Figure 1.

A Summary of the glycogen metabolism axis, including agents that pharmacologically modulate the axis. Glucose enters cells via glucose transporters (GLUTs), where it is phosphorylated to glucose-6-phosphate (G-6-P) by hexokinase (HK), followed by a transfer of the phosphate group from carbon 6 to 1 by phosphoglucomutase (PGM) to yieldglucose-1-phosphate (G-1-P). The resultant G-1-P is converted to UDP-glucose (UDP-G) by UDP-glucose pyrophosphorylase (UPP). This is then used by glycogenin (GYG; in dimerized form), a specialized primer of glycogen synthesis, to auto-glucosylate and extend its chain. After auto-glucosylation, glycogen synthase (GS) elongates these initial chains and creates further α-1,4-glycosidic linkages. Branchpoints of α-1,6-glycosidic linkages are mediated by the glycogen branching enzyme (GBE). GS is heavily regulated allosterically and by a network of kinases. Phosphorylation of GS decreases its activity and hence the rate of glycogen synthesis. GS has phosphorylation sites for Glycogen Synthase Kinase 3 (GSK3), protein kinase A (PKA), protein kinase C (PKC), calmodulin-dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK), casein kinase 1 (CK1), and casein kinase 2 (CK2). GS is also positively regulated: allosterically by glucose-6-phosphate, and via dephosphorylation by protein phosphatase 1, regulatory subunit 3 (PPP1R3C). Phosphorylation can also mediate activity with phosphorylase kinase (PhK) activating the enzyme and driving glycogenolysis. A proportion of glycogen is also degraded via the lysosomal autophagy route by the enzyme acid maltase (AM). Enzymes of the pathway implicated in tumorigenesis are highlighted by black squares, those implicated in tumor suppressive roles (PhK and AGL) are italicized. Red boxes indicate means of pharmacologically modulating the axis, highlighting glycogen-targeted drugs that have already been used for clear cell cancers. Glucose entry and processing can be inhibited by 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3BP), and lonidamine. AKT and GSK which inactivate GS by phosphorylation can be targeted with GSK3B inhibitors (e.g., AR-A014418 and SB-2216763), as well as PI3K (Perifosine), AKT (MK2202) and mTOR (Everolimus) inhibitors. AMPK can be activated to promote glycogen synthesis, as has been performed with metformin and resveratrol. PYG has been targeted using inhibitors such as CP91149, CP320626, and flavoperidol, to prevent glycogen mobilization. Furthermore, the downstream effects of AGL on hyaluronic acid synthesis can be disrupted using 4-methylumbelliferone (4MU).