Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 137, Issue 37, Pages 11904-11907Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.5b07816
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Funding
- NIH [1DP1GM106413, 1R01GM085128]
- Zhejiang University
- English-Speaking Union (Lindemann Trust Fellowship)
- NSF [CHE-1361104, OCI-1053575]
- Natural Science Foundation of China [31470178]
- Direct For Mathematical & Physical Scien [1361104] Funding Source: National Science Foundation
- Division Of Chemistry [1361104] Funding Source: National Science Foundation
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AurovertinS are fungal polyketides that exhibit potent inhibition of adenosine triphosphate synthase. Aurovertins contain a 2,6-dioxabicyclo[3.2.1]octane ring that is proposed to be derived from a polyene precursor through regioselective oxidations and epoxide openings. In this study, we identified only four enzymes required to produce aurovertin E. The core polyketide synthase produces a polyene alpha-pyrone. Following pyrone O-methylation by a methyltransferase, a flavin-dependent mono-oxygenase and an epoxide hydrolase can iteratively transform the terminal triene portion of the precursor into the dioxabicyclo[3.2.1]octane scaffold. We demonstrate that a tetrahydrofuranyl polyene is the first stable intermediate in the transformation, which can undergo epoxidation and anti-Baldwin 6-endo-tet ring opening to yield the cyclic ether product. Our results further demonstrate the highly concise and efficient ways in which fungal biosynthetic pathways can generate complex natural product scaffolds.
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