Heterologous Biosynthesis of Nodulisporic Acid F

• Published in: Journal of the American Chemical Society 2018-01, Vol.140 (2), p.582-585
• Main Authors: Van de Bittner, Kyle C, Nicholson, Matthew J, Bustamante, Leyla Y, Kessans, Sarah A, Ram, Arvina, van Dolleweerd, Craig J, Scott, Barry, Parker, Emily J
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.7b10909

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.