Glycogen metabolism Biochem 4511 Figures Essential of Biochemistry 3e by Pratt and Cornely Moran Principles of Biochemistry 4th 5th edition Tymoczko Berg Stryer Biochemistry A Short Course McKee McKee Biochemistry Glycogenesis production of glycogen from glucose Glycogen is a branched polysaccharide that serves as a form of energy storage in animals and fungi In animals glycogen is produced and stored primarily in the liver and muscle and functions as the intermediate term energy storage as opposed to the long term triglyceride depots in the adipose tissue Cytoplasm Mitochondria Glycolysis Krebs cycle Respiratory chain Most of gluconeogenesis Chemi osmotic ATP production Glycogenesis Fatty acid breakdown Glycogenolysis Fatty acid synthesis Glycogen granules 2 Glucose phosphate isomerization Glucose 6P is enzymatically isomerized to Glucose 1P This reaction traps glucose in a cyclic form The enzyme contains a Phospho Serine group Glucose 1P requires further activation before polymerization into glycogen Is glucose 1P a reducing sugar Activation of glucose via formation of a UDPglucose precursor Glycogen synthesis consumes the free energy of UTP Catalyzed by UDP glucose pyrophosphorylase This is a near equilibrium reaction unless it s coupled to PPi hydrolysis Hydrolysis of PPi by inorganic pyrophosphatase drives the reaction large negative G Synthesis of Glycogen A Priming by B Elongation Glycogenin a nucleating enzyme Catalyzes attachment of first 8 glucose moieties C Branching by Branching enzyme amilo 1 4 1 6 transglycosylase Transfers 4 oligosaccharide residues from a non reducing end to the side 5 Priming by Glycogenin Glucogenin was discovered only in 1984 It catalyzes the following reaction UDP alpha D glucose glycogenin UDP alpha D glucosyl glycogenin A Priming by Glycogenin a nucleating enzyme Catalyzes attachment of first 4 8 glucose moieties Strictly speaking glycogen is not a polysaccharide but a proteoglycan Glycogen Synthesis Elongation Glycogen synthase adds glucose residue to extend the linear polymer UDP is released UTP is restocked by UDPkinase UDP ATP UTP ADP What about branches 2014 John Wiley Sons Inc All rights reserved Synthesis of Glycogen Elongation UDP glucose activated form of glucose 3 What about branches 8 8 Glycogen Synthesis Branching Branching enzyme amilo 1 4 1 6 transglycosylase Catalyzes transfers of 4 oligosaccharide residues from a non reducing end to the side Net balance NET Starting from G 6 P 1 high energy bond of ATP is required for adding glucose moiety to glycogen How many ATP molecules are required starting from Glucose 10 Glycogenolysis Glycogen breakdown Glycogen synthesis and glycogen breakdown occur via a different set of reactions Linear chains are broken down via phosphorolysis by glycogen phosphorylase Branched chains of glycogen are broken down via hydrolysis next page Glucose 6 phosphate can enter glycolysis at Step 2 One less ATP is consumed compared to glucose from the bloodstream Net gain of ATP is higher G6P can be dephosphorylated and transported to blood G6P can undergo conversion to ribose5P generating NADPH Pentose phosphate shunt Glycogenolysis Debranching Dual activity of Debranching enzyme 1 4 glucanotransferase activity 2 Amylo 1 6 glucosidase activity leads to hydrolysis i e forms glucose and not glucose phosphate How many reducing ends are in a glycogen molecule 12 Regulation of Glycogenolysis and Glycogenesis Glycogen synthesis and degradation reciprocally regulated I Allosteric by Energy charge and Substrate AMP activates Glycogen Phosphorylase GP and inhibits Glycogen Synthase GS This type of regulation serves the needs of the glycogen containing organ e g muscle Glucose 6P allosterically activates Glycogen Synthase in response to glucose entry feed forward activation 1 Glycogen phosphorylase is activated by AMP inhibited by ATP and Glucose 6P 2 Glycogen synthase is activated by Glucose 6P Regulation of Glycogenolysis and Glycogenesis Glycogen synthesis and degradation reciprocally regulated II Hormone mediated Implemented via post translational modifications of GP and GS enzymes Glucagon and epinephrin activate A GPCR cascade activate Protein Kinase A which activates glycogen synthase kinase and glycogen phosphorylase kinase which phosphorylate the corresponding enzymes GP phosphorylation leads to its activation GS phosphorylation leads to its inhibition Therefore glycogen is broken down to release glucose for energy and release to blood Insulin activates Protein Phosphatase 1 PP1 which reverses the PKA Effects and stimulates glycogen synthesis Homework Problems 43 45 47 48 49 52 53 Insulin and Glucagon Hormonal regulation of glucose metabolism Figures Essential of Biochemistry 3e by Pratt and Cornely Moran Principles of Biochemistry 4th 5th edition Tymoczko Berg Stryer Biochemistry A Short Course McKee McKee Biochemistry Insulin and Glucagon Glucose homeostasis is regulated mainly by these two hormones 17 Insulin Produced by cell of the pancreas Peptide hormone Stored as inactive hexamer Active form is a monomer Reduces blood glucose Glucagon Produced by pancreatic cells Peptide hormone Increases blood glucose level Insulin production correlates with glucose release to blood Blood glucose insulin levels upon food consumption Notice that particularly high peaks of glucose levels are followed by profound deeps The higher the peaks the more damaging this for your body 19 Glucose 5mM Insulin Glucose 4mM Glucagon Both hormones are always produced at the basal level Both hormones are always produced at the basal level 20 The body generates glucose and ketone bodies during starvation 2014 John Wiley Sons Inc All rights reserved Glucose transport Glucose transporters1 3 GLUT1 3 Low transport capacity high affinity Km 1mM Glucose transporter 2 GLUT2 is a carrier for passive glucose movement across the membrane Principal transporter for glucose transfer from blood to liver and for renal glucose reabsorption GLUT2 has high transport capacity but low affinity high Km ca 15 20 mM Glucose transporter4 GLUT4 Glut4 transporter is localized to the cytoplasmic vesicles Redistributed to the cytoplasmic membrane in response to insulin Glut1 fetal tissues Glut3neuronal tissues In liver kidney Pancreas in addition to GLUT4 Adipose and muscle tissues 22 Impact of Insulin on glucose uptake by muscle and adipose tissues Insulin triggers vesicle fusion to the plasma membrane Glucose transporter proteins GLUT4 are presented to the