4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE RESEARCH
DOI: 10.1038/s41467-021-22395-7

Keywords

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Funding

  1. MOST [2018YFC1706205, 2018YFA0902000, 2019YFC0312500]
  2. NSFC [81925033, 21861142005, 21803030, 81773591, 81673333, 81803380, 81991522, 81991524, 2171101213]
  3. Fundamental Research Funds for the Central Universities [14380092, 14380113, 143801389]
  4. Jiangsu Innovation & Entrepreneurship Talents Plan

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The researchers identified three oxidoreductases that fix the required 10/6/6-tryciclic core and demonstrated that the [6+4]-cycloaddition adduct is the bona fide biosynthetic intermediate in the process of streptoseomycin biosynthesis.
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. Streptoseomycin is a potent antibiotic that contains a pentacyclic 5/14/10/6/6 ring system. Here, the authors report the enzymatic and non-enzymatic steps of the downstream modification of streptoseomycin biosynthesis and show a [6+4]-cycloaddition adduct as an unexpected biosynthetic intermediate.

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