Chemoenzymatic Synthesis of Heparan Sulfate and Heparin

Heparan sulfate (HS) is a polysaccharide that performs essential physiological functions in the animal kingdom. Heparin, a highly sulfated form of heparan sulfate, is a widely prescribed anticoagulant drug worldwide. The heparan sulfate and heparin isolated from natural sources are highly heterogeneous mixtures differing in polysaccharide chain lengths and sulfation patterns. Heparin and HS exhibit distinct functions in organisms. Because of their structural diversity, heparin and HS play pivotal roles in human physiological and pathophysiological processes. The challenge in studying heparin and heparan sulfate-related biological functions is to determine the relationship between the structure and functions. The access to structurally defined heparan sulfate and heparin is critically important to advance the studies. The synthesis of heparan sulfate and heparin, using a purely chemical approach, has proved to be extremely difficult, especially for targets larger than octasaccharides having a high degree of sulfations. An emerging chemoenzymatic method has offered an effective alternative approach. This method utilizes recombinant heparan sulfate biosynthetic enzymes combined with an unnatural sugar nucleotide donor. Recent examples demonstrate the successful synthesis of libraries with complex structures, ultra-low molecular weight heparin and low-molecular weight heparin with unprecedented efficiency. The new method opens an opportunity to develop HS based therapeutics.