6A5G

The structure of [4+2] and [6+4] cyclase in the biosynthetic pathway of streptoseomycin

6A5G の概要

• エントリーDOI: 10.2210/pdb6a5g/pdb
• 分子名称: [4+2] and [4+6] cyclase StmD (2 entities in total)
• 機能のキーワード: [4+2] and [4+6] cyclase, streptoseomycin, biosynthesis, biosynthetic protein
• 由来する生物種: Streptomyces seoulensis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 72647.81

構造登録者

Zhang, B.,Ge, H.M. (登録日: 2018-06-23, 公開日: 2019-02-06, 最終更新日: 2023-11-22)

主引用文献

Zhang, B.,Wang, K.B.,Wang, W.,Wang, X.,Liu, F.,Zhu, J.,Shi, J.,Li, L.Y.,Han, H.,Xu, K.,Qiao, H.Y.,Zhang, X.,Jiao, R.H.,Houk, K.N.,Liang, Y.,Tan, R.X.,Ge, H.M.
Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products.
Nature, 568:122-126, 2019

PubMed 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 interest. [4+2] cycloadditions (Diels-Alder reactions) have been widely used in organic synthesis for the formation of six-membered rings and are now well-established in biosynthesis. [6+4] and other 'higher-order' cycloadditions were predicted in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system. However, although enzyme-catalysed [6+4] cycloadditions have been proposed, 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. 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.

PubMed: 30867595
DOI: 10.1038/s41586-019-1021-x

実験手法

X-RAY DIFFRACTION (2.3 Å)