Structural and functional analysis of the human glycogen-degrading enzyme, a key player in the glycogen metabolism

• Applicant: Dr. Christian Roth
• Subject Area: Structural Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552217538

Glycogen metabolism is of fundamental importance for the energy balance of the human body. Five enzymes are essential for a balanced glycogen metabolism. The build-up takes place via glycogenin as the starting point; the glycogen particle is then built up by two further enzymes, glycogen synthase and the glycogen branching enzyme. Degradation, and thus the rapid provision of energy, is carried out by glycogen phosphorylase and glycogen debranching enzyme (GDE). Mutations in one of these key enzymes leads to a variety of diseases, which are collectively referred to as glycogen storage diseases. Changes in glycogen metabolism also play a role in the development of cancer. For example, GDE has been identified as a suppressor in bladder cancer. Despite the importance of these enzymes, the human representatives are scarcely characterized functionally and structurally in detail. A full understanding of the function of the individual enzymes in this complex, highly regulated dynamic system is essential to understand how mutations lead to the various phenotypic manifestations of glycogen storage diseases and how the GDE influences glycogen metabolism in health and disease. With the advancement of chemical synthesis and structural biology methods, we are now in an ideal position to answer these fundamental questions about glycogen metabolism. Using a combination of experimental methods, cryo-EM, crystallography, NMR, enzyme biochemistry, together with bioinformatic methods and automated chemical glycan synthesis, we will determine the structure and function of the human glycogen degradation enzyme and its role in glycogen metabolism and energy balance in humans. We will determine the function of the individual structural elements and define their role in the enzymatic function of GDE and thereby the glycogen turnover. We will determine how the enzyme interacts with the glycogen particle itself, other enzymes and proteins active in glycogen metabolism to achieve optimal and rapid degradation of glycogen for energy production. We will also elucidate regulatory principles and mechanisms govern that process. The results obtained will lead to a deeper understanding of the role of mutations on the activity of the enzyme and thus the various phenotypic expressions of glycogen storage disease 3 (GSD3) and define the role of GDE mutations in other diseases, for example cancer. This will then allow the development of targeted therapies that correct these abnormalities in the dynamic glycogen homeostasis.

• DFG Programme: Research Grants