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J Am Chem Soc. 2018 Jan 17;140(2):582-585. doi: 10.1021/jacs.7b10909. Epub 2018 Jan 8.

Heterologous Biosynthesis of Nodulisporic Acid F.

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Ferrier Research Institute, Victoria University of Wellington , Wellington 6012, New Zealand.
Biomolecular Interaction Centre, University of Canterbury , 20 Kirkwood Avenue, Christchurch 8041, New Zealand.
Institute of Fundamental Sciences, Massey University , Private Bag 11 222, Palmerston North 4442, New Zealand.
Protein Science & Engineering, Callaghan Innovation, University of Canterbury , Private Bag 4800, Christchurch 8140, New Zealand.


Nodulisporic acids comprise a group of valuable indole diterpenes that exhibit potent insecticidal activities. We report the identification of a gene cluster in the genome of the filamentous fungus Hypoxylon pulicicidum (Nodulisporium sp.) that contains genes responsible for the biosynthesis of nodulisporic acids. Using Penicillium paxilli as a heterologous host, and through pathway reconstitution experiments, we identified the function of four genes involved in the biosynthesis of the nodulisporic acid core compound, nodulisporic acid F (NAF). Two of these genes (nodM and nodW) are especially significant as they encode enzymes with previously unreported functionality: nodM encodes a 3-geranylgeranylindole epoxidase capable of catalyzing only a single epoxidation step to prime formation of the distinctive ring structure of nodulisporic acids, and nodW encodes the first reported gene product capable of introducing a carboxylic acid moiety to an indole diterpene core structure that acts as a reactive handle for further modification. Here, we present the enzymatic basis for the biosynthetic branch point that gives rise to nodulisporic acids.

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