Carbohydrates and Glycogen Metabolism Lecture 3 PDF

Carbohydrates and Glycogen Metabolism Assoc. Prof. S. Sibel Erdem Istanbul Medipol University International School of Medicine  PART I: CARBOHYDRATES  Carbohydrates Carbohydrates (saccharides)are the most abundant organic molecules in nature. Simpler...

Carbohydrates and Glycogen Metabolism Assoc. Prof. S. Sibel Erdem Istanbul Medipol University International School of Medicine  PART I: CARBOHYDRATES  Carbohydrates Carbohydrates (saccharides)are the most abundant organic molecules in nature. Simpler carbohydrate is (CH2O)n, where n ≥ 3 They have variety of functions; storage form of energy, cell membrane component, exoskeleton of many insects. 45% to 65% of the diet can be carbohydrates depending upon the individual needs.  Classification of Carbohydrates Monosaccharide: Simple monosaccharides consist of linear chain of three or more carbon atoms. They are classified according the number of carbons If the carbonyl group is ketone, the sugar is a ketose; If the carbonyl group is aldehyde, the sugar is a aldose.  Haworth Fischer Isomers, Epimers, Enantiomers: Isomers: Compounds that have same chemical formula but different structures are called isomers. Epimers: Isomer that differ in configuration only one carbon atom Enantiomers: Special type of isomerism for a compound having a chiral center. The groups attached to the asymmetric carbon atom can be arranged to form two different isomers that are mirror images of each other are not superimposable. C6H12O6  If OH group on the asymmetric carbon farthest from the carbonyl carbon is on the left it is called L; if it is on right it is called D enantiomers.  Question: Are D-mannose and D-galactose stereoisomers? Are they epimers of each other? Answer: They are stereoisomers. They have the same chemical formula but differ in the position of two hydroxyl groups.  Cyclization of Monosaccharides Often times, five or more carbon containing carbohydrates exists predominantly in a cyclic form. During cyclization, the carbonyl carbon transforms into a new stereocenter.  Cyclization of Monosaccharides The new stereocenter is referred to as the anomeric carbon. Position of the OH group is critical If the OH group on the anomeric carbon is axial DOWN, anomeric carbon is α If the OH group on the anomeric carbon is equatorial up, anomeric carbon is β How Do I locate the Anomeric Carbon? 1. Locate the oxygen inside the ring. 2. Look at the carbons on either side of the oxygen. One will be attached to a CH2OH group. Do not focus on this one. The carbon on the other side is the anomeric carbon! Anomeric Carbon  36% 16 -  Disaccharides Monosaccharides undergoes condensation reaction and forms disaccharide. Sucrose, lactose and maltose are most common types of disaccharides. Are All Disaccharides Reducing Sugar? Non-reducing sugar REDUCING SUGAR REDUCING SUGAR  Polysaccharides Natural carbohydrates are usually found as polymers These polysaccharides can be o homopolysaccharides o heteropolysaccharides o linear o Branched Polysaccharides do not have a defined molecular weight.  Glycogen Glycogen is a branched homopolysaccharide of glucose – Glucose monomers form (a1 ® 4) linked chains – Branch-points with (a1 ® 6) linkers every 8–12 residues – Molecular weight reaches several millions – Functions as the main storage polysaccharide in animals  Starch Starch is a mixture of two homopolysaccharides of glucose Amylose is an unbranched polymer of (a1 ® 4) linked residues Amylopectin is branched like glycogen but the branch-points with (a1 ® 6) linkers occur every 24–30 residues Molecular weight of amylopectin is up to 200 million Starch is the main storage polysaccharide in plants Digestion of Dietary Carbohydrates Dietary carbohydrates are composed of poly-, oligo- and disaccharides. They are digested to monosaccharides; glucose, and fructose that are absorbed by cells of the small intestine. Enzymes known as glycoside hydrolases (glycosidases) hydrolyze glycosidic bonds in poly-and oligo-saccharides. Enzymes known as disaccharidases hydrolyze tri-and di-saccharides into their reducing sugars.  