PPP_glycogen_metabolism Part 2 الفريق الطبي األكاديمي. Done By: - Shady Soghayr

Transcription

1 PPP_glycogen_metabolism Part 2 الفريق الطبي األكاديمي Done By: - Shady Soghayr لكية الطب البرشي البلقاء التطبيقية / املركز /

2 **How we get glucose-1-phosphate from glucose (source of glucose-1- phosphate)? From glucose-6-phosphate by phosphoglucomutase Page 1

3 **From where we get glucose-6-phosphate? Glucose is converted to glucose-6-phosphate by hexokinase **glucose-1-phosphate is not used directly to be incorporated into glycogen by glycogen synthase, it must be converted to activated intermediate. **the active intermediate of glucose-1-phosphate is synthesized by the reaction of glucose-1-phosphate with UTP (Uridinile Tri Phosphate) **UTP is a high energy compound Page 2

4 **activated intermediate is going to be used by glycogen synthase in order to incorporate glucose units to the growing chain of glycogen **Why we use this activated intermediate (activated intermediate)? In order to make α(1-4) glycosidic bonds for the incorporation of glucose into the growing chain of glycogen (this intermediate has very high energy bond that when Page 3

5 hydrolyzed it will be able to incorporate glucose and forming α(1-4) glycosidic bond **the energy of the activated intermediate is stronger than the energy of α (1-4) glycosidic bond **the activated intermediate is UDP-glucose **glycogen synthase will incorporate the glucose molecule to the glycogen chain +UDP **how to make the α (1-6) glycosidic bond? The (branching enzyme) and it works by carrying a bunch of glucose units breaking the α(1-4)glycosidic bond and forming the α(1-6)glycosidic bond **the energy needed to make the α(1-6) glycosidic bond is taken from the hydrolysis of the α(1-4) glycosidic bond **the body depends on glucose that comes from glycogen because it comes very fast and it comes when needed Page 4

6 **the body will activate glycogen degradation and in the same time inhibits glycogen synthesis ** function of glycogen phosphorylase? Degradation of glycogen by phosphorolases **how phosphorolyses of glycogen will take place? By adding a phosphate group (in the presence of phosphate and glycogen phosphorylase,phosphate will be added to glucose giving a glucose-1-phosphate) **glycogen phosphorylase is regulated by 2 different mechanisms the first is covalent modification (include phosphorylation and DE phosphorylation) and the second is allosteric regulation **in the pic from right to left or from left to right is covalent modification and what is involved in it is the phosphorylation of glycogen by an enzyme called phosphorylase kinase **phosphorylate kinase will phosphorylate glycogen phosphorylase and become phosphorylated **at the de phosphorylation of glycogen phosphorylase "is taking place in this direction" by an enzyme called (phospho protein phosphatase) **when glycogen phosphorylase is phosphorylated it is activated and when de phosphorylated it will be inactivated **glycogen phosphorylase is found in 2 forms 1-glycogen phosphorylase b (the less active) 2-glycogen phosphorylase a (the most active) **when (glycogen phosphorylase b) is phosphorylated it is converted to (glycogen phosphorylase a) and when glycogen phosphorylase a is dephosphorated is is converted to glycogen phosphorylase b which is less active or,in active **allosteric regulation means that glycogen phosphorylase is found in two states the R-state and the T-state **glycogen phosphorylase in allosteric regulation has positive allosteric effectors and negative allosteric effectors **each form of glycogen phosphorylases is found in two states the R-state and the T-state Page 5

7 **what happens to glycogen phosphorylase a in the liver? When you have a carbohydrate rich food you will have a high level of glucose in the blood (high energy) and this will allosterically convert the glycogen phosphorylase a from the R-state to T-state of GPa **glucose is a negative allosteric effector for the GPa **in most of the cases in the body there is no glucose "playing around" because it is poison to cells,so the cell will deal with it and not leaving the glucose in cells so the T-state will be converted to the R-state in most of the times Page 6

8 **GPb in the muscle is allosterically converted from R-state to T-state by ATP and glucose-6-phosphate **ATP and glucose-6-phosphate represents high energy ** when the muscle contracts and losses all its ATP from creatinephosphate there will be an accumulation of AMP(AMP represents low energy)so it will convert the T-state to the R-state of the GPb until the hormone comes (glucagon or epinephrine)to give a signal to phosphorylate GPb to be converted to GPa in order to start glycogen degredation Page 7

