Synthesis of bioengineered heparin by recombinant yeast Pichia pastoris

Heparin, the most widely used anticoagulant drug, is mainly acquired from livestock. Variable structures and contaminations of other glycosaminoglycans of animal-sourced heparin aggravate risks in medical treatments and hamper the structure–activity relationship study. While chemically synthesized h...

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Bibliographic Details
Published in:Green chemistry : an international journal and green chemistry resource : GC 2022-04, Vol.24 (8), p.3180-3192
Main Authors: Zhang, Yonglin, Wang, Yang, Zhou, Zhengxiong, Wang, Peilin, Xi, Xintong, Hu, Shan, Xu, RuiRui, Du, Guocheng, Li, Jianghua, Chen, Jian, Kang, Zhen
Format: Article
Language:English
Subjects:
Anticoagulants
Batch culture
Bioengineering
Biosynthesis
Chemical activity
Epimerase
Glycosaminoglycans
Green chemistry
Heparin
Livestock
Lysates
Medical treatment
N-Deacetylase
N-deacetylase/N-sulfotransferase
N-sulfotransferase
Pichia pastoris
Sulfotransferase
Yeast
Yeasts
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Summary:Heparin, the most widely used anticoagulant drug, is mainly acquired from livestock. Variable structures and contaminations of other glycosaminoglycans of animal-sourced heparin aggravate risks in medical treatments and hamper the structure–activity relationship study. While chemically synthesized heparin products with refined structures are largely unaffordable. We present bioengineered heparin synthesized using an yeast platform. After achieving efficient expression of C5 epimerase and all the essential sulfotransferases in particular the bifunctional enzyme N -deacetylase/ N -sulfotransferase, a green cell-free synthesis system for heparin was established by recruiting all the enzymes from cell lysates. The bioengineered heparin, transformed from heparosan with a ratio of 41%, exhibits comparable anticoagulant activity to commercial heparin extracted from animals. A Pichia pastoris cell factory for the de novo biosynthesis of heparin from methanol was further constructed, which enabled the production of 2.08 g L −1 bioengineered heparin in fed-batch cultures. The strategies developed have potential to be scaled up to produce non-animal sourced heparin.
ISSN:1463-9262
1463-9270
DOI:10.1039/D1GC04672A