Biosynthetic production of anticoagulant heparin polysaccharides through metabolic and sulfotransferases engineering strategies

Jian-Qun Deng, Yi Li, Yu-Jia Wang, Ya-Lin Cao, Si-Yu Xin, Xin-Yu Li, Rui-Min Xi, Feng-Shan Wang and Ju-Zheng Sheng ()
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Jian-Qun Deng: Shandong University
Yi Li: Shandong University
Yu-Jia Wang: Shandong University
Ya-Lin Cao: Shandong University
Si-Yu Xin: Shandong University
Xin-Yu Li: Shandong University
Rui-Min Xi: Shandong University
Feng-Shan Wang: Shandong University
Ju-Zheng Sheng: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Heparin is an important anticoagulant drug, and microbial heparin biosynthesis is a potential alternative to animal-derived heparin production. However, effectively using heparin synthesis enzymes faces challenges, especially with microbial recombinant expression of active heparan sulfate N-deacetylase/N-sulfotransferase. Here, we introduce the monosaccharide N-trifluoroacetylglucosamine into Escherichia coli K5 to facilitate sulfation modification. The Protein Repair One-Stop Service-Focused Rational Iterative Site-specific Mutagenesis (PROSS-FRISM) platform is used to enhance sulfotransferase efficiency, resulting in the engineered NST-M8 enzyme with significantly improved stability (11.32-fold) and activity (2.53-fold) compared to the wild-type N-sulfotransferase. This approach can be applied to engineering various sulfotransferases. The multienzyme cascade reaction enables the production of active heparin from bioengineered heparosan, demonstrating anti-FXa (246.09 IU/mg) and anti-FIIa (48.62 IU/mg) activities. This study offers insights into overcoming challenges in heparin synthesis and modification, paving the way for the future development of animal-free heparins using a cellular system-based semisynthetic strategy.

Date: 2024
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DOI: 10.1038/s41467-024-48193-5

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