Insights into Brain Glycogen Metabolism

Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å) and in complex with its allosteric activator AMP (3.4 Å). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen.

[1]  S. Vidal,et al.  Glycogen phosphorylase inhibitors: a patent review (2013 - 2015) , 2016, Expert opinion on therapeutic patents.

[2]  J. Guinovart,et al.  Brain glycogen in health and disease. , 2015, Molecular aspects of medicine.

[3]  J. Delgado-García,et al.  Role of brain glycogen in the response to hypoxia and in susceptibility to epilepsy , 2015, Front. Cell. Neurosci..

[4]  H. Luhmann,et al.  Oligodendroglial Argonaute protein Ago2 associates with molecules of the Mbp mRNA localization machinery and is a downstream target of Fyn kinase , 2015, Front. Cell. Neurosci..

[5]  E. Seaquist,et al.  Revisiting Glycogen Content in the Human Brain , 2015, Neurochemical Research.

[6]  L. K. Bak,et al.  Isoform‐selective regulation of glycogen phosphorylase by energy deprivation and phosphorylation in astrocytes , 2015, Glia.

[7]  J. Delgado-García,et al.  Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. , 2014, Human molecular genetics.

[8]  D. Stapleton,et al.  Molecular Basis of Impaired Glycogen Metabolism during Ischemic Stroke and Hypoxia , 2014, PloS one.

[9]  Marco Biasini,et al.  SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information , 2014, Nucleic Acids Res..

[10]  J. Guinovart,et al.  Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  R. Goyal,et al.  Glycogen phosphorylase-a is a common target for anti-diabetic effect of iridoid and secoiridoid glycosides. , 2013, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[12]  A. Skaltsounis,et al.  Glycogen phosphorylase inhibitors: a patent review (2008 – 2012) , 2013, Expert opinion on therapeutic patents.

[13]  J. Delgado-García,et al.  Impairment in Long-Term Memory Formation and Learning-Dependent Synaptic Plasticity in Mice Lacking Glycogen Synthase in the Brain , 2013, Journal of Cerebral Blood Flow and Metabolism.

[14]  Albert J R Heck,et al.  High-sensitivity Orbitrap mass analysis of intact macromolecular assemblies , 2012, Nature Methods.

[15]  Pierre J Magistretti,et al.  Sweet Sixteen for ANLS , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[16]  D. Hutchinson,et al.  Rapid Turnover of Glycogen in Memory Formation , 2012, Neurochemical Research.

[17]  J. Calbó,et al.  Deleterious effects of neuronal accumulation of glycogen in flies and mice , 2012, EMBO molecular medicine.

[18]  A. Schousboe,et al.  Brain glycogen—new perspectives on its metabolic function and regulation at the subcellular level , 2012, Front. Neuroenerg..

[19]  Paul E. Gold,et al.  Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing , 2011, PloS one.

[20]  J. Cloix,et al.  Glycogen as a Putative Target for Diagnosis and Therapy in Brain Pathologies , 2011 .

[21]  N. Pannu,et al.  REFMAC5 for the refinement of macromolecular crystal structures , 2011, Acta crystallographica. Section D, Biological crystallography.

[22]  Randy J. Read,et al.  Overview of the CCP4 suite and current developments , 2011, Acta crystallographica. Section D, Biological crystallography.

[23]  Sarah A. Stern,et al.  Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation , 2011, Cell.

[24]  Hongbin Sun,et al.  Pharmacological manipulation of brain glycogenolysis as a therapeutic approach to cerebral ischemia. , 2010, Mini-Reviews in Medical Chemistry.

[25]  L. Agius Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors. , 2010, Mini reviews in medicinal chemistry.

[26]  P. Emsley,et al.  Features and development of Coot , 2010, Acta crystallographica. Section D, Biological crystallography.

[27]  J. Cloix,et al.  Epilepsy, Regulation of Brain Energy Metabolism and Neurotransmission , 2009, Current medicinal chemistry.

[28]  Eduardo Soriano,et al.  Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy , 2007, Nature Neuroscience.

[29]  Randy J. Read,et al.  Phaser crystallographic software , 2007, Journal of applied crystallography.

[30]  J. Treadway,et al.  Astrocyte Glycogen Sustains Neuronal Activity during Hypoglycemia: Studies with the Glycogen Phosphorylase Inhibitor CP-316,819 ([R-R*,S*]-5-Chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide) , 2007, Journal of Pharmacology and Experimental Therapeutics.

[31]  Leif Hertz,et al.  Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens , 2006, Glia.

[32]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[33]  Angus M. Brown Brain glycogen re‐awakened , 2004, Journal of neurochemistry.

[34]  G. Jung,et al.  Immunocytochemical localization of glycogen phosphorylase isozymes in rat nervous tissues by using isozyme‐specific antibodies , 2003, Journal of neurochemistry.

[35]  R. Gruetter,et al.  Effect of hypoglycemia on brain glycogen metabolism in vivo , 2003, Journal of neuroscience research.

[36]  V. L. Rath,et al.  Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core. , 2000, Molecular cell.

[37]  R. Fletterick,et al.  Chimeric Muscle and Brain Glycogen Phosphorylases Define Protein Domains Governing Isozyme-specific Responses to Allosteric Activation (*) , 1995, The Journal of Biological Chemistry.

[38]  L. Johnson,et al.  Structural mechanism for glycogen phosphorylase control by phosphorylation and AMP. , 1992, Journal of molecular biology.

[39]  L. Johnson,et al.  The molecular mechanism for the tetrameric association of glycogen phosphorylase promoted by protein phosphorylation , 1992, Protein science : a publication of the Protein Society.

[40]  S. Sprang,et al.  Structural basis for the activation of glycogen phosphorylase b by adenosine monophosphate. , 1991, Science.

[41]  L. Johnson,et al.  The allosteric transition of glycogen phosphorylase , 1989, Nature.

[42]  F. Sharp,et al.  Regional brain glycogen stores and metabolism during complete global ischaemia. , 1989, Neurological research.

[43]  R. Fletterick,et al.  Human brain glycogen phosphorylase. Cloning, sequence analysis, chromosomal mapping, tissue expression, and comparison with the human liver and muscle isozymes. , 1988, The Journal of biological chemistry.

[44]  R. Fletterick,et al.  The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14. , 1987, American journal of human genetics.

[45]  R. Fletterick,et al.  High-resolution chromosome sorting and DNA spot-blot analysis assign McArdle's syndrome to chromosome 11. , 1984, Science.

[46]  R. Fletterick,et al.  Structure of glycogen phosphorylase a at 3.0 A resolution and its ligand binding sites at 6 A. , 1976, The Journal of biological chemistry.

[47]  N. Madsen,et al.  Kinetics of purified liver phosphorylase. , 1966, The Journal of biological chemistry.

[48]  R. Fletterick,et al.  The family of glycogen phosphorylases: structure and function. , 1989, Critical reviews in biochemistry and molecular biology.