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Synthesis, NMR Solution Structure, and Neuritogenic Activity of Chondroitin Sulfate D and E


Yang, Kuang-Wei (2018) Synthesis, NMR Solution Structure, and Neuritogenic Activity of Chondroitin Sulfate D and E. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/TPD7-FB87.


Chondroitin sulfate are ubiquitously expressed linear, sulfated polysaccharides that play critical roles in neuronal development and regeneration growth factor signaling, morphogenesis, and virus invasion. The diverse sulfation patterns presented by chondroitin sulfate has been suggested to regulate its activity, but the structural complexity and heterogeneity have hampered the understanding of structure-activity relationship. Therefore, we envisioned that chemically synthesized chondroitin sulfate oligosaccharide may provide a unique opportunity to specifically study the functions of sulfation patterns.

Here, we report the synthesis of a CS-D and CS-E tetrasaccharide in a step-efficient manner. By generating a disaccharide precursor from hydrolysis of polysaccharides, we were able to streamline the synthesis and reduce the number of steps by one-third comparing to the traditional synthesis without losing versatility of the synthetic route and functionality of the final product. With the structurally defined molecules, we were able to determine the NMR solution structure of CS-D and CS-E. In this work, we accomplished the first structural study of CS-D tetrasaccharide and the most thorough study of CS-E to date. Furthermore, we also discovered the existence of a second conformer in CS-D, which is the first time for such behavior to be observed experimentally in chondroitin sulfate. The electrostatic potential surface constructed based on the NMR structure presented unique structural features that may allow proteins to interact specifically.

The CS-D and CS-E tetrasaccharide, along with a CS-D disaccharide, was investigated for their neuritogenic activity. We discovered that the CS-D tetrasaccharide specifically stimulates dendritic growth whereas the CS-E tetrasaccharide preferentially promoted axonal growth, revealing the potential critical role chondroitin sulfate with specific sulfation patterns may play in the nervous system. The lack of activity of the CS-D disaccharide suggested that the minimum motif required for activity of CS-D is a tetrasaccharide.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:carbohydrate; chondroitin sulfate; chemical biology; synthesis; NMR structure, neurite outgrowth
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Hsieh-Wilson, Linda C.
Thesis Committee:
  • Dougherty, Dennis A. (chair)
  • Goddard, William A., III
  • Reisman, Sarah E.
  • Hsieh-Wilson, Linda C.
Defense Date:23 March 2018
Record Number:CaltechTHESIS:05292018-232454800
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10967
Deposited By: Kuang Wei Yang
Deposited On:30 May 2018 19:16
Last Modified:04 Oct 2019 00:21

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