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| Main Authors: | , , , , , , |
|---|---|
| Format: | Artículo científico |
| Language: | en |
| Published: |
JACS Au
2025
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| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41311954/ |
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Table of Contents:
- Enzymatic Synthesis and Anticoagulant Evaluation of Fucosylated Chondroitin Sulfate Polysaccharides with Defined Sulfation Patterns. Li, Rongfeng Liu, Yuanjie Li, Kaiqiang Li, Guantian Yu, Huahua Liu, Song Xing, Ronge Fucosylated chondroitin sulfate (FCS), a uniquely structured glycosaminoglycan with outstanding anticoagulant activity and a lower risk of bleeding, is a promising anticoagulant candidate. However, the complex and heterogeneous structure of the natural FCS polysaccharide presents significant challenges in developing novel anticoagulant drugs and elucidating the structure-activity relationship. Herein, we developed an enzymatic system for the synthesis of FCS polysaccharides with defined sulfation and fucosylation patterns using bifunctional L-fucokinase-GDP-L-fucose pyrophosphorylase (FKP) and α1-3-fucosyltransferases mutant (α1, 3-FucTM) and successfully synthesized FCS polysaccharides with α1-3-linked fucose (FCS), 4-O-sulfated fucose (FCS), 2, 4-O-disulfated fucose (FCS), and natural-like mixed sulfated fucose (FCS), respectively. FCS polysaccharide displayed excellent intrinsic anticoagulant activity, which is significantly stronger than clinical anticoagulant low molecular weight heparin and nature-like FCS. Additionally, we also elucidated the precise anticoagulant mechanism of FCS that its sulfation patterns play a crucial role in the anticoagulant activity. Specifically, FCS selectively binds to the positively charged arginine and lysine on the surface of the intrinsic factor IXa factor ( = 1.05 × 10) predominantly by the negative-charged sulfate group of fucose on its side chain. This one-pot enzymatic cascade approach enables the high-yield synthesis of FCS with defined structure and outstanding anticoagulant activity, thereby providing a promising route for the development of next-generation anticoagulant drugs.