Discovery of exolytic heparinases and their catalytic mechanism and potential application

Qingdong Zhang, Hai-Yan Cao, Lin Wei, Danrong Lu, Min Du, Min Yuan, Deling Shi, Xiangxue Chen, Peng Wang, Xiu-Lan Chen, Lianli Chi, Yu-Zhong Zhang () and Fuchuan Li ()
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Qingdong Zhang: Shandong University
Hai-Yan Cao: Shandong University
Lin Wei: Shandong University
Danrong Lu: Shandong University
Min Du: Shandong University
Min Yuan: Shandong University
Deling Shi: Shandong University
Xiangxue Chen: Tiandong Pharma
Peng Wang: Ocean University of China
Xiu-Lan Chen: Shandong University
Lianli Chi: Shandong University
Yu-Zhong Zhang: Ocean University of China
Fuchuan Li: Shandong University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Heparinases (Hepases) are critical tools for the studies of highly heterogeneous heparin (HP)/heparan sulfate (HS). However, exolytic heparinases urgently needed for the sequencing of HP/HS chains remain undiscovered. Herein, a type of exolytic heparinases (exoHepases) is identified from the genomes of different bacteria. These exoHepases share almost no homology with known Hepases and prefer to digest HP rather than HS chains by sequentially releasing unsaturated disaccharides from their reducing ends. The structural study of an exoHepase (BIexoHep) shows that an N-terminal conserved DUF4962 superfamily domain is essential to the enzyme activities of these exoHepases, which is involved in the formation of a unique L-shaped catalytic cavity controlling the sequential digestion of substrates through electrostatic interactions. Further, several HP octasaccharides have been preliminarily sequenced by using BIexoHep. Overall, this study fills the research gap of exoHepases and provides urgently needed tools for the structural and functional studies of HP/HS chains.

Date: 2021
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DOI: 10.1038/s41467-021-21441-8

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