The biosynthesis of fungal bicyclo[2.2.2]diazaoctane indole alkaloids with a wide spectrum of biological activities have attracted increasing interest. Until recently, the details of these biosynthetic pathways have remained largely unknown due to lack of information on the fungal derived biosynthetic gene clusters. Herein, we report identification of three new fungal gene clusters responsible for biosynthesis of a select group of bicyclo[2.2.2]diazaoctane indole alkaloids including (+)-notoamide, paraherquamide and malbrancheamide by genome mining. In each gene cluster, we identified a non-ribosomal peptide synthetase, a variant number of prenyltransferases, and a series of oxidases responsible for the diverse tailoring modifications of the cyclodipeptide structural core. Based on the comparative analysis of four natural product metabolic systems including (+)/(−)-notoamide, paraherquamide and malbrancheamide, we were able to propose an enzyme for each step in the respective biosynthetic pathways through deep gene annotation and on-going biochemical studies. We proposed that two different types of intramolecular Diels-Alderases operate to generate the monooxopiperazine and dioxopiperazine ring systems for this class of alkaloid natural products.
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