Nature has provided a variety of stereoselective tools, which are encoded for within gene clusters of various organisms from all over the world, that catalyze specific chemical reactions to generate complex natural products. One particular class of natural products, the bicyclo[2.2.2]diazaoctane fungal alkaloids, has recently garnered much interest due to their unique synthetic chemistry and clinical applications. Affordable and efficient high throughput sequencing techniques, combined with bioinformatic analyses of genomes for identification of biosynthetic gene clusters, have facilitated a sequence-based discovery approach to the biosyntheses of structurally similar fungal alkaloids. Despite advancements in technology, a strong biochemical understanding of the chemical transformations that produce a variety of similar products and the development of a methodical chemical biology approach are necessary to broaden the pool of chemical diversity. Here, we summarize the progress in genome mining and identification of four fungal alkaloid gene clusters (+)/(-)-notoamide, paraherquamide, and malbrancheamide. By comparative analysis, we are able to construct a putative biosynthetic pathway for each product based on biochemical and bioinformatic data. These data have allowed us to progress toward a better understanding of the biosynthetic pathways that construct these molecules and include the pursuit of an elusive Diels-Alderase candidate that is expected to form the bicyclo[2.2.2]diazaoctane core.

Biosynthesis of bicyclo[2.2.2]diazaoctane fungal alkaloids: Malbrancheamide, paraherquamide, and (+)/(-)-notoamide

244th National Meeting (2012)

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