Scientists from Institute of Biophysics, CAS Decipher Key Enzyme in Glucose Metabolism
2025-07-23 16:17:39 GMT+0800
Recently, the team led by Zhao Yan from the Institute of Biophysics, Chinese Academy of Sciences has made a significant discovery: they revealed the structural basis of human glucose-6-phosphatase catalytic subunit 1 (hG6PC1) in recognizing and catalyzing different substrates, depicted the dynamic process of enzyme-substrate induced fit, and provided new insights into the potential mechanism of phosphatidylserine (PS) regulating hG6PC1 activity. The relevant paper was published in Cell Discovery on July 15.
In energy metabolism, glucose is the most fundamental energy source for most organisms, and its homeostasis is strictly regulated through multiple pathways such as glycogen synthesis, glycogen breakdown, glycolysis, and gluconeogenesis. hG6PC1 is a key enzyme in human glucose metabolism. Its functional abnormalities or mutations can lead to severe metabolic genetic diseases. In addition, the increased activity of hG6PC1 is closely related to glucose metabolism disorders in diabetes, making it an important target for the treatment of glucose metabolism disorders. Although previous studies have revealed part of the catalytic mechanism of hG6PC1, its systematic molecular mechanism is still unclear.
This study deeply reveals the molecular basis of hG6PC1 recognizing different substrates, undergoing conformational changes, and catalyzing reactions, and systematically clarifies the direct impact of GSD-1a pathogenic mutations on enzyme function. In addition, this study reports for the first time the regulatory effect of PS on hG6PC1 activity. These findings provide a basis for rational drug design targeting GSD-1a and construct a drug design framework based on the PS binding site, thus opening up broad prospects for the effective treatment of glucose metabolism disorders.
Researcher Zhao Yan from the Institute of Biophysics, Chinese Academy of Sciences is the corresponding author of the paper, and doctoral students Chen Qihao, Wang Yuhang, and Li Renjie from the Institute of Biophysics, Chinese Academy of Sciences are the co-first authors. In addition, doctoral student Bai Qinru from the Institute of Biophysics, Chinese Academy of Sciences also contributed to the research. The study was funded by the Science and Technology Innovation 2030 "Brain Science and Brain-Inspired Research" major project, the National Key R&D Program, the Chinese Academy of Sciences' Stable Support Program for Youth Teams in Basic Research, and the National Natural Science Foundation of China. The collection of cryo-electron microscopy data was supported by the technical support of the Biological Microstructure Research Platform of the Peking University Institute of Advanced Agricultural Sciences.