Steps of Digestion 1. Salivary α-amylase: Hydrolyzes poly-saccharides via random αlpha-1,4 glycosidic bond cleavage to produce short branched and unbranched oligo- saccharides known as dextrins. 2. Pancreatic α-amylase : pancreas secretes bicarbonate and under neutralized conditions in small intestines, digestion of starch continues. 3. Intestinal Disaccharidases: Final stage of the digestion of carbohydrates are being done by several enzymes (isomaltase, maltase,lactase etc). All bonds are cleaved to produce monosaccharides. 4. Intestinal Absorption of Monosaccharides: monosachharides are taken into the cells via different glucose transporters depending on the sugar.  Digestive Enzyme Deficiencies Genetic deficiencies of some disaccharidases results in intolerance. Alterations in disaccharide degradation, change in mucosal lining of the intestine, age dependent loss of enzyme malnutrition, intestinal diseases my also cause digestion problems of disaccharides. Symptoms: If carbohydrate degradation is deficient; disaccharides will pass into the large intestine, where it can cause osmotic diarrhea. Bacterial fermentation of material causes large volumes of H2 and CO2 generation, bloating, cramps, diarrhea. Diagnoses: Oral tolerance test with individual disaccharides. Measurement of H2 gas in breath shows metabolite but not absorbed carbohydrates  Digestive Enzyme Deficiencies Lactose Intolerance: Lactase deficient people can not digest lactose (>70% world population). Treatment: Dietary restriction of milk, consuming yogurt, cheese instead. Sucrose-isomaltase Deficiency: Autosomal recessive disorder. (0.02 % in European people) Treatment: Enzyme replacement therapy, dietary restriction of sucrose Summary  PART II: GLYCOGEN METABOLISM Sources of Blood Glucose Diet Gluconeogenesis à slow Degradation of Glycogen  Overview Glucose is essential energy source for body. Blood glucose can be obtained from: diet, glycogen, and gluconeogenesis. Dietary glucose is not always constant, depends on the diet so it is not a reliable source of blood glucose. Glycogen is the storage form of glucose in most types of cells. If needed, the glycogen is degraded to glucose, called glycogenolysis. When there is excess of glucose, it is used to synthesize glycogen, called glycogenesis. When glycogen stores are depleted , specific tissues synthesize glucose de novo, using amino acids from the body’s proteins as primary source of carbons via gluconeogenesis.  Storage Form of Carbohydrates C,H,O + O2 à CO2 + H2O + energy (24/7) Luckily our bodies are designed in a way to store food If needed the stored food (carbohydrate, protein, fat) can be used to retrieve fuel. * Graph  Glycogen Glycogen is branched oligosaccharide composed of αlpha 1,4 and αlpha 1,6 glycosidic bonds. Branches occur more frequently in the center It has only one anomeric carbon Reducing end is attached to the protein glycogenin by glycosidic bond. 2/3 of glycogen is water Glycogen Storage LIVER is the unselfish “good guy” Skeletal muscle and liver are the major source of stored glycogen Liver glycogen can maintain blood glucose for 18 h. Liver glycogen stores increase during well-fed state and depleted during fasting state 100 g of glycogen is stored in liver  MUSCLE is Selfish Glycogen gets broken to Glucose6-P and never leaves the muscle cell. Pyruvate and lactate are produced Muscle glycogen is not affected by short periods of fasting time (few days) Moderate decrease is seen after Glycogen storage weeks of fasting. : MUSCLE = 4009 400g of glycogen is stored in muscle LIVER = 1009 Effect of Fasting on Liver Glycogen Content Our body has ability to store only small amount of glycogen. Why is this? In other words: Why body store energy in the form of adipose tissue not as glycogen?  