number 14 Done by Dergam Al-Tarawneh Corrected by Maya Attarakih Doctor Nayef Karadsheh 1 P a g e
Glycogen metabolism Note: Everything written in orange is from the book not mentioned by the doctor. In the last lecture the doctor has finished talking about gluconeogenesis; the mechanism in which glucose is the final product. In this lecture we will start talking about a much bigger subject which is glycogen metabolism, and when we say metabolism we meansynthesis,degradation, and finally the regulation of this process. The first thing we should know: from where doesthe body get its glucose supply?there are some blood glucose sources and they are: 1- Diet It represents food found in our daily diet that contains starch which gives arise to glucose and other disaccharides, but the process of starch uptake here is sporadically,which means that we take them from time to time and not constantly. It also depends on the type of food we eat(if the kind of food has a good amount of sugar). 2- Gluconeogenesis Although it has a SLOW response during fasting but it gives us a SUSTAINED amount of blood glucose that can go for days and days. 3- Glycogen The glycogen present in the body has a privilege of having a RAPIDresponse to the body needs of glucose, so as soon as a decrease in the blood glucose is detected,glycogenolysis starts; the process of metabolism so it can be degraded to supply the body with blood glucose and maintain blood glucose level in the body. However, glycogenis limited and doesn t last for long (if the person is well fed it may last up to 15 hours not more than that). Glycogen is mainly abundant in the liver.kidneys also have a small amount of glycogen, but it is mainly stored in the liver. It is present in the muscle tissue in fairly small amounts, but in the case of muscle glycogen the glycogen here isn t available for metabolism and degradation unless the muscle tissue undergoes exercise, and that s the difference between liver and muscle glycogen, the liver glycogen is for the whole body while muscle glycogen is only for its self. 2 P a g e
Since we ve started talking about glycogen, it is important to know its structure so we can further talk about its metabolism. Glycogen is a branched chain polysaccharide that is made of α D- glucose residues, the glucose has two types of bonding in glycogen: - α(1-4)glycosidic bond for linkage. - α(1-6) glycosidic bond for branching sides. Each branch ends by what we call anon-reducing end (it s non-reducing because the anomeric carbon is involved in glycosidic linkage and it doesn t exist in an open chain conformation). We will start talking about glycogen degradation and synthesis: Glycogen degradation 1- Phosphorylysis by glycogen phosphorylase When glycogen is mobilised, its non-reducing ends undergo Phosphorylysisby the enzyme (Glycogen Phosphorylase) which requires pyridoxal phosphate as a cofactor. This step results in the release of glucose molecule as Glucose-1- phosphate. This process of phosphorylysis continues until we reach a point that the branch contains only 4 residues. Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6 3 P a g e
2- Debranching by Debrancher enzyme Here we have an enzyme that shows its function by the name implied to it which is debrancher enzyme. It contains oligoα(1-4) to α(1-4) transferase in its structure (it is called 4:4 transferase). This transferase takes 3 residues from the branch left (4 residues) and moves them to any neighbouring branch. It takes them from α(1-4) and moves them to a neighbouring α(1-4). Debrancher is a BIFUNCTIONAL enzyme which contains two domains: 1. The first domain contains the 4:4 transferasewhich we ve mentioned earlier 2. The other domain contains α(1-6) glucosidasewhich reacts with the remaining residue on the branch with the α(1-6) glycosidic bond and releases it as FREE GLUCOSE. After the debrancher finishes its work, the glycogen phosphorylasebegins again with this process until we have a complete degradation of the glycogen chain present, and that s how the degradation occurs. The released glucose-1-phosphate by glycogen phosphorylase is later converted to glucose-6-phosphate by the enzyme PhosphoglucoMUTASE. Degradation of glycogen completely will give us 8% free glucose and the rest is glucose-1-phosphate. 4 P a g e
