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Transcript
Glycogen Metabolism, Electron Transport/Oxidative Phosphorylation Pawlose Ketema Introduction to Glycogen • Glycogen is the storage form of glucose. • It is a long polymer of glucose molecules that branches about every ten glucose residues. • Glycogen consists of two types of bond linkage; α-1,4 glycosidic linkage as well as α-1,6 glycosidic linkage (branching points). • There are two types of cells in the body that are responsible for storing glycogen. • Each cell have a different role in regulating the amount of glucose that is there at a given time. Glycogen: Polymer of Glucose • In a wide range of organisms, excess glucose is converted to polymeric forms for storage as glycogen in vertebrates and as starch in plants. • The only difference between the two is what bonds link the glucose monomers. • Glycogen is found primarily in the liver and skeletal muscle. • Exists in a branched spiral, very compact Glycogen in the liver • Cells such as hepatocytes can use glycogen to regulate the blood glucose levels of the body. This is especially important because our brain almost exclusively depend on glucose for energy. • So if for instance our blood glucose level is low, the liver will breakdown glycogen releasing glucose thus bringing the blood glucose level to its normal concentration. This is especially true during state of fasting. Glycogen granules in a hepatocyte. Glycogen in skeletal muscles • Our body depends on glycogen breakdown during periods of vigorous activity. The glucose obtained from glycogen can be used to produce energy under anaerobic activity( no O2). • It is important to recognize that glycogen stored in skeletal muscle provides rapid energy needed for sudden and strenuous activity. Glycogen Breakdown • Glycogen breakdown is catalyzed by the enzyme glycogen phosphorylase. • In skeletal muscle and liver, the glucose units of the outer branches of glycogen enter the glycolytic pathway through the action of three enzymes: • Glycogen phosphorylase- release G-1-P • Glycogen debranching enzymerestructuring glycogen • Phosphoglucomutase – conversion of G-1-P to G-6-P Glycogen (Glucose)n-1 (Glucose)n Glucose-!-Phosphate Glucose-6-Phsophate Fate of Glucose-6-Phophate 1. In skeletal muscle it can enter glycolysis and serve as an energy source to support muscle contraction. 2. In liver it can release glucose into the blood when the blood glucose level drops, as it does between meals. 3. G-6-P can also enter pentose phosphate pathway to produce NADPH. Metabolism: Glucose and Insulin • What we know: • Glucose is a quick, easy form of energy • Our brain only uses glucose as a source of energy , so it’s important to have! • Glucose is broken down via glycolysis into ATP, NADH and Pyruvate, which then go on to make more energy… • However, glucose is transported in the blood. How does it get into the cell to undergo glycolysis? Insulin: Energy Gatekeeper • • • • Insulin is like a key: it opens up cells so glucose can enter from the blood • sugar content in the blood is called blood sugar It is a peptide hormone, produced in the beta cells of the pancreas According to various feedback mechanisms, insulin is released when sugar levels are high in the blood, usually after a meal • this time is called “post-prandial”, or posteating Insulin is a protein homo-hexamer arranged around a zinc iron -- quaternary Structure? Meet Hanna • • • • Hanna just ate a piece of cake What is happening in her body? • Sugars broken down by gastric enzymes and transported into the blood • Pancreas beta-cells sense sugar influx and release insulin • Insulin spreads throughout the body and binds to cells, allowing glucose inside Result: huge influx of sugar is quickly taken out of the blood and into cells where it is converted to energy or stored for future use Body’s response to “challenge” is so quick that hyperglycemia never happens Meet Dan the Diabetic • Dan just ate a cookie • What is happening in his body? • Sugars broken down by gastric enzymes and transported into the blood, then… What