosphor fructokinase 1 and it's a very important control point and a rate limiting step of glycolysis and that's because pfk1 is inhibited by high levels of at P so if you have a lot of energy within the cell you have a lot of ATP you don't need to keep converting glucose into its products and creating more ATP so if you have a lot of ATP that inhibits pfk1 which then inhibits glycolysis from continuing it is also inhibited by high levels of citate which increases also with energy abundance because you have a lot of action within your TCA cycle we'll get to citrate later on on in other chapters but essentially pfk1 gets inhibited Whenever there is energy abundance now pfk1 can get activated by something else called fructose 26 bis phosphate now fructose 2 SE bis phosphate sounds very similar to the product of what pfk produces which is fructose 1 SE bis phosphate so don't get those too confused we have fructose one as phosphate which goes on for gly olsis and then we have fructose 2 bis phosphate which regulates pfk1 so fructose 26 bis phosphate is going to increase the levels of pfk1 when there is a wellfed state and you have high levels of insulin it's going to get a little confusing going through this diagram here but we'll try to keep it as simple as possible essentially fructose 2 bis phosphate the activator of pfk1 gets created by pfk2 so pfk2 creates fructose 2 B phosphate which then activates pfk1 to create more fructose one six B phosphinate pfk2 is an enzyme that is bifunctional meaning that it can act as both a kinase when it is Def phosphorated or a phosphatase when it is phosphorated now it gets Def phosphorated and acts as a kise in the presence of high insulin in a wellfed state to create fructose 2 6 B phosphate to activate BFK 1 during fasting you have high levels of glucagon low levels of insulin which inhibits glycolysis by phosphor your pfk2 which then activates the phosphotase portion of pfk2 which then actually acts to activate glucon neoen genis so that is the creation of glucose so active pfk2 is going to act as a kise to then increased glycolysis during a wellfed state during fasting when you have active phosphatase activity of your pfk2 due to phosphorilation that is going to increase gluconeogenesis it's a little confusing try to just review this diagram here which may make it a little helpful the next step is the cleavage of fructose once a phosphate and glycolysis which is reversible and not regulated boring let's move on to the next portion the next portion is a little confusing where we just have isomerization of dhap into glyceride 3 phosphate so you can see that over here with fructose 16 B phosphate Elder hose is going to cleave it either into dhap or glycer alide 3 phosphate trios phosphate isomes is able to just interconvert the two now it's glyceride 3 phosphate that continues in your glycolysis pathway which has a relatively important role in actually being the first oxidation reduction reaction so this is where we create our first nadh via a dehydrogenase enzyme so you can see that over here balide 3 phosphate which has one phosphate molecule here has a phosphate molecule added and also we create nadh so we end up with 13 bis phosphoglycerate which you'll notice has two phosphate molecules on it that's important because the next reaction then generates our first ATP molecules to create three phosphoglycerate and take away that phosphate molecule or as you can see it may be converted into two3 bis phosphoglycerate or 23 BPG now this only really occurs in red blood cells okay so it has a main role in red blood cells to help to change the Affinity of the red blood cell to oxygen it helps to release oxygen from red blood cells in the presence of metabolism we talked about this in previous chapters talking about the oxygen hemoglobin dissociation curve so this little extra armor here occurs in red blood cells otherwise we're just going to focus on what happens here how 1 three bis phosphoglycerate creat an ATP molecule as that phosphate group is taken away and added to ADP so then we end up with three phosphoglycerate now it's important to note that this is the generation of two ATP molecules here two nadh molecules over here because we have created two molecules of glycer alide 3 phosphate for every glucose molecule now that's going to trace back probably should have mentioned this earlier back to this other figure over here where you can see that fructose 16us phosphate has this blue Group which is going to be the dhap molecule and the orange Group which is glyceride 3 phosphat so one molecule of previous glucose gets converted into two molecules that's able to go through the rest of glycolysis so one molecule is represented in this entire diagram so you just double up the products so two NAD molecules gets created from that one glucose two atps are produced here from that one glucose and then as you can see down the bottom here we have these two other reactions which are kind of insignificant is just reshuffling of this phosphate group we eventually have PE or phospho enol pyruvate also getting converted into