Glycosaminoglycan biosynthesis: deciphering the divergent step

Glycosaminoglycans (GAGs) are negatively charged polysaccharides that form a key part of the extracellular matrix in animal tissues, from marine corals to humans. They play crucial roles in cell signaling, mediating processes such as embryonic development, cell growth and proliferation, cell adhesion, anticoagulation, and wound repair. Given their diverse functions, GAG dysregulation is linked to various medical conditions, including neurological, cardiovascular, infectious, and inflammatory diseases, as well as diabetic complications and cancer. While much is known about their roles in health and disease, gaps remain in understanding of how they are synthetized in human tissues. This project aims to investigate glycosyltransferases that participate in the synthesis of heparan sulfate and chondroitin/dermatan sulfate at a molecular level. By integrating biochemistry, structural biology (including cryo-electron microscopy and X-ray crystallography), and cell biology, our goal is to uncover the molecular mechanisms that distinguish these polysaccharides. Thus, this project aims to address fundamental questions in GAG biosynthesis and to provide a molecular basis for the development of GAG-based therapies in future studies.