then??? • It depends on what kind of diabetic Dan is Meet Dan the Diabetic • Type 1: Auto-Immune. Body is destroying beta cells, insulin is no longer produced • No insulin, no sugar transport • Type 2: Dan has eaten so much sugar over a lifetime that his cells won’t acknowledge insulin anymore cells have “down regulated” (decreased) the amount of insulin receptors on the cell surface Insulin doesn’t bind, no sugar transport The result is the same: sugar stays in the blood, unable to gain access to cells and be transformed into energy or stored for later (Sneak preview for your 11/11 lecture) Hyperglycemia • Too much glucose in blood Often suggests malfunction in insulin pathway • Often seen in diabetes mellitus • Chronic hyperglycemia carries several long term effects: Increased risk of cardiovascular disease and stroke Frequent hunger, thirst, and need for urination Tissue damage (e.g., retinopathy, nephropathy, neuropathy) Ketoacidosis Consequences of Hyperglycemia • Sugar in the blood is damaging for vital organs such as kidneys, eyes and circulation problems in extremities • If an area cannot get blood, it cannot get oxygen and cannot get immuno-protective cells like WBC… • Limb infections for diabetics are sometimes life-threatening • Because there is no circulation, bacteria that are usually killed by oxygen (anaerobic) can thrive -- these are the most dangerous kind! • Cells cannot access main energy source • Urine is saturated with sugar • Conclusion: Hyperglycemia is not good or fun or desired! Hypoglycemia • Too little glucose in blood • A number of potential causes: Improper insulin dosage in diabetes patients Oversecretion of bodily insulin Long-term fasting Liver dysfunction due to alcohol The Brain. Most researchers agree: it is important. • Body responds via glucagon and epinephrine • This is a medical emergency CNS requires continuous supply of glucose Even brief denial of glucose to brain can cause long-term damage Healthy Hanna and the Fasting State • It’s been awhile since that piece of cake! How does Hanna’s body get energy? • When blood sugar is low, a peptide hormone called glucagon is released from the alpha cells of the pancreas • promotes mobilization and breakdown of stored glycogen • quick and easy • glucose molecules are released and body can survive until next influx of fuel Feeding, Fasting, and Blood Sugar • Feeding: Consuming a meal Breakdown of carbs = sharp increase in blood glucose Body responds with insulin Glucagon inhibited (unless meal is predominantly protein) • Fasting: Skipping a meal, or otherwise refraining from eating Glucose steadily falling Insulin falls, glucagon/epinephrine rise Body calls upon storage to meet energy demands Feed/Fast Cycle Summarized The key is that insulin and glucagon work in tandem to maintain blood glucose levels in response to food intake, or lack thereof. Alternate Pathways: Resources • What happens if there’s no sugar in your blood? • Glucagon is released and glycogen broken down • What happens when there’s no more glycogen to use? • Next, the body begins to mobilize (from adipose) and break down free fatty acids for energy • This can happen during exercise or short-term fasting • What happens when you run out of fat? • Next, your body begins to break down proteins for energy • This occurs only after several days of no food. • The accessible sources of proteins in your body are muscles and lean body tissue. You start to “eat” your muscles • 1) sugar (easy to move and store), 2) fats (HUGELY energetic, 2.25x sugar) and hopefully never 3) proteins (last resource, energetically equal to sugar) Oxidative Phosphorylation Oxidative Phosphorylation • AKA, The Electron Transport Chain • Does everybody remember The Mighty Mitochondria, The Powerhouse of the Cell? Mitochondria • Mitochondria produce energy for the cell • this energy is ATP • Obviously, the mitochondria aren’t the ONLY source of ATP • Glycolysis, Citric Acid Cycle, etc • Most efficient mechanism of ATP production is Oxidative Phosphorylation, which is conducted through an electron transport chain