BBA Clinical 5 (2016) 85–100 Contents lists available at ScienceDirect BBA Clinical journal homepage: www.elsevier.com/locate/bbaclin Glycogen metabolism in humans☆,☆☆ María M. Adeva-Andany ⁎, Manuel González-Lucán, Cristóbal Donapetry-García, Carlos Fernández-Fernández, Eva Ameneiros-Rodríguez Nephrology Division, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain article info abstract Article history: In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle Received 25 November 2015 that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contrac- Received in revised form 10 February 2016 tion. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, Accepted 16 February 2016 but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that Available online 27 February 2016 include glucose entrance into the cell through transporters, phosphorylation of glucose to glucose 6-phosphate, isomerization to glucose 1-phosphate, and formation of uridine 5ʹ-diphosphate-glucose, which is the direct glu- Keywords: Glucose cose donor for glycogen synthesis. Glycogenin catalyzes the formation of a short glucose polymer that is extended Glucokinase by the action of glycogen synthase. Glycogen branching enzyme introduces branch points in the glycogen particle Phosphoglucomutases at even intervals. Laforin and malin are proteins involved in glycogen assembly but their specificfunctionremains Glycogen synthase elusive in humans. Glycogen is accumulated in the liver primarily during the postprandial period and in the skel- Glycogen phosphorylase etal muscle predominantly after exercise. In the cytosol, glycogen breakdown or glycogenolysis is carried out by α -Glucosidase two enzymes, glycogen phosphorylase which releases glucose 1-phosphate from the linear chains of glycogen, Glycogen storage diseases and glycogen debranching enzyme which untangles the branch points. In the lysosomes, glycogen degradation is catalyzed by α-glucosidase. The glucose 6-phosphatase system catalyzes the dephosphorylation of glucose 6-phosphate to glucose, a necessary step for free glucose to leave the cell. Mutations in the genes encoding the enzymes involved in glycogen metabolism cause glycogen storage diseases. © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction.............................................................. 86 2. Glycogensynthesis........................................................... 86 2.1. Glucoseuptake:glucosetransporters................................................ 86 2.1.1. Glucoseuptakeintothebrain............................................... 87 2.1.2. Glucoseuptakeinskeletalmuscle............................................. 87 2.1.3. Glucoseuptakeinliverandpancreas............................................ 88 2.1.4. Glucose transporter-2 deficiency or Fanconi–Bickeldisease(GSDtypeXI)........................... 88 2.2. Glucosephosphorylation:hexokinases............................................... 88 2.3. Glucoseisomerization:phosphoglucomutases............................................ 88 2.3.1. Phosphoglucomutase-1(PGM1).............................................. 89 2.3.2. Phosphoglucomutase-3(PGM3).............................................. 90 2.4. Formation of uridine 5ʹ-diphosphate-glucose:UDP-glucosepyrophosphorylaseorglucose1-phosphateuridyltransferase.......... 90 2.5. Initiationofglycogensynthesis:glycogenin............................................. 91 2.6. Elongationofthelinearglycogenchain:glycogensynthase...................................... 91 2.6.1. Muscle glycogen synthase deficiency(muscleGSD0).................................... 91 2.6.2. Liver glycogen synthase deficiency(liverGSD0)....................................... 91 2.6.3. Glycogensynthasekinases................................................. 91 2.6.4. Glycogensynthasephosphatases:proteinphosphatase-1................................... 