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Hapalindole/Ambiguine Biogenesis Is Mediated by a Cope Rearrangement, C-C Bond-Forming Cascade.

ABSTRACT: Hapalindoles are bioactive indole alkaloids with fascinating polycyclic ring systems whose biosynthetic assembly mechanism has remained unknown since their initial discovery in the 1980s. In this study, we describe the fam gene cluster from the cyanobacterium Fischerella ambigua UTEX 1903 encoding hapalindole and ambiguine biosynthesis along with the characterization of two aromatic prenyltransferases, FamD1 and FamD2, and a previously undescribed cyclase, FamC1. These studies demonstrate that FamD2 and FamC1 act in concert to form the tetracyclic core ring system of the hapalindoles from cis-indole isonitrile and geranyl pyrophosphate through a presumed biosynthetic Cope rearrangement and subsequent 6-exo-trig cyclization/electrophilic aromatic substitution reaction.

SUBMITTER: Li S

PROVIDER: S-EPMC4681624 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Hapalindole/Ambiguine Biogenesis Is Mediated by a Cope Rearrangement, C-C Bond-Forming Cascade.

Li Shasha S Lowell Andrew N AN Yu Fengan F Raveh Avi A Newmister Sean A SA Bair Nathan N Schaub Jeffrey M JM Williams Robert M RM Sherman David H DH

Journal of the American Chemical Society 20151202 49

Hapalindoles are bioactive indole alkaloids with fascinating polycyclic ring systems whose biosynthetic assembly mechanism has remained unknown since their initial discovery in the 1980s. In this study, we describe the fam gene cluster from the cyanobacterium Fischerella ambigua UTEX 1903 encoding hapalindole and ambiguine biosynthesis along with the characterization of two aromatic prenyltransferases, FamD1 and FamD2, and a previously undescribed cyclase, FamC1. These studies demonstrate that F ...[more]

PMID: 26629885

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Project description:BackgroundThe hapalindole-type family of natural products