Synergistic regulation of phosphorylase a by glucose and caffeine.

Kasvinsky, Peter J.; Shechosky, Shirley; Fletterick, Robert J.

doi:10.1016/s0021-9258(17)34291-6

Cited by 116 publications

(29 citation statements)

References 29 publications

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“…2 Weak inhibitors of glycogen phosphorylase are weakly hypoglycemic. 3 These observations suggest that inhibitors of glycogen phosphorylase may help shift the balance between glycogen synthesis and glycogen degradation in favor of glycogen synthesis in both muscle and liver, and such inhibitors may be useful therapeutic agents for treatment of diabetes. Thus, glucose analogue inhibitors of glycogen phosphorylase may be of clinical interest in the regulation of glycogen metabolism in diabetes.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Ligand−Receptor Binding Free Energy by 4D-QSAR Analysis: Application to a Set of Glucose Analogue Inhibitors of Glycogen Phosphorylase

Venkatarangan

Hopfinger

1999

J. Chem. Inf. Comput. Sci.

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A set of 47 glucose analogue inhibitors of glycogen phosphorylase was investigated using 4D-QSAR analysis. A single significant 4D-QSAR model, having no outliers, was found as a function of alignment and conformational sampling. This 4D-QSAR model consists of six grid cell occupancy descriptors which defines the thermodynamic averaged spatial pharmacophore for this set of analogues. The 4D-QSAR model was validated by aligning it upon the crystal structures of glycogen phosphorylase with some bound inhibitors of the training set. Validation of the 4D-QSAR model was realized by establishing the consistency of the types and locations of the grid cell occupancy descriptors relative to the binding interaction sites of the crystal complex. The loss in binding free energy, due to loss in inhibitor conformational entropy upon binding to the enzyme, was computed and found to be in the 0-2 kcal/mol range for these inhibitors. The "active" conformation of each analogue was also postulated from the 4D-QSAR model.

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Section: Introductionmentioning

confidence: 99%

Prediction of Ligand−Receptor Binding Free Energy by 4D-QSAR Analysis: Application to a Set of Glucose Analogue Inhibitors of Glycogen Phosphorylase

Venkatarangan

Hopfinger

1999

J. Chem. Inf. Comput. Sci.

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“…Synthetic G-6-P analogues and a dihydropyridinedicarboxylic acid also inhibit at the nucleotide activation site of rabbit muscle glycogen phosphorylase b (RMGP b ). Most reported phosphorylase inhibitors 10 are glucose or other sugar-based analogues, which have in numerous instances been shown to bind at the catalytic site of RMGP b . − Caffeine and other nucleosides inhibit at another allosteric site, termed the purine inhibitor site . No physiologic role or ligand for the purine inhibitor site is known, although xanthines may regulate phosphorylase activity here in certain physiologic states. , Inhibition by caffeine and glucose is synergistic, because of cooperative ordering of both binding sites .…”

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confidence: 99%

Indole-2-carboxamide Inhibitors of Human Liver Glycogen Phosphorylase

et al. 1998

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“…Inhibitory site ligands interact with a loop called the 280s loop that forms a gate to block substrate access to the active site. Communication with the AMP-binding site decreases AMP binding to hinder GP activation ( Kasvinsky et al, 1978b ; Buchbinder and Fletterick 1996 ; Ekstrom et al, 2002 ). The indole site was first discovered in human lGP during a screening of antidiabetic agents targeting GP ( Rath et al, 2000b ).…”

Section: Diverse Plp-dependent Proteins and Their Allosteric Mechanismsmentioning

confidence: 99%

Structural Basis for Allostery in PLP-dependent Enzymes

Tran

Brown

2022

Front. Mol. Biosci.

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Pyridoxal 5′-phosphate (PLP)-dependent enzymes are found ubiquitously in nature and are involved in a variety of biological pathways, from natural product synthesis to amino acid and glucose metabolism. The first structure of a PLP-dependent enzyme was reported over 40 years ago, and since that time, there is a steady wealth of structural and functional information revealed for a wide array of these enzymes. A functional mechanism that is gaining more appreciation due to its relevance in drug design is that of protein allostery, where binding of a protein or ligand at a distal site influences the structure, organization, and function at the active site. Here, we present a review of current structure-based mechanisms of allostery for select members of each PLP-dependent enzyme family. Knowledge of these mechanisms may have a larger potential for identifying key similarities and differences among enzyme families that can eventually be exploited for therapeutic development.

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Synergistic regulation of phosphorylase a by glucose and caffeine.

Cited by 116 publications

References 29 publications

Prediction of Ligand−Receptor Binding Free Energy by 4D-QSAR Analysis: Application to a Set of Glucose Analogue Inhibitors of Glycogen Phosphorylase

Prediction of Ligand−Receptor Binding Free Energy by 4D-QSAR Analysis: Application to a Set of Glucose Analogue Inhibitors of Glycogen Phosphorylase

Indole-2-carboxamide Inhibitors of Human Liver Glycogen Phosphorylase

Structural Basis for Allostery in PLP-dependent Enzymes

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