The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba

Qi Ding, Nianxin Guo, Lei Gao (), Michelle McKee, Dongshan Wu, Jun Yang, Junping Fan, Jing-Ke Weng and Xiaoguang Lei ()
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Qi Ding: Tsinghua University
Nianxin Guo: Peking University
Lei Gao: Peking University
Michelle McKee: Whitehead Institute for Biomedical Research
Dongshan Wu: Peking University
Jun Yang: Peking University
Junping Fan: Peking University
Jing-Ke Weng: Whitehead Institute for Biomedical Research
Xiaoguang Lei: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families.

Date: 2024
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DOI: 10.1038/s41467-024-46845-0

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