6A5F

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

Summary for 6A5F

• Entry DOI: 10.2210/pdb6a5f/pdb
• Descriptor: NgnD (2 entities in total)
• Functional Keywords: nargenicin, biosynthesis, biosynthetic protein
• Biological source: Nocardia argentinensis ATCC 31306
• Total number of polymer chains: 2
• Total formula weight: 36187.98

Authors

Zhang, B.,Ge, H.M. (deposition date: 2018-06-23, release date: 2019-02-06, Last modification date: 2024-03-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.05 Å)