Glycogen Phosphorylase as a Molecular Target for Type 2 Diabetes Therapy

Abstract

The regulation of the hepatic glucose output through glycogenolysis is an important target for type 2 diabetes therapy. Glycogenolysis is catalyzed in liver, muscle and brain by tissue specific isoforms of glycogen phosphorylase (GP). Because of its central role in glycogen metabolism, GP has been exploited as a model for structure-assisted design of potent inhibitors, which may be relevant to the control of blood glucose concentrations in type 2 diabetes. Several regulatory binding sites have been identified in GP, such as the catalytic, the allosteric, and the inhibitor binding sites. Protein crystallography has contributed significant structural information on the specificity and interactions that distinguish the binding sites, and also revealed a new unexpected binding site (new allosteric site). In this review, the kinetic, crystallographic binding, and physiological studies of a number of compounds, inhibitors of GP, are described, and the essential inhibitory and binding properties of specific compounds are analyzed in an effort to provide rationalizations for the affinities of these compounds and to exploit the molecular interactions that might give rise to a better inhibitor. These studies have given new insights into fundamental structural aspects of the enzyme enhancing our understanding of how the enzyme recognizes and specifically binds ligands, that could be of potential therapeutic value in the treatment of type 2 diabetes.

Crataegus pinnatifida: Chemical Constituents, Pharmacology, and Potential Applications

“…Later, (3R,5S,6S,7E,9S)-megastigman-7-ene-3,5,6,9-tetrol-9-O-β-D-glucopyranoside (69) What's more, 1β,9α-dihydroxyeudesm-3-en-5β,6α,7α,11αH-12,6-olide (83) was isolated and identified from the fruits of C. pinnatifida [37]. In addition, six others were subsequently isolated from the leaves of C. pinnatifida, [35], and gibberellic acid (87) [38] (Figure 7). …”

“…Glycogenolysis is catalyzed in liver, muscle and brain by tissue specific isoforms of glycogen phosphorylase (GP). Because of its central role in glycogen metabolism, GP had been exploited as a model for structure assisted design of potent inhibitors, which might be relevant to the control of blood glucose concentrations in type II diabetes [87,88]. Maslinic acid isolated from C. pinnatifida was found to inhibit GP in moderate strength; the IC50 was 28 µmol/L.…”

Carbohydrate Derivatives and Glycomimetic Compounds in Established and Investigational Therapies of Type 2 Diabetes Mellitus

“…Glycogen phosphorylases (existing as 'muscle', 'brain', or 'liver' isoforms) are allosterically regulated enzymes consisting of a dimeric arrangement of two identical subunits related to each other by a C2 symmetry. Protein crystallographic studies (Chrysina, 2010;Oikonomakos, 2002) revealed the existence of six binding sites in GP (Fig. 1): the catalytic, the inhibitor, the allosteric, the glycogen storage, and the new allosteric sites, as well as the newly discovered benzimidazole site (Chrysina et al, 2005).…”

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

“…A possible mechanism for the inactivation of phosphorylase is through changes in the concentrations of metabolites that bind to phosphorylase. Allosteric ligands of phosphorylase, such as glucose and glucose 6-phosphate, which favour the T (tense) conformation, cause dephosphorylation (inactivation) because the T state is a better substrate for dephosphorylation than the relaxed (R) conformation [30]. Conversely, AMP, which induces the R state, favours phosphorylation.…”