9 Page 8

10 Once these enzymes bind to their receptors, they will activate g proteins including adenylate cyclase system, which would convert ATP to camp and camp when activate protein kinase A from inactive to active form. Protein kinase A is the enzyme that is not phosphorylated but it phosphorylates other proteins such as phosphorylase kinase that is going to phosphorylate glycogen phosphorylase as well as phosphorylating glycogen synthase. now remember, when glycogen phosphorylase is phosphorylated it is activated and at the same time when glycogen synthase is phosphorylated by protein kinase it is inactivated. So it is nonsense to activate glycogen phosphorylase and at the same time activate glycogen synthase, this is their reciprocal regulation, activation of glycogen phosphorylase and inactivation of glycogen synthase by the phosphorylation by glucagon or epinephrine indirectly by signal transduction. Does the body require the adenylate Cyclase to be active all the time? And what is the function of Cyclase? It converts ATP to camp, which is considered one of the second messengers, this camp will activate protein kinase A by allosteric regulation, it will dissociate the catalytic subunit from the regulatory subunit of protein kinase A and thus activate the catalytic subunit to start phosphorylating other proteins, so protein kinase A is a common kinase enzyme that will phosphorylate many proteins including glycogen phosphorylase and glycogen synthase. In order to control this system, the cell could degrade the camp and get rid of it converting it to AMP by an enzyme called phosphodiesterase. Phosphodiesterase will control the system by decreasing the concentration of camp and thus inhibiting protein kinase A thus stopping the phosphorylation or the Covalent modification of glycogen phosphorylase and glycogen synthase. It was found that phosphodiesterase which degrades camp, is inhibited by caffeine. At high levels of glucagon and epinephrine the body degrades glycogen. At high levels of insulin the opposite happens, glycogen is synthesized, and the degradation of glycogen is inhibited. Insulin is For the synthesis of glycogen and glycolysis while epinephrine or glucagon is for degradation of glucose and inhibiting glycolysis and activating gluconeogenesis. Page 9

11 Phosphorylase Kinase Regulation How phosphorylase kinase is regulated? Protein kinase A will phosphorylate phosphorylase kinase. Phosphorylase kinase could be activated in 2 pathways. It Could be activated first, by phosphorylation by protein kinase A, then by calcium to give fully active phosphorylase kinase. Or it could be activated allosterically first by calcium so it's partially active, then it is phosphorylated to fully active phosphorylase kinase. This is very important because when the muscle is Contracting there's no enough energy under phosphorylase kinase did not yet receive the signal from the glucagon or epinephrine but because of the continuous muscle contraction high levels of calcium is produced, which is going to partially activate the phosphorylase kinase and help the muscle to degrade its glycogen, even before the phosphorylation starts by the signals of hormones. Page 10

12 Glucagon is a hormone protein when epinephrine is not a hormone protein, it is a hormone but not a protein. As a summary, when glucose levels are low, epinephrine or glucagon increases glucose concentration by favoring glycogen breakdown by activating glycogen phosphorylase and inhibiting glycogen synthesis by inhibiting glycogen synthase. Insulin stimulates phosphoprotein phosphatase, which removes phosphate group from glycogen enzymes, which are glycogen phosphorylase and glycogen synthase. So phosphoprotein phosphatase will dephosphorylate glycogen phosphorylase a, and glycogen synthase a, which means there would be inhibition of glycogen degradation and activation of glycogen synthesis. Page 11

13 Insulin Signaling Countering the Epinephrine/Glucagon System is the Insulin System Insulin Stimulates Phosphoprotein Phosphatase to Remove Phosphates From Glycogen Enzymes 1. Favoring Glycogen Synthesis (Activates Glycogen Synthase) and 2. Inhibiting Glycogen Breakdown (Inhibits Glycogen Phosphorylase) Insulin Also Stimulates Uptake of Glucose by Cells, Reducing Blood Glucose Levels So insulin counteracts the reactions of epinephrine and glucagon. How insulin activates glycogen synthase? It dephosphorylates phosphate from glycogen synthase and convert it to non phosphorylated glycogen synthase which is the active form ->Inhibiting glycogen breakdown by inhibiting glycogen phosphorylase. How it inhibits glycogen phosphorylase? By activating phosphoprotein phosphatase which will dephosphorylate the glycogen phosphorylase. Insulin also stimulates uptake of glucose by cells, how? By Simulating low glucose transporters like gluts, that binds with glucose taking them inside the cells. What does insulin do this glucose in the cells? Start the glycolysis pathway. Thank you Page 12