FR258900, a Novel Glycogen Phosphorylase Inhibitor Isolated from Fungus No. 138354

Furukawa, Shigetada; Tsurumi, Yasuhisa; Murakami, Kiyoshi; Nakanishi, Tomoko; Ohsumi, Keisuke; Hashimoto, Michizane; Nishikawa, Motoaki; Takase, Shigehiro; Numata, Osamu; Hino, Motohiro

doi:10.1038/ja.2005.66

Cited by 14 publications

(10 citation statements)

References 16 publications

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“…The glycogen phosphorylase inhibitor FR258900 was discovered in a screen for increased glycogen synthesis in rat primary hepatocytes 86 . FR258900 is a 23-carbon pentanedioic acid that binds to the AMP site of glycogen phosphorylase and stabilizes its inactive conformation 87 .…”

Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismmentioning

confidence: 99%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

281

244

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Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis resulting in hyperglycemia. Although current diabetes treatments have exhibited some success in lowering blood glucose, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycemia. Novel diabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver in order to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

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Section: Strategies To Modulate Liver Glucose and Glycogen Metabolismmentioning

confidence: 99%

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Rines

Sharabi

Tavares

et al. 2016

Nat Rev Drug Discov

281

244

View full text Add to dashboard Cite

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“…This position prevents the crucial conformational changes that take place on activation of the enzyme that are critical for catalytic activity and create the phosphate recognition site. Residues that contribute to the catalytic site come from 6 (134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150), 13 (371-376), and 18 (478-484) in domain 1 and from 19 (562-570), the loop (571-574) between 19 (562-570) and 18 (575-593), and the loop (666-675) between 22 (661-665) and 21 (676-684) in domain 2 [48][49][50]. On transition from T state to R state (activation of the enzyme), the 280s loop becomes disordered and displaced, opening a channel that allows a crucial residue, Arg569, to enter the catalytic site in place of Asp283 and create the recognition site for the substrate phosphate; that also allows access of the glycogen substrate to reach the catalytic site and promotes a favourable electrostatic environment for the 5'-phosphate of the essential cofactor pyridoxal-5'-phosphate (PLP); the substrate phosphate site is within hydrogen-bonding distance of the 5'-phosphate group of PLP [51][52][53][54] volves movement of the 380s loop (377-384) which results in closure of the catalytic site and creation of the recognition site for oligosaccharide [55].…”

Section: Catalytic Sitementioning

confidence: 99%

New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents

Somsák

Czifrák

Tóth

et al. 2008

CMC

140

132

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The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity. The present survey is focused on recent new molecules, potential inhibitors of the enzyme. The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes. Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver). The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design. In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed.

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“…The compound exhibited a potent inhibitory action on human liver GPa (hlGPa), and significantly reduced the plasma glucose concentrations in diabetic mice models. These effects were accompanied by increased liver glycogen contents (Furukawa et al 2005b), suggesting that it may activate glycogen synthesis via glycogen phosphorylase inhibition and therefore provide a new potential antihyperglycemic agent.…”

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confidence: 99%

FR258900, a potential anti‐hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase

et al. 2007

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FR258900 has been discovered as a novel inhibitor of human liver glycogen phosphorylase a and proved to suppress hepatic glycogen breakdown and reduce plasma glucose concentrations in diabetic mice models. To elucidate the mechanism of inhibition, we have determined the crystal structure of the cocrystallized rabbit muscle glycogen phosphorylase b-FR258900 complex and refined it to 2.2 Å resolution. The structure demonstrates that the inhibitor binds at the allosteric activator site, where the physiological activator AMP binds. The contacts from FR258900 to glycogen phosphorylase are dominated by nonpolar van der Waals interactions with Gln71, Gln72, Phe196, and Val459 (from the symmetry-related subunit), and also by ionic interactions from the carboxylate groups to the three arginine residues (Arg242, Arg309, and Arg310) that form the allosteric phosphate-recognition subsite. The binding of FR258900 to the protein promotes conformational changes that stabilize an inactive T-state quaternary conformation of the enzyme. The ligand-binding mode is different from those of the potent phenoxy-phthalate and acyl urea inhibitors, previously described, illustrating the broad specificity of the allosteric site.Keywords: FR258900; glycogen phosphorylase; inhibition; X-ray crystallography; type 2 diabetes Inhibition of glycogenolysis has been proposed as a therapeutic strategy for the treatment of type 2 diabetes. Glycogen phosphorylase (GP) catalyzes the first step in glycogen degradation, and it is expected that inhibition of GP will inhibit glycogenolysis, reduce hepatic glucose production, and lower blood glucose, thereby providing a potential new treatment for type 2 diabetes (McCormack et al. 2001;Treadway et al. 2001;Sarabu and Tilley 2005;Baker et al. 2006). GP is physiologically regulated through small molecule allosteric effectors as well as through phosphorylation at Ser14, resulting in a structural switch between active (R-state) and inactive (T-state) conformation (for a review, see Johnson et al. 1989;Johnson 1992;Oikonomakos et al. 1992). Several binding sites on the enzyme such as the catalytic, allosteric, inhibitor, and the new allosteric site have been identified as specific targets for inhibitor binding (for a review, see Oikonomakos 2002).The allosteric site, which binds the activator AMP (Barford et al. 1991;Sprang et al. 1991) Abbreviations: GP, glycogen phosphorylase; 1,4-a-D-glucan, orthophosphate a-glucosyltransferase (EC 2.4.1.1); rmGPb, rabbit muscle glycogen phosphorylase b; rmGPa, rabbit muscle glycogen phosphorylase a; hlGPa, human liver glycogen phosphorylase a; PLP, pyridoxal 59-phosphate; glucose, a-D-glucose; Glc-1-P, a-D-glucose 1-phosphate; Glc-6-P, D-glucose 6-phosphate; FR258900, (2R,3S) 2,3-bis((E)-3-(4-hydroxyphenyl) acryloyloxy) pentanedioic acid; W1807, (À)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarboxylate; compound 4j, 4-[2,4-Bis-(3-nitrobenzoylamino) phenoxy]phthalic acid; compound 21, 1-(2-chloro-4-fluorobenzoyl)-3-(5-hydroxy-...

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FR258900, a Novel Glycogen Phosphorylase Inhibitor Isolated from Fungus No. 138354

Cited by 14 publications

References 16 publications

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents

FR258900, a potential anti‐hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase

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