Oxidative Phosphorylation • The only aerobic (oxygen-requiring) energy process in the body of the three main parts of cellular respiration • Oxidative = oxidation, oxygen • Phosphorylation = attaching a P directly to ADP, making ATP • Making ATP via oxidation • Substrates: NADH and FADH2 produced from glycolysis and the TCA cycle • NADH = 3 ATP, FADH2 = 2 ATP Oxidative Phosphorylation • • • Glycolysis and the citric acid cycle yield NADH and FADH2. Both these electron carriers are energy-rich molecules because their electrons have a high transfer [redox] potentials. Oxidative phosphorylation is the process of converting this high redox potential into energy-rich ATP molecules. 26 • • • Mitochondrial structure plays a critical role in forming and utilizing the proton gradient to synthesize ATP. Protons are “pumped” from the matrix across the inner membrane into the intermembrane space. ATP is synthesized in the matrix, as protons flow back through the membrane. 27 Chemiosmotic Potential • The result of introducing NADH into the electron transfer chain • NADH ➔ NAD+ and H+ and 2e• NAD+ goes back into the cytoplasm to work as a redox cofactor • The electrons are handed off through a series of carriers, releasing small energies • The H+ are transported through the membrane to collect on the opposite side • This creates an overwhelming number of H+ on ONE side of the membrane, leading to 1) a molecule imbalance (H versus no H) and 2) a charge imbalance (+ vs - ) • The body, due to homeostasis/osmosis/equilibrium, REALLY wants to correct that imbalance (there is stress) • This creates a gradient that the body harnesses to create ATP Chemiosmotic Potential • • H+ are gathered on one side of the mitochondrial membrane, donated from metabolic cofactors NADH and FADH2 They are slowly “leaked” across the membrane through a molecular machine that fuses P to ADP, creating ATP • Think about it like stuffing water into a balloon. The balloon stretches and pressure builds: if you let the water out slowly, one spurt at a time, it will be high-pressure and could be used to move an object ATP Synthase Video: https://www.youtube.com/watch?v=3y1dO4nNaKY OxPhos Products and Waste • Substrates: NADH and FADH2 • Citric Acid Cycle occurs in the mitochondrial matrix, so all the necessary ingredients are within reach • O2 (oxygen) is split and capped with spare hydrogens, creating 2x H2O as “waste” • The process is aerobic, or requires oxygen • Desired product: ATP from ADP + P OxPhos Inhibitors • • OxPhos is the most prolific generator of ATP in the body • What would happen if it were disrupted or “tricked”? Electron Chain Inhibitors or “de-couplers” are used as poisons • Cyanide: takes the place of oxygen on cytochrome C oxidase, preventing the reduction of O2 to H2O • leads to “suffocation” where the victim is breathing but cannot use the oxygen to create ATP, and so dies • Carbon monoxide and hydrogen sulfide also work this way OxPhos Inhibitors • CCCP and 2,4-dinitrophenol are ionophores, or molecules that carry H+ across membranes, from high concentration to low concentration • this disrupts the ion gradient, weakening (but not eliminating) the chemiosmotic force that moves ATP synthase • Called an “uncoupler” • Not fatal but dangerous, lessens the “bang for buck” of fuel • Used as a weight-loss supplement in the 1930’s • Why and how did this make sense? • Food ➡ NADH ➡ ATP Let’s Do The Math... • 1 glucose molecule • Glycolysis: 2 NADH, 2 ATP, 2 Pyruvate • 2 ATP, 2 NADH = 6 ATP • 8 ATP total • 2 pyruvate go through TCA cycle • Pyruvate ➡ Acetyl-Coa creates 2 NADH • 2 NADH = 6 ATP • 2 GTP, 6 NADH, 2 FADH • 2 GTP, 6 NADH = 18 ATP, 2 FADH = 4 • 30 ATP total • 8 ATP (Glycolysis) + 30 ATP (TCA) = 38 ATP Glucose: 4 kCal/g Other Sources of Energy • • • Glucose = 4 kCal/g Proteins = 4 kCal/g • Same caloric count as glucose, but much more “nutritious” • Contains N-compounds and necessary building blocks for life, essential amino acids Lipids (Fats) = 9 kCal/g • All free fatty acids broken down to Acetyl-CoA, which goes directly to the TCA cycle • LOTS OF ENERGY