New chemoenzymatic methods for synthesizing complex carbohydrates

Project: Research project

Project Details

Description

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Complex carbohydrates play important roles in biological systems. However, it is very difficult to obtain these
structures in pure homogeneous forms either by isolation from nature or by chemical synthesis. Therefore, the
detailed structure-activity relationship is usually not clear, even for well known compounds with important
functions. The ultimate goal of this project is to develop novel chemoenzymatic synthetic methods to efficiently
obtain synthetically challenging carbohydrates and analogs in amounts large enough for structural
characterization, functional studies, and therapeutic applications. For the current funding period, we are
focusing on the synthesis of heparin and heparan sulfate (HS) oligosaccharide analogs.
We hypothesize that N-sulfated analogs can mimic heparin/HS oligosaccharides for binding to their target
proteins and have similar bioactivities. In addition, the N-sulfated analogs with synthetically controllable N-
sulfation patterns can be powerful tools to probe the important roles of individual sulfations and provide critical
information about individual roles of related O-sulfation in functional heparin/HS oligosaccharides. To test this
hypothesis, we propose to synthesize a list of N3-modified GlcNAc or GlcA derivatives that can be used as
substrates for UDP-GlcNAc and UDP-GlcA biosynthetic enzymes and heparosan synthases for producing N3-
containing oligosaccharides. The azido group can then be reduced to an amino group and followed by
chemical N-sulfation to provide N-sulfated analogs of heparin/HS oligosaccharides for testing their activities.
Four specific aims are 1) chemical synthesis of N-acetylglucosamine (GlcNAc) and uronic acid derivatives as
monosaccharide precursors; 2) synthesis of UDP-GlcNAc, UDP-uronic acids, and their derivatives; 3)
enzymatic synthesis of heparin and heparan sulfate oligosaccharide analogs using heparosan synthases; 4)
structure-activity relationship (SAR) studies using heparin/heparan sulfate-binding proteins. In addition, we will
collaborate with our colleague and long-time collaborator, Prof. Andrew Fisher, an expert structural biologist
with special expertise on protein crystal structural studies to solve the crystal structures of heparosan
synthases, which are important enzymes for the assembly of heparin/HS polysaccharide structures. The
information learned and the products obtained will facilitate the discovery and development of new
therapeutics.
StatusFinished
Effective start/end date9/20/135/31/17

Funding

  • National Institutes of Health: $296,002.00
  • National Institutes of Health: $296,002.00
  • National Institutes of Health: $296,002.00
  • National Institutes of Health: $296,002.00

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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