title: Expansion of bisindole biosynthetic pathways by combinatorial construction.
abstract: Cladoniamides are indolotryptoline natural products that derive from indolocarbazole precursors. Here, we present a microbial platform to artificially redirect the cladoniamide pathway to generate unnatural bisindoles for drug discovery. Specifically, we target glycosyltransferase, halogenase, and oxidoreductase genes from the phylogenetically related indolocarbazole rebeccamycin and staurosporine pathways. We generate a series of novel compounds, reveal details about the substrate specificities of a number of enzymes, and set the stage for future efforts to develop new catalysts and compounds by engineering of bisindole genes. The strategy for structural diversification we use here could furthermore be applied to other natural product families with known biosynthetic genes.
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Du
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ryan
mesh_terms: D001688:Biological Products / Q000737:chemistry / Q000378:metabolism*; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism; D005818:Genetic Engineering; D026121:Indole Alkaloids / Q000737:chemistry / Q000378:metabolism*; D060847:Metabolic Engineering; D005810:Multigene Family; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism
chemical_list: D001688:Biological Products; D002227:Carbazoles; D026121:Indole Alkaloids; C053339:rebeccamycin
keywords: bisindole biosynthesis; combinatorial engineering; flavin-dependent monooxygenase; glycosyltransferase; halogenase; synthetic pathways