Molecular insights into the catalytic promiscuity of a bacterial diterpene synthase

Zhong Li, Lilan Zhang, Kangwei Xu, Yuanyuan Jiang, Jieke Du, Xingwang Zhang, Ling-Hong Meng, Qile Wu, Lei Du, Xiaoju Li, Yuechan Hu, Zhenzhen Xie, Xukai Jiang, Ya-Jie Tang, Ruibo Wu (), Rey-Ting Guo () and Shengying Li ()
Additional contact information
Zhong Li: Shandong University
Lilan Zhang: Hubei University
Kangwei Xu: Sun Yat-sen University
Yuanyuan Jiang: Shandong University
Jieke Du: Shandong University
Xingwang Zhang: Shandong University
Ling-Hong Meng: Institute of Oceanology, Chinese Academy of Sciences
Qile Wu: Shandong University
Lei Du: Shandong University
Xiaoju Li: Shandong University
Yuechan Hu: Hubei University
Zhenzhen Xie: Hubei University
Xukai Jiang: Shandong University
Ya-Jie Tang: Shandong University
Ruibo Wu: Sun Yat-sen University
Rey-Ting Guo: Hubei University
Shengying Li: Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Diterpene synthase VenA is responsible for assembling venezuelaene A with a unique 5-5-6-7 tetracyclic skeleton from geranylgeranyl pyrophosphate. VenA also demonstrates substrate promiscuity by accepting geranyl pyrophosphate and farnesyl pyrophosphate as alternative substrates. Herein, we report the crystal structures of VenA in both apo form and holo form in complex with a trinuclear magnesium cluster and pyrophosphate group. Functional and structural investigations on the atypical 115DSFVSD120 motif of VenA, versus the canonical Asp-rich motif of DDXX(X)D/E, reveal that the absent second Asp of canonical motif is functionally replaced by Ser116 and Gln83, together with bioinformatics analysis identifying a hidden subclass of type I microbial terpene synthases. Further structural analysis, multiscale computational simulations, and structure-directed mutagenesis provide significant mechanistic insights into the substrate selectivity and catalytic promiscuity of VenA. Finally, VenA is semi-rationally engineered into a sesterterpene synthase to recognize the larger substrate geranylfarnesyl pyrophosphate.

Date: 2023
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DOI: 10.1038/s41467-023-39706-9

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