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

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.

Brain Glucose Metabolism: Integration of Energetics with Function

“…Recent reviews on brain glycogen have focused on its roles in brain energetics (148,152,172), K ϩ homeostasis (169,271,401), functions in brain (170,285), structure (411,412), regulation of glycogen phosphorylase (413), and Lafora disease, a lethal inherited disorder caused by dysregulation of glycogen degradation (528). The following material briefly discusses these topics as they relate to aerobic glycolysis, lactate shuttling, and memory and learning.…”

The many metabolic sources of acetyl-CoA to support histone acetylation and influence cancer progression

“…Still, in NSCLC, the beneficial effects of promoting histone acetylation (instead of blocking it) is supported by encouraging results obtained with HDAC inhibitors such as vorinostat or suberoylanilide hydroxamic acid (SAHA) (10,11). Moreover, the option of blocking GP may expose cancer patients to various adverse effects since GP exists as different tissue isoforms exhibiting up to 80% homology (12). Blocking GP activity may for instance interfere with ATP generation required for muscle contraction but also with the capacity of the central nervous system to handle periods of severe hypoglycemia.…”

A thermodynamic function of glycogen in brain and muscle

“…Astrocytes contain both the brain isoform (PGYB) and the muscle isoform (PGYM), and low levels of the brain isoform also detectable in some neurons (Pfeiffer-Guglielmi et al, 2003). The isoforms differ in response to various regulatory influences (Mathieu et al, 2017). Glycogen phosphorylase is regulated by changes in energy state through allosteric effects of ATP and glucose-6-phosphate, which slow enzymatic activity, and AMP, which accelerates activity.…”