Shimalactone Biosynthesis Involves Spontaneous Double Bicyclo-Ring Formation with 8π-6π Electrocyclization.
Isao Fujii1, Makoto Hashimoto1,2, Kaori Konishi1
1Division of Natural Product Sciences, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate, 028-3694, Japan.
Angewandte Chemie (International Ed. in English)
|March 5, 2020
Summary
Marine fungus Emericella variecolor GF10 produces neuritogenic polyketides shimalactones A and B. Biosynthetic gene cluster analysis and heterologous expression revealed non-enzymatic ring formation from preshimalactone epoxide.
Area of Science:
- Natural Product Chemistry
- Marine Microbiology
- Synthetic Biology
Background:
- Shimalactones A and B are neuritogenic polyketides from marine fungus Emericella variecolor GF10.
- These compounds feature unique oxabicyclo[2.2.1]heptane and bicyclo[4.2.0]octadiene ring systems.
Purpose of the Study:
- To elucidate the biosynthetic pathway of shimalactones A and B.
- To identify the key enzymes and reactions involved in their formation.
- To understand the mechanism of the complex ring system formation.
Main Methods:
- Identification of a candidate biosynthetic gene cluster.
- Heterologous expression of genes in Aspergillus oryzae and Saccharomyces cerevisiae.
- In vitro enzymatic assays and DFT calculations.
Main Results:
- Heterologous expression of ShmA produced preshimalactone.
- Expression of ShmA and ShmB yielded shimalactones A and B.
- Preshimalactone epoxide was confirmed to form in vitro and convert non-enzymatically to shimalactones.
- DFT calculations supported spontaneous, non-enzymatic ring formation via electrocyclization.
Conclusions:
- The double bicyclo-ring formation in shimalactones proceeds non-enzymatically from preshimalactone epoxide.
- Protonation-initiated epoxide ring opening triggers spontaneous oxabicyclo-ring formation and electrocyclization.
- This study clarifies the biosynthesis and non-enzymatic chemical transformations of these complex marine natural products.
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