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The structure of brain glycogen phosphorylase—from allosteric regulation mechanisms to clinical perspectives
Author(s) -
Mathieu Cécile,
Dupret JeanMarie,
Rodrigues Lima Fernando
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13937
Subject(s) - allosteric regulation , glycogen phosphorylase , glycogen , isozyme , enzyme , activator (genetics) , biochemistry , biology , adenosine monophosphate , allosteric enzyme , phosphorylase kinase , glycogen synthase , chemistry , receptor
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.