Glucose-6-phosphate: - If it was in the muscle tissue it will go on to glycolysis(glucose-6- phosphatase is absent). - If it was in the liver it will go to the ER to be released to the blood as free Important: The metabolism of a glucose molecule originated from glycogen metabolism in the muscle tissue results in 2 pyruvate molecules and 2 NADH molecules in addition to 3 ATP molecule instead of the 2 ATP we get from glycolysis.that s because the glucose enters as an already phosphorylated glucose so we neglect one of the original invested ATP molecules resulting in a net of 3 ATP molecules (4-1 instead of 4-2). glucose. Glycogen synthesis First thing to do before initiating the process of synthesis is converting the glucose-6-phosphate back to glucose-1-phosphate and that s done by the same enzyme which is Phosphoglucomutase. The process of converting glucose-6-phosphate to glucose-1-phosphate is done by the donation of a phosphate group that is found in the mutase enzyme structure to the glucose-6-phosphate resulting in glucose 1,6 phosphate, then the 6-phosphate is dragged back to the enzyme leaving only the glucose-1-phosphate molecule. 1- Activation of glucose-1-phosphate by linking UDP : The glucose-1-phosphate needs to be incorporated so the glucose should be activeto be donated. The activation occurs by the interaction between UDP and glucose-1-phosphate. This interaction is catalysed by the enzyme UDP-glucose pyrophosphorylase, which results in the release of a pyrophosphate group that will be later hydrolysed by pyrophosphatase releasing energy.remember that the energy released from pyrophosphate hydrolysis makes the reaction highly irreversible(exergonic reaction). Note: glycogen can be composed of up to 100 million residues, and the more branched the glycogen the more soluble it becomes. 5 P a g e
Glycogen exists as granules in the cytoplasm, those granules contain the enzymes that are responsible for the synthesis and degradation all together. Sugars activation mainly involves binding to UDP. In lipids,they can also bind to CDP, but the main activator is UDP. 2- CORE synthesis by Glycogenin enzyme(initiate glycogen synthesis) Glycogen synthase can t initiate chain synthesis using free glucose, it can only elongate already existing chains, and therefore it requires a primer (core). What if we don t have glycogen at all? The UDP-glucose can t bind to a free glucose molecule, nonetheless it needs a core that at least has 8 residues so it can bind to it. A fragment of glycogen can serve as a primer in cells whose glycogen stores are not totally depleted. Here comes the benefit of an enzyme called GLYCOGENIN, this enzyme undergoes a process of self/auto-glycosylation (because the reaction is catalysed by glycogenin itself), it has a tyrosine residue, and it does so by: Taking the glucose out of the UDP-glucose And add it to the -OH group of the tyrosine Then catalyse the transfer of the next molecule until we have an 8 residue core (primer). 6 P a g e
3- The synthesis by Glycogen Synthase Now that we have the core that we need, the glycogen synthase enzyme can start working. It begins the elongation of the chain by adding glucose residues to the core made by Glycogenin enzyme, when the chain reaches 11-12 residues length, an enzyme called BRANCHINGENZYME(common 4-6 transferase)takes a 5-8 residues long piece linked by α(1-4) and link it in an α(1-6) to the chain making a branch out of it, and most frequently the branches are 8 residues apart. The UDP left is regenerated so it can be reused later. The branches are more soluble than the single unbranched amylose chain and it gives more non-reducing ends for later degradation when needed. Now we ve finished talking about the process where glycogen is degraded and synthesised, so we willtalk about its genetic abnormalities and deficiencies. Glycogen storage diseases We have a bunch of diseases called glycogen storage diseases that result from deficiencies in the synthesis(rarely)or degradation pathways. Firstly, it s a genetic abnormality that can either produce glycogen with abnormal structureor produce it in excess amounts with normal structure (normal glycogen accumulation). 7 P a g e