Glycogenesis (Glycogen Synthesis) Glycogen is synthesized from molecules of alpha-D- glucose The process occurs in cytosol It requires energy for the phosphorylation of glucose) and supplied by ATP and Uridine triphosphate (UTP)  Glycogenesis (Glycogen Synthesis) In order glycogen to be synthesized, glucose has to be linked to high energy # molecule, UDP. (UDP-glucose pyrophosphorylase) Glycogen Synthase makes α(1à4) glycosidic bonds using a fragment of glycogen as primer. If it is missing, protein called glycogene serves as an acceptor of glucose. Branches are made by branching enzyme amylo- α(1à4) àα(1à6) transglucosidase (4,6 trasnferase branching enzyme) Glycogenesis Cont’d (Glycogen Synthesis)  Glycogenolysis (Degradation of Glycogen) Glycogen phosphorylase sequentially cleaves the α(1à4) glycosidic bonds by simply phosphorylation and producing glucose1- phosphate Debranching enzymes removes branches.(4:4 transferase and 1:6 glucosidase) Glycogenolysis Cont’d Limit Dextrin Conversion of Glucose 1- phosphate to Glucose  Hormones Regulate the Use of Glycogen One player is insulin. Three other hormonal players are Epinephrine (adrenaline) Glucagon Cortisol Insulin stimulates the storage of fuel; Epinephrine, glucagon and cortisol stimulate the release of fuel from storage in the tissue  Insulin’s action: to reduce glucose levels in blood Glucagon’s action: to stimulate the release of glucose from stored glycogen Epinephrine’s action: to elicit a short term release of glucose from stores. Cortisol’s action: to stimulate make of glucose from proteins Regulation of Glycogenesis and Glycogenolysis In the LIVER: Insulin/glucagon levels and blood glucose levels are important parameters to regulate glycogenolysis. RATIO Well-fed state;(insulin/glucagon(level is high, secretion of insulin is high, glycogenesis is high Absorptive state;(insulin/glucagon( level is low, glycogenolysis is favored. Degradation of liver glycogen is also regulated by epinephrine After a high carb meal while blood glucose and insulin levels increase; glucagon levels decrease. Rise in insulin/glucagon ratio stimulates glycogen synthesis. That brings blood glucose levels back to normal range (80-100 mg/dl) After a period of time, blood glucose levels drops, and body starts to use glycogen store. Glucagon action in glycogen metabolism in liver. ⊕, pathways stimulated by glucagon; ⊖ pathways inhibited by glucagon. Regulation of Glycogenesis and Glycogenolysis In the skeletal MUSCLE: When the muscle is at rest; glycogenesis occurs. During exercise; glycogenolysis takes place. Glycogenolysis is regulated by Adenosine Monophospate (AMP), epinephrine and Ca2+. Hormonal Regulation of the Enzymes Glycogen synthase and glycogen phosphorylase are the two enzymes control the mechanism These enzymes are hormonally and allostrerically regulated.  Summary of Hormonal Regulation of Glycogen Metabolism Hormone Skeletal Action Liver Name Muscle Insulin Activated by Insulin Glycogen Glucose Synthase Glucogan Inhibited by Epinephrine Epinephrine Epineprine Glucogan Activated by AMP Glycogen Epinephrine Ca2+ Phosphorylase Insulin Inhibited by Insulin ATP Allosteric Regulation of Glycogen Synthesis and Degradation Glycogen Storage Diseases Glycogen Storage Diseases Glycogen Storage Diseases What name is given to monosaccharides that differ in configuration at the hemiacetal carbon atom? A. Enantiomers B. Glycosides C. Isomers D. Epimers E. Anomers Which O-glycosidic bond is commonly found in amylose, amylopectin and glycogen? A. (β 1 " 4) B. (α 1 " 6) C. (α 1 " 4) D. (β 1 " 6) E. (α 1 " 3) What term is given to carbohydrates linked at their anomeric carbons? A. Non-reducing sugars B. Glycosides C. Glycans D. Anomers E. Hemiketals Which of the following statement regarding dietary carbohydrates is correct? A. α-amylase is only able to hydrolyze α1à6 bonds in glycogen and starch B. α-amylase is secreted by both the salivary gland and the pancreas C. Disaccharidases are synthesized in and released from pancreas D. Low pH in the stomach accelerates hydrolysis of carbohydrates E. Amylopectin is a linear chain of glucosyl residue.  In humans, metabolism of glycogen is not a strict on/off process. Gradations of activity in at least one enzyme are documented. Activity of the enzymes associated with glycogen metabolism is modulated by the degree of phosphorylation of the enzyme protein? A. Debranching enzyme B. Adenylate cyclase C. UDP-glucose pyrophosphorylase D. Glycogen synthase E. Branching enzyme