91 ☆ The authors declare that there are no conflicts of interest. ☆☆ There was no financial support for this work. ⁎ Corresponding author. E-mail address: [email protected] (M.M. Adeva-Andany). http://dx.doi.org/10.1016/j.bbacli.2016.02.001 2214-6474/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 86 M.M. Adeva-Andany et al. / BBA Clinical 5 (2016) 85–100 2.6.5. Effectofglucose6-phosphateonhepaticglycogensynthaseactivity..............................92 2.6.6. Balancedcontrolofglycogenphosphorylaseandglycogensynthaseactivities..........................92 2.7. Branchingoftheglycogenparticle:glycogenbranchingenzyme....................................92 2.7.1. Glycogen branching enzyme deficiencyorAndersendisease(GSDIV).............................92 2.8. Laforin,malin,andPRDM8.....................................................92 2.8.1. Laforadisease.......................................................92 3. Glycogendegradation..........................................................92 3.1. Glycogendegradationinthecytosol.................................................92 3.1.1. Glycogenphosphorylase..................................................93 3.1.2. Glycogendebranchingenzyme...............................................94 3.2. Glycogen degradation in the lysosomes: lysosomal acid α-glucosidase(GAA)..............................94 3.2.1. Lysosomal α-glucosidase (acid maltase) deficiencyorPompedisease(GSDII)..........................94 4. Glucosedephosphorylation:glucose6-phosphatasesystem.........................................95 4.1. Glucose6-phosphatetranslocaseorglucose6-phosphatetransporter..................................95 4.2. Glucose6-phosphataseisoenzymes.................................................95 4.2.1. Glucose 6-phosphatase system deficiencyorvonGierkedisease(GSDI)............................95 4.2.2. MutationsintheG6PC1gene(GSDIa)...........................................95 4.2.3. MutationsintheG6PTgene(GSDIb)............................................95 4.2.4. Glucose 6-phosphatase catalytic-3 deficiency........................................95 5. Glycogen storage diseases induced by congenital deficiencyofglycolyticenzymes...............................96 5.1. Phosphofructokinase deficiencyorTaruidisease(GSDVII).......................................96 5.2. Phosphoglycerate mutase deficiency(GSDX)............................................96 5.3. Aldolase A deficiency(GSDXII)...................................................96 5.3.1. β-Enolase (enolase-3) deficiency(GSDXIII).........................................96 5.4. Lactate dehydrogenase deficiency..................................................96 6. Glycogenmetabolisminliverandskeletalmuscleofhealthyhumans.....................................96 6.1. Glycogenmetabolismintheliver..................................................96 6.2. Glycogenmetabolismintheskeletalmuscle.............................................97 6.2.1. Exercisediminishesglycogenconcentrationincontractingskeletalmuscle...........................97 6.2.2. Exercisepromotesglycogenstorageinthepreviouslyactiveskeletalmuscle..........................97 6.2.3. Dietary modifications alone do not alter significantlyglycogenstoragecapacityinrestingmuscles................97 6.2.4. Roleofexerciseinglycogenstoragediseases.........................................97 Transparencydocument............................................................98 Acknowledgments..............................................................98 References..................................................................98 1. Introduction The source of the glucose residues that form the glycogen particle is either the ingested food (direct pathway of glycogen synthesis) or the Glycogen is a branched polymer of glucose that contains a minor gluconeogenesis route (indirect pathway), in which gluconeogenic pre- amount of phosphate and glucosamine. In the linear chains, the glucose cursors such as lactate and alanine produce glucose 6-phosphate that residues are connected by α-1,4-glycosidic linkages while α-1,6-glyco- may be used to synthesize glycogen. sidic bonds create the branch points. Branches within normal glycogen Glycogen degradation takes place both in the cytoplasm and inside are distributed at even intervals resulting in a structure with spherical the lysosomes. In the cytosol, glycogen breakdown is accomplished by shape. The source and function of phosphate and glucosamine in the coordinated action of two enzymes, glycogen phosphorylase, which human glycogen are unclear. The glycogen particle consists of up to releases glucose 1-phosphate by untangling the α-1,4-glycosidic link- 55.000 glucose residues. In skeletal muscle, glycogen particles have a ages, and glycogen debranching enzyme that unfastens the branch points size of 10–44 nm in diameter while in the liver measure approximately releasing free glucose (Fig. 2). Glucose 1-phosphate derived from glyco- 110–290 nm. Glycogen can be identified by electron microscopy inside gen in the cytosol may be isomerized into glucose 6-phosphate which the cells [1]. is dephosphorylated to free glucose by glucose 6-phosphatase (Fig. 3) The synthesis of glycogen requires the