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

Fanzhen Yu; Yingxin Wang; Yilong Teng; Shutong Yang; Yanming He; Zeng Zhang; Hongjie Yang; Chuan-Fan Ding; Ping Zhou

doi:10.1021/acsomega.1c04244

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

ACS Omega. 2021 Oct 27;6(44):29804-29813. doi: 10.1021/acsomega.1c04244. eCollection 2021 Nov 9.

Authors

Fanzhen Yu¹, Yingxin Wang¹, Yilong Teng¹, Shutong Yang², Yanming He³, Zeng Zhang³, Hongjie Yang³, Chuan-Fan Ding^{2

4}, Ping Zhou¹

Affiliations

¹ State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, China.
² Department of Chemistry, Fudan University, Shanghai 200433, China.
³ Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China.
⁴ Zhejiang Provincial Key Laboratory of Advanced Mass Spectrometry and Molecular Analysis, Institute of Mass Spectrometry, School of Material Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang 315211, China.

Abstract

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 Ganoderma lucidum, namely, Fudan-Yueyang G. Lucidum (FYGL), was demonstrated capable of inhibiting the activity of PTP1B. Here, to identify the effective active components of FYGL, three different components, the polysaccharide FYGL-1, proteoglycans FYGL-2, and FYGL-3, were isolated from FYGL, and then, the protein moiety of FYGL-3 was further separated, namely, FYGL-3-P. 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 FYGL-3 and FYGL-3-P significantly enhanced the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, detected by the glucose oxidase method. Also, the FYGL-3-P protein moiety in FYGL played an essential role in inhibiting the activity of PTP1B. A strong, enthalpy-driven, and multitargeted interaction by electrostatic forces between PTP1B and FYGL-3-P dramatically inhibited the catalytic activity of PTP1B. These results provided deep insights into the molecular mechanisms of FYGL inhibiting the activity of PTP1B and structurally helped researchers seek natural PTP1B inhibitors.