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Oxidative steps during the biosynthesis of squalestatin S1

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Abstract

The squalestatins are a class of highly complex fungal metabolites which are potent inhibitors of squalene synthase with potential use in the control of cholesterol biosynthesis. Little is known of the chemical steps involved in the construction of the 4,8-dioxa-bicyclo[3.2.1]octane core. Here, using a combination of directed gene knockout and heterologous expression experiments, we show that two putative non-heme-iron-dependent enzymes appear to catalyse a remarkable series of six consecutive oxidations which set up the bioactive core of the squalestatins. This is followed by the action of an unusual copper-dependent oxygenase which introduces a hydroxyl required for later acetylation.

Graphical abstract: Oxidative steps during the biosynthesis of squalestatin S1

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Publication details

The article was received on 13 Jun 2018, accepted on 14 Nov 2018 and first published on 15 Nov 2018


Article type: Edge Article
DOI: 10.1039/C8SC02615G
Citation: Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
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    Oxidative steps during the biosynthesis of squalestatin S1

    K. E. Lebe and R. J. Cox, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C8SC02615G

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