期刊
NATURE
卷 568, 期 7750, 页码 122-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1021-x
关键词
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资金
- Ministry of Science and Technology [2018YFC1706200]
- National Natural Science Foundation of China [21572100, 21803030, 81522042, 81773591, 81530089, 81673333, 21861142005, 21761142001, 21661140001]
- National Thousand Young Talents Program
- Jiangsu Specially-Appointed Professor Plan
- Natural Science Foundation of Jiangsu Province in China [BK20170631]
- US National Institutes of General Medical Sciences, National Institutes of Health [GM 124480]
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 interest(1). [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 biosynthesis(3-6). [6+4] and other 'higher-order' cycloadditions were predicted(7) in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system(8,9). However, although enzyme-catalysed [6+4] cycloadditions have been proposed(10-12), 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 proposals(11,12). 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.
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