Functional expression of a highly-reducing polyketide synthase of Emericella variecolor IFM42010, an asteltoxin-producing strain, resulted in production of two polyenoic β-ketolactones with opposite stereochemistry

Makoto Hashimoto; Hitomi Ichijo; Kotaro Fujiwara; Hitoshi Sugasawa; Seika Abo; Kimihito Matsudo; Nahoko Uchiyama; Yukihiro Goda; Isao Fujii

doi:10.1016/j.bmcl.2019.126686

Functional expression of a highly-reducing polyketide synthase of Emericella variecolor IFM42010, an asteltoxin-producing strain, resulted in production of two polyenoic β-ketolactones with opposite stereochemistry

Bioorg Med Chem Lett. 2019 Dec 15;29(24):126686. doi: 10.1016/j.bmcl.2019.126686. Epub 2019 Oct 14.

Authors

Makoto Hashimoto¹, Hitomi Ichijo², Kotaro Fujiwara², Hitoshi Sugasawa², Seika Abo², Kimihito Matsudo², Nahoko Uchiyama³, Yukihiro Goda³, Isao Fujii⁴

Affiliations

¹ School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate 028-3694, Japan; Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20, Shinmachi, Nishitokyo, Tokyo 202-8585, Japan. Electronic address: mhashimo@musashino-u.ac.jp.
² School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate 028-3694, Japan.
³ National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
⁴ School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate 028-3694, Japan. Electronic address: ifujii@iwate-med.ac.jp.

PMID: 31678008
DOI: 10.1016/j.bmcl.2019.126686

Abstract

The asteltoxin-producing fungus Emericella variecolor IFM42010 possesses 22 highly-reducing polyketide synthase (HR-PKS) genes. Of these, an HR-PKS with a methyltransferase domain but lacking an enoylreductase domain could be involved in the biosynthesis of asteltoxin and related compounds. From six such candidate HR-PKS genes, Ev460pks was analyzed by gene disruption in E. variecolor and heterologous expression in Aspergillus oryzae. The Ev460pks-disrupted strain retained asteltoxin production ability, indicating that Ev460pks is not involved in asteltoxin biosynthesis. The A. oryzae transformant harboring the Ev460pks gene produced compounds 1 and 2, along with several unidentified products possibly decomposed from 2. Spectroscopic analyses revealed that 1 was a 4-methyl-β-ketolactone with a methylheptatriene side-chain at the C-5 position, and 2 was also a 4-methyl-β-ketolactone, bearing a dimethyltetradecahexaene side-chain at the same position. The relative configuration at C-4 in compounds 1 and 2 was opposite.

Keywords: Biosynthesis; Fungi; Highly-reducing polyketide synthase; Polyenoic; Polyketide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Emericella / genetics*
Polyketide Synthases / metabolism*
Stereoisomerism

Substances

Polyketide Synthases