The defected enzymes can involve a specific tissues isoenzymes or it can be generalized, and the severity of the defect can be mild, moderate, or in some cases severe which is fatal in young and early ages. Each disease is given a number, it s not important to memorise those numbers asdr.nayef said, but the most important thing is to know the mechanism.we will talk about them and try to give a biochemical reason of each one of them or at least the ones the doctor concentrated on the most. ZERO- GLYCOGEN SYNTHASE diseases (the dr only mentioned it and it has the number zero between the diseases). The second type of the diseases is referred to by the number, and it consists of two types: a glucose-6-phosphatase deficiency (more common) b- glucose-6-phosphate translocase deficiency - VON GIERKE disease (more prevalent): it can be caused by glucose- 6-phosphate or glucose-6-phosphate translocase deficiency. And both deficiencies result in the same abnormalities which are: - Fasting hypoglycaemia: glucose-6-phosphatase is present in the liver and kidneys so if we have a glucose-6-phosphatase deficiency we will always have a SEVERE fasting hypoglycaemia because we can t get glucose neither from glycogen nor gluconeogenesis since the glucose-6-phosphatase is the last product in both of them. - Fatty liver and liver enlargement (hepatomegaly): the accumulation of glycogen will result in enlargement of the liver or what we call hepatomegaly, and the production of acetyl-coa will result in fat synthesis resulting inn fat liver production. - Progressive renal disease : caused by the accumulation of glycogen - General growth is affected ( growth retardation ) 8 P a g e
- Hyper lactic acidemia: glucose gives pyruvate which gives lactic acid the increase in lactic acid blood level is called hyper lactic acidemia. - Hyperuricemia: glucose-6-phosphate can result in the making of ribose-5-phosphate that is involved in nucleotides synthesis which gives uric acid upon degradation resulting in an elevation in uric acid levels. - Hyperlipidemia: same mechanism as in fatty liver but the fat gets to the circulation increasing blood lipids level. Those diseases can be caused by both a and b, but there are some limited to b (translocase deficiency) and those are neutropenia(low level of neutrophils) and recurrent infections. - Lysosomalglucosidase deficiency(pompe disease): almost 1%-3% of glycogen is degraded by lysosomal enzymes so the deficiency in those will lead to accumulation of glycogen granules resulting in excessive glycogen constrictive abnormal vacuoles in the cytosol affecting the heart, liver, and muscles leading to CARDIOMEGALY (enlargement of the heart muscle, infants die early from heart failure). - Debrancher deficiency (CORI disease): a deficiency in 4:4 Transferase and/or amylo alpha (1-6) glucosidase resulting in fasting hypoglycaemia and accumulation of abnormal glycogen. IV Brancher (Anderson Enzyme) deficiency: leading to formation of unbranched linear chain leading to LIVER CIRRHOSIS and DEATH. V- Muscle glycogen phosphorylase deficiency (McArdle syndrome)myophosphorylase deficiency: here the liver isn t affected cause here we deal with a whole different gene than the liver, what happens is that we will have a defect in glycogen mobilization in skeletal muscles and we know that the mobilization occurs when muscles undergo activity or exercise so that will lead to what we call exercise intolerance 9 P a g e
leading to muscle cramps and pain and there won t be an increase in lactate etc. VI- Liver glycogen phosphorylase deficiency: HERS disease VII- Phosphofructokinase deficiency (in muscle and RBC) : we ve said earlier that the glucose coming from glycogen to the muscle goes into glycolysis but if we have a defect in glycolysis glucose won t be mobilized from glycogen of the muscle so we will have a defect in glucose mobilization from glycogen of the muscle and it s the same as number 5 ( V ), but here half of the enzyme ( muscle glycogen phosphorylase ) is present, leading to a defect in red blood cells shape and they will suffer from HEMOLYSIS, so here we have two halves if the half that is present in the muscle is affected this will be affected. The doctor mentioned a question type that can be in the exam: If a patient is administered to the hospital with an exercise intolerance with normal muscle glycogen, normal liver glycogen and with no increase in the lactate level in his blood after the exercise, what would the affected enzymebe? a) Liver phosphorylase b) Muscle phosphorylase c) Brancher d) Debrancher The answer is B muscle phosphorylase Writer s note: I thought that thefollowing table might help a little in knowing the basics about glycogen storage diseases. I hope that I did not miss any details and simplified some of the concepts in a way that we students can manage, for better understanding. Thanks :) 10 P a g e
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