An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP

J Biol Chem. 2016 Nov 11;291(46):23842-23853. doi: 10.1074/jbc.M116.757062. Epub 2016 Sep 22.

Abstract

Brain glycogen and its metabolism are increasingly recognized as major players in brain functions. Moreover, alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. In the brain, both muscle and brain glycogen phosphorylase isozymes regulate glycogen mobilization. However, given their distinct regulatory features, these two isozymes could confer distinct metabolic functions of glycogen in brain. Interestingly, recent proteomics studies have identified isozyme-specific reactive cysteine residues in brain glycogen phosphorylase (bGP). In this study, we show that the activity of human bGP is redox-regulated through the formation of a disulfide bond involving a highly reactive cysteine unique to the bGP isozyme. We found that this disulfide bond acts as a redox switch that precludes the allosteric activation of the enzyme by AMP without affecting its activation by phosphorylation. This unique regulatory feature of bGP sheds new light on the isoform-specific regulation of glycogen phosphorylase and glycogen metabolism.

Keywords: allosteric regulation; brain metabolism; carbohydrate metabolism; disulfide; glycogen; glycogen storage disease; redox regulation.

MeSH terms

  • Adenosine Monophosphate / chemistry
  • Adenosine Monophosphate / metabolism
  • Allosteric Regulation / physiology
  • Animals
  • Cysteine / chemistry
  • Cysteine / genetics
  • Cysteine / metabolism
  • Disulfides / chemistry*
  • Disulfides / metabolism
  • Glycogen / chemistry
  • Glycogen / metabolism
  • Glycogen Phosphorylase, Brain Form / chemistry*
  • Glycogen Phosphorylase, Brain Form / genetics
  • Glycogen Phosphorylase, Brain Form / metabolism
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Oxidation-Reduction
  • Phosphorylation / physiology
  • Rabbits
  • Rats

Substances

  • Disulfides
  • Isoenzymes
  • Adenosine Monophosphate
  • Glycogen
  • Glycogen Phosphorylase, Brain Form
  • Cysteine

Associated data

  • PDB/5IKP