Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products

Bo Zhang, Kai Biao Wang, Wen Wang, Xin Wang, Fang Liu, Jiapeng Zhu, Jing Shi, Ling Yu Li, Hao Han, Kuang Xu, Hong Yun Qiao, Xiao Zhang, Rui Hua Jiao, Kendall N. Houk (), Yong Liang (), Ren Xiang Tan () and Hui Ming Ge ()
Additional contact information
Bo Zhang: Nanjing University
Kai Biao Wang: Nanjing University
Wen Wang: Nanjing University
Xin Wang: Nanjing University
Fang Liu: Nanjing University
Jiapeng Zhu: Nanjing University of Chinese Medicine
Jing Shi: Nanjing University
Ling Yu Li: Nanjing University
Hao Han: Nanjing University
Kuang Xu: Nanjing University
Hong Yun Qiao: Nanjing University
Xiao Zhang: Nanjing University
Rui Hua Jiao: Nanjing University
Kendall N. Houk: University of California, Los Angeles
Yong Liang: Nanjing University
Ren Xiang Tan: Nanjing University
Hui Ming Ge: Nanjing University

Nature, 2019, vol. 568, issue 7750, 122-126

Abstract: Abstract Pericyclic reactions are powerful transformations for the construction of carbon–carbon and carbon–heteroatom bonds in organic synthesis. Their role in biosynthesis is increasingly apparent, and mechanisms by which pericyclases can catalyse reactions are of major interest1. [4+2] cycloadditions (Diels–Alder reactions) have been widely used in organic synthesis2 for the formation of six-membered rings and are now well-established in biosynthesis3–6. [6+4] and other ‘higher-order’ cycloadditions were predicted7 in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system8,9. However, although enzyme-catalysed [6+4] cycloadditions have been proposed10–12, they have not been proven to occur. Here we demonstrate a group of enzymes that catalyse a pericyclic [6+4] cycloaddition, which is a crucial step in the biosynthesis of streptoseomycin-type natural products. This type of pericyclase catalyses [6+4] and [4+2] cycloadditions through a single ambimodal transition state, which is consistent with previous proposals11,12. The [6+4] product is transformed to a less stable [4+2] adduct via a facile Cope rearrangement, and the [4+2] adduct is converted into the natural product enzymatically. Crystal structures of three pericyclases, computational simulations of potential energies and molecular dynamics, and site-directed mutagenesis establish the mechanism of this transformation. This work shows how enzymes are able to catalyse concerted pericyclic reactions involving ambimodal transition states.

Date: 2019
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DOI: 10.1038/s41586-019-1021-x

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