Glycogen synthase 1 (GYS1) (GYS1)

Glycogen synthase 1 (GYS1) is the rate-limiting enzyme responsible for the synthesis of glycogen in skeletal muscle and other non-hepatic tissues (UniProt: P13807). It catalyzes the addition of glucose monomers from UDP-glucose to a glycogen primer, forming alpha-1,4-glycosidic bonds (NCBI Gene: 2997). In diseases like Pompe disease and Lafora disease, the accumulation of glycogen or abnormal polyglucosan bodies causes progressive muscle weakness and neurodegeneration (PubMed: 31515460). Therapeutic strategies targeting GYS1 mRNA or the enzyme itself utilize substrate reduction therapy to decrease the rate of glycogen production, thereby mitigating the toxic effects of its accumulation. Current clinical candidates include antisense oligonucleotides like BMN 331 and small molecule inhibitors like MZE001 (ClinicalTrials.gov: NCT05249621). However, excessive inhibition of GYS1 may lead to exercise intolerance or muscle fatigue, as seen in patients with primary GYS1 deficiency (PubMed: 20301514).

Other names

Muscle glycogen synthaseGYS1GSYGlycogen synthase 1 (muscle)GYS1 mRNAGYS1 gene expression

Substrate reduction therapy (SRT) via antisense-mediated knockdown of GYS1 mRNA or small molecule inhibition of the GYS1 enzyme (PubMed: 31515460).