Issue 8, 2022

Synthesis of bioengineered heparin by recombinant yeast Pichia pastoris

Abstract

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.

Graphical abstract: Synthesis of bioengineered heparin by recombinant yeast Pichia pastoris

Supplementary files

Article information

Article type
Paper
Submitted
15 Dec 2021
Accepted
14 Mar 2022
First published
06 Apr 2022

Green Chem., 2022,24, 3180-3192

Synthesis of bioengineered heparin by recombinant yeast Pichia pastoris

Y. Zhang, Y. Wang, Z. Zhou, P. Wang, X. Xi, S. Hu, R. Xu, G. Du, J. Li, J. Chen and Z. Kang, Green Chem., 2022, 24, 3180 DOI: 10.1039/D1GC04672A

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