Chemoenzymatic Synthesis of Heparin and Heparan Sulfate

Heparan sulfate (HS) are a family of structurally complex heteropolysaccharides that is found on the surfaces of animal cells and in the extracellular matrix and exhibits a wide range of biological functions controlling angiogenesis, inflammatory responses, tumor metastasis, and blood coagulation. Heparin is a special form of HS, which has a higher level of sulfation, a higher IdoA content, and displays strong anticoagulant activity. Unfortunately, naturally derived HS/heparin are highly heterogeneous, limiting studies of their structure−activity relationships and even resulting in safety concerns. For example, the heparin contamination crisis in 2007 reportedly killed more than a hundred people in the United States. The chemical synthesis of GAGs by organic carbohydrate chemists has been extremely difficult. Chemoenzymatic synthesis, that integrates the flexibility of chemical derivatization with enzyme-catalyzed reactions, mimic the biosynthetic pathway of GAGs, was developed and represents a promising strategy to solve these synthetic challenges^1-3. We will attempt to summarize the progress of the chemoenzymatic synthetic method and, in particular, its application to show physiological and pharmacological importance.

References

1. Zhang, X.; Lin, L.; Huang, H.; Linhardt, R. J., Chemoenzymatic Synthesis of Glycosaminoglycans. Accounts of Chemical Research 2020, 53 (2), 335-346.
2. Zhang, X.; Han, X.; Xia, K.; Xu, Y.; Yang, Y.; Oshima, K.; Haeger, S. M.; Perez, M. J.; McMurtry, S. A.; Hippensteel, J. A.; Ford, J. A.; Herson, P. S.; Liu, J.; Schmidt, E. P.; Linhardt, R. J., Circulating heparin oligosaccharides rapidly target the hippocampus in sepsis, potentially impacting cognitive functions. Proceedings of the National Academy of Sciences 2019, 116 (19), 9208.
3. Zhang, X.; Pagadala, V.; Jester, Hannah M.; Lim, A. M.; Pham, T. Q.; Goulas, A. M. P.; Liu, J.; Linhardt, R. J., Chemoenzymatic synthesis of heparan sulfate and heparin oligosaccharides and NMR analysis: paving the way to a diverse library for glycobiologists. Chemical Science 2017, 8 (12), 7932-7940.