GYS1

Glycogen synthase 1 (GYS1) is the central enzyme in muscle glycogen biosynthesis, extending the GYG1-primed glycogen chain during glycogen synthesis^[1][2]. Mechanistically, GYS1 activity is inhibited by phosphorylation of its N- and C-termini and relieved by allosteric activation of glucose-6-phosphate, linking glycogen synthase regulation to glucose storage and energy metabolism^[1]. In disease models, inducible Gys1 knockout halted glycogen accumulation and partially prevented Lafora body formation and neuroinflammation in murine Lafora disease^[3]. Gys1 antisense therapy further prevented Lafora body formation in young mice and inhibited further accumulation in older mice, supporting GYS1 reduction as an experimental strategy for glycogen-driven neuropathology^[4]. Compared with related isoforms, GYS1 functions broadly in non-liver glycogen synthesis, whereas GYS2 is the liver isoform; this distinction guides isoform-selective compound design^[1][5]. For experimental applications, MZ-101 potently inhibited GYS1 in vitro and in vivo without inhibiting GYS2, depleted muscle glycogen, and supported substrate-reduction studies in Pompe disease and other glycogen storage disorders^[5]. Conversely, AJS1669 acted as a small-molecule muscle glycogen synthase activator and improved glucose metabolism in mice^[6].- GYS1 links glycogen biosynthesis, glucose-6-phosphate regulation, and disease-relevant glycogen accumulation models. - Isoform selectivity over GYS2 is central for designing liver-sparing GYS1 inhibitors. - GYS1 inhibitors and activators support mechanistic studies of glycogen storage and glucose metabolism.