The structure of brain glycogen phosphorylase-from allosteric regulation mechanisms to clinical perspectives

FEBS J. 2017 Feb;284(4):546-554. doi: 10.1111/febs.13937. Epub 2016 Nov 12.

Abstract

Glycogen phosphorylase (GP) is the key enzyme that regulates glycogen mobilization in cells. GP is a complex allosteric enzyme that comprises a family of three isozymes: muscle GP (mGP), liver GP (lGP), and brain GP (bGP). Although the three isozymes display high similarity and catalyze the same reaction, they differ in their sensitivity to the allosteric activator adenosine monophosphate (AMP). Moreover, inactivating mutations in mGP and lGP have been known to be associated with glycogen storage diseases (McArdle and Hers disease, respectively). The determination, decades ago, of the structure of mGP and lGP have allowed to better understand the allosteric regulation of these two isoforms and the development of specific inhibitors. Despite its important role in brain glycogen metabolism, the structure of the brain GP had remained elusive. Here, we provide an overview of the human brain GP structure and its relationship with the two other members of this key family of the metabolic enzymes. We also summarize how this structure provides valuable information to understand the regulation of bGP and to design specific ligands of potential pharmacological interest.

Keywords: allosteric regulation; crystal structure; glycogen metabolism; phosphorylase.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / chemistry*
  • Adenosine Monophosphate / metabolism
  • Allosteric Regulation
  • Allosteric Site
  • Amino Acid Motifs
  • Binding Sites
  • Brain / enzymology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression
  • Glycogen / chemistry*
  • Glycogen / metabolism
  • Glycogen Phosphorylase / chemistry*
  • Glycogen Phosphorylase / genetics
  • Glycogen Phosphorylase / metabolism
  • Glycogen Storage Disease / drug therapy
  • Glycogen Storage Disease / enzymology
  • Glycogen Storage Disease / genetics
  • Glycogen Storage Disease / pathology
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Liver / enzymology
  • Models, Molecular
  • Muscles / enzymology
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Structural Homology, Protein
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Isoenzymes
  • Adenosine Monophosphate
  • Glycogen
  • Glycogen Phosphorylase