With this award, the Chemical Synthesis Program is funding Professor Xuefei Huang of the Department of Chemistry at Michigan State University to establish a chemoenzymatic method to synthesize heparan sulfate peptidoglycans (HSPG's) containing homogeneous heparan sulfate glycans. The project involves a collaboration on the enzymatic side with Professor Jian Liu at the University of North Carolina. HSPG's are implicated in biological processes as diverse as wound healing, cancer metastasis, cell adhesion, viral infection and cell proliferation. Yet biological studies have been hampered by limited access to homogeneous HSPGs, particularly with regard to the extent and position of sulfation. The glycopeptides will be assembled through chemical synthesis. The glycan chains will then be extended and the sulfations performed enzymatically to create specific heparan sulfate structures in a divergent manner. The interfacing of chemical and enzymatic synthesis creates a potentially powerful approach to access these complex glycoconjugates which will lay the foundation for the eventual synthesis of homogeneous heparan sulfate proteoglycans.
The Broader Impacts of this project involve the advancement of glycoconjugate chemistry by establishing new methods to access heparan sulfate (HS) peptidoglycans. The availability of HS peptidoglycans with both a well-defined degree and position of sulfation should have a scientific broader impact on the field of chemical biology, by providing opportunities to unravel structure-function relationships for distinct HS-peptidoglycans. The research activities will be incorporated into education, training and community outreach. This research project is expected to help build the talent pool of next generation glycoscientists, who are in high demand especially in the difficult and specialized field of complex oligosaccharide and glycoconjugate synthesis.
Heparan sulfate proteoglycans are a class of molecules known to play vital roles in various biological processes, such as blood coagulation, cell proliferation, differentiation, adhesion, and wound repair. To thoroughly understand the functions of HSPGs, it is necessary to have homogeneous forms of heparan sulfate proteoglycans and their derivatives. However, due to the complexity of their structures, no methods were available to synthesize these compounds. In this project, novel methodologies have been developed by combining chemical synthesis with enzymatic modifications to produce heparan sulfate glycopeptides bearing well defined carbohydrate structures. This work has demonstrated that this type of complex structures can be produced. The availability of these compounds opens up new opportunities to investigate their fascinating biological properties. The broader impacts of the results are in several areas. Through participation of the research, postdoctoral researchers, graduate, undergraduate and high school students have gained experience in total synthesis of complex glycoconjugates and in integrating synthesis with biological applications. This will be very valuable for their future scientific careers. Multiple students from under-represented and economically disadvantaged backgrounds have been recruited to research. This not only provided great opportunities for them to learn science, but also exposed them to new possibilities that normally exist beyond their regular circles of contacts. Besides providing trainings, this NSF support enabled the organization of conferences to enhance scientific exchange as well as community outreach programs, which are other essential aspects of the activities.