Structure-based engineering of substrate specificity for pinoresinol-lariciresinol reductases

Ying Xiao, Kai Shao, Jingwen Zhou, Lian Wang, Xueqi Ma, Di Wu, Yingbo Yang, Junfeng Chen, Jingxian Feng, Shi Qiu, Zongyou Lv, Lei Zhang (), Peng Zhang () and Wansheng Chen ()
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Ying Xiao: Shanghai University of Traditional Chinese Medicine
Kai Shao: Chinese Academy of Sciences
Jingwen Zhou: Jiangnan University
Lian Wang: Jiangnan University
Xueqi Ma: Shanghai University of Traditional Chinese Medicine
Di Wu: Jiangnan University
Yingbo Yang: Shanghai University of Traditional Chinese Medicine
Junfeng Chen: Shanghai University of Traditional Chinese Medicine
Jingxian Feng: Shanghai University of Traditional Chinese Medicine
Shi Qiu: Shanghai University of Traditional Chinese Medicine
Zongyou Lv: Shanghai University of Traditional Chinese Medicine
Lei Zhang: Naval Medical University (Second Military Medical University)
Peng Zhang: Chinese Academy of Sciences
Wansheng Chen: Shanghai University of Traditional Chinese Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Pinoresinol–lariciresinol reductases (PLRs) are enzymes involved in the lignan biosynthesis after the initial dimerization of two monolignols, and this represents the entry point for the synthesis of 8-8′ lignans and contributes greatly to their structural diversity. Of particular interest has been the determination of how differing substrate specificities are achieved with these enzymes. Here, we present crystal structures of IiPLR1 from Isatis indigotica and pinoresinol reductases (PrRs) AtPrR1 and AtPrR2 from Arabidopsis thaliana, in the apo, substrate-bound and product-bound states. Each structure contains a head-to-tail homodimer, and the catalytic pocket comprises structural elements from both monomers. β4 loop covers the top of the pocket, and residue 98 from the loop governs catalytic specificity. The substrate specificities of IiPLR1 and AtPrR2 can be switched via structure-guided mutagenesis. Our study provides insight into the molecular mechanism underlying the substrate specificity of PLRs/PrRs and suggests an efficient strategy for the large-scale commercial production of the pharmaceutically valuable compound lariciresinol.

Date: 2021
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DOI: 10.1038/s41467-021-23095-y

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