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

Abstract

A novel glycogen phosphorylase inhibitor FR258900 was isolated from the cultured broth of a fungal strain No. 138354. We examined the hypoglycemic effects of FR258900 in diabetic animal models. FR258900 treatment significantly reduced the plasma glucose concentrations during oral glucose tolerance tests in diabetic mice models, including db/db mice and STZinduced diabetic mice. Furthermore, FR258900 treatment resulted in rapid decrease in the plasma glucose levels in db/db mice. These improvements in glucose disposal were accompanied by increased liver glycogen contents, suggesting that the glucose lowering effects of FR258900 were attributed to suppressed hepatic glycogen breakdown and increased hepatic glycogen synthesis. Taken together, our results suggest that glycogen phosphorylase is a potentially useful target in new therapies against diabetes.Keywords fungal metabolite, glycogen phosphorylase inhibitor, hypoglycemic effect

Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

“…FR258900 is a 23-carbon pentanedioic acid that binds to the AMP site of glycogen phosphorylase and stabilizes its inactive conformation 87 . This compound significantly decreased plasma glucose levels and increased hepatic glycogen levels in db/db and streptozocin-induced diabetic mouse models 31 , but long-term effects or actions in other tissues were not studied. CP-316,819, is an indole carboxamide compound 32 that decreased hepatic glucose output in fasted dogs with basal or elevated glucagon levels 33 , although thorough analysis of potential effects on other tissues was not performed.…”

New Inhibitors of Glycogen Phosphorylase as Potential Antidiabetic Agents

“…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].…”

“…13835, FR258900 was shown to inhibit HLGPa [136]. The compound proved effective in lowering plasma glucose levels in animal models of diabetes [137]. The structure of the co-crystallised GPb-FR258900 complex [138], determined to 2.2 Å resolution, revealed that FR258900 binds at the allosteric site where the natural allosteric activator AMP, and the natural allosteric inhibitor Glc-6-P bind.…”

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

“…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 anti‐hyperglycemic agent.…”