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Biosynthesis of Ambiguine Indole Alkaloids in Cyanobacterium Fischerella ambigua

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Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
Cite this: ACS Chem. Biol. 2014, 9, 2, 372–377
Publication Date (Web):November 1, 2013
https://doi.org/10.1021/cb400681n
Copyright © 2013 American Chemical Society

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    Abstract

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    Ambiguines belong to a family of hapalindole-type indole alkaloid natural products, with many of the members possessing up to eight consecutive carbon stereocenters in a fused pentacyclic 6-6-6-5-7 ring scaffold. Here, we report the identification of a 42 kbp ambiguine (amb) biosynthetic gene cluster that harbors 32 protein-coding genes in its native producer Fischerella ambigua UTEX1903. Association of the amb cluster with ambiguine biosynthesis was confirmed by both bioinformatic analysis and in vitro characterizations of enzymes responsible for 3-((Z)-2′-isocyanoethenyl) indole and geranyl pyrophosphate biosynthesis and a C-2 indole dimethylallyltransferase that regiospecifically tailors hapalindole G to ambiguine A. The presence of five nonheme iron-dependent oxygenase coding genes (including four Rieske-type oxygenases) within the amb cluster suggests late-stage C–H activations are likely responsible for the structural diversities of ambiguines by regio- and stereospecific chlorination, hydroxylation, epoxidation, and sp2–sp3 C–C bond formation.

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    Materials and Methods; Figures SI-1 to SI-12; Tables SI-1 & SI-2. This material is available free of charge via the Internet at http://pubs.acs.org. The nucleotide sequence of the amb cluster was deposited in GenBank under accession number KF664586.

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