A [6+4]-cycloaddition adduct is the biosynthetic intermediate in streptoseomycin biosynthesis

Kai Biao Wang, Wen Wang, Bo Zhang, Xin Wang, Yu Chen, Hong Jie Zhu, Yong Liang (), Ren Xiang Tan () and Hui Ming Ge ()
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Kai Biao Wang: Nanjing University
Wen Wang: Nanjing University
Bo Zhang: Nanjing University
Xin Wang: Nanjing University
Yu Chen: Nanjing University
Hong Jie Zhu: Nanjing University
Yong Liang: Nanjing University
Ren Xiang Tan: Nanjing University
Hui Ming Ge: Nanjing University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Streptoseomycin (STM, 1) is a bacterial macrolactone that has a unique 5/14/10/6/6-pentacyclic ring with an ether bridge. We have previously identified the biosynthetic gene cluster for 1 and characterized StmD as [6 + 4]- and [4 + 2]-bispericyclase that catalyze a reaction leading to both 6/10/6- and 10/6/6-tricyclic adducts (6 and 7). The remaining steps, especially how to install and stabilize the required 10/6/6-tricyclic core for downstream modifications, remain unknown. In this work, we have identified three oxidoreductases that fix the required 10/6/6-tryciclic core. A pair of flavin-dependent oxidoreductases, StmO1 and StmO2, catalyze the direct hydroxylation at [6 + 4]-adduct (6). Subsequently, a spontaneous [3,3]-Cope rearrangement and an enol-ketone tautomerization result in the formation of 10/6/6-tricyclic intermediate 12b, which can be further converted to a stable 10/6/6-tricyclic alcohol 11 through a ketoreduction by StmK. Crystal structure of the heterodimeric complex NtfO1-NtfO2, homologues of StmO1-StmO2 with equivalent function, reveals protein-protein interactions. Our results demonstrate that the [6 + 4]-adduct instead of [4 + 2]-adduct is the bona fide biosynthetic intermediate.

Date: 2021
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DOI: 10.1038/s41467-021-22395-7

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