pyruvate by creating ATP is that phosphate group is taken away with that ADP and that occurs under the enzyme pyruvate kise so you can see we have the generation of two nadh molecules here two atps here and two atps here giving us a total production of four atps two nadh's and two pyruvates but we also put two ATP molecules into the system earlier to convert fructose 6 phosphate into fructose six this phosphonate so then our net production is two atps two nadhs two pyrates so that is the key point of glycolysis now this last reaction here is that third irreversible reaction that I promised you so this is that third irreversible process that is also activated by fructose once b phosphinate or pfk1 now that is important because increased glycolysis is going to occur with increased pfk1 activity due to increased ADP molecules not ATP remember ATP is going to inhibit pfk1 now when pfk1 gets activated due to increased a DP then your pfk1 is also going to increase the activity of pyruvate kise so that's COA activation of these kyes molecules to speed up glycolysis and produce more ATP molecules when we have an energy deficiency pyruvates fate is then determined by the presence of oxygen with oxygen it's going to get converted into acetal coenzyme a to go into the crib cycle or the TCA cycle that we'll talk about later absence of oxygen it's going to get converted into lactate by lactate dehydrogenase or LDH and remember that's to remove the accumulation of pyate and N ADH so then glycolysis can continue and continue to produce ATP and the absence of oxygen it's a less efficient system you produce less ATP per glucose molecule but at least your cells are able to continue to survive for a little bit longer in the absence of oxygen now you're just hoping that you're able to get some oxygen supply to that cell at some point because you generate an oxygen debt all that extra lact needs to go to the liver and then use oxygen to actually convert it back into glucose So eventually your oxygen debt is going to catch up to you and you're going to be able to eventually reconvert it back into aerobic metabolism but in the absence of a oxygen replenishment then you're going to result in a lactic acidosis State and that's going to occur with intense exercise regardless of how much you're breathing the absence of a pathological region you know if you're running a marathon and you're not used to it you're going to build up some lactate and that's a reason for cramping because all that extra lactate is an acid and that's going to reduce the ph and that's going to cause muscle cramping or you're going to get lactic acidosis when any type of pathological hypoxic state so if you olude blood supply to a Lim for example as a more dramatic example so we've talked about pyruvate getting converted to lactate um there is a py at kise deficiency disorder here which is mainly affecting red blood cells so that's an inability to convert P to pyruvate because you don't have pyruvate kise that means that red blood cells cannot do this final equation here and have a lack of ATP that means that they have a lack of energy so their membranes get distorted because their membranes are using a lot of energy for the ion pumps that membrane Distortion then results in them being broken down early from macrofagos and since all those red blood cells are getting broken down you end up with an anemia because you can't replenish those broken down red blood cells as quickly so we've talked about lactate and death already remember we're just able to utilize lactate so then glycolysis can continue produce some ATP yield we talked about anerobic versus aerobic glycolysis now insulin activates all of these enzymes to increase glycolysis whereas glucon inhibits these reactions so you're trying to release more glucose insulin is released when you have high blood sugar so you're trying to utilize it more or store it more glucagon is released when you have essentially low blood sugar so you're trying to release it into the blood so you're trying to prevent glycolysis from occurring now there are alternative fates of pyruvate we talked about atile COA we talked about lactate it can also get carboxilate into something called oxy loate which is involved with the TCA cycle or the crib cycle and that provides a substrate for the replenishment of glucose via gluconeogenesis and then it's also how you create alcohol um yeast and other microorganisms have the ability to convert pyruvate into ethanol humans obviously don't have that ability or else you'll be able to create alcohol in your own body but yeast is able to do it that's how you get beer and wine and that's due to the conversion of pyate into ethanol these species and so that really comes to the conclusion of chapter 8 there is a chapter summary over here as per the other chapters as well and then there are some chapter questions feel free to pause it and then there are the answers there as well so feel free to pause at each point if you want to study that material otherwise I hope you enjoyed it feel free to drop a comment and we'll see you in the next one