Interaction and Inhibition of a Proteoglycan on PTP1B Activity for Anti-diabetes.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and an effective target for the treatment of type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from , namely, Fudan-Yueyang (), was demonstrated capable of inhibiting the activity of PTP1B. Here, to identify the effective active components of , three different components, the polysaccharide , proteoglycans , and , were isolated from , and then, the protein moiety of was further separated, namely, . Their abilities to enhance the glucose uptake in cells and inhibit the activity of PTP1B were compared. The inhibitory mechanisms were systematically explored by spectroscopic methods and MD simulations. The results showed that and significantly enhanced the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, detected by the glucose oxidase method. Also, the protein moiety in played an essential role in inhibiting the activity of PTP1B. A strong, enthalpy-driven, and multitargeted interaction by electrostatic forces between PTP1B and dramatically inhibited the catalytic activity of PTP1B. These results provided deep insights into the molecular mechanisms of inhibiting the activity of PTP1B and structurally helped researchers seek natural PTP1B inhibitors.