Efficient Biosynthesis of Fungal Polyketides Containing the Dioxabicyclo-octane Ring System.
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 α-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.
College of Life Sciences, Zhejiang University , Hangzhou 310058, China.
Xu-Ming
XM
Mao
College of Pharmaceutical Science, Zhejiang University of Technology , Hangzhou 310014, China.
Zha-Jun
ZJ
Zhan
Matthew N
MN
Grayson
Man-Cheng
MC
Tang
Wei
W
Xu
College of Life Sciences, Zhejiang University , Hangzhou 310058, China.
Yong-Quan
YQ
Li
Wen-Bing
WB
Yin
Hsiao-Ching
HC
Lin
Yit-Heng
YH
Chooi
K N
KN
Houk
Yi
Y
Tang
D001313:Aurovertins / Q000737:chemistry / Q000378:metabolism; D005658:Fungi / Q000201:enzymology / Q000378:metabolism*; D009795:Octanes / Q000737:chemistry*; D061065:Polyketides / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism
D001313:Aurovertins; D009795:Octanes; D061065:Polyketides; C504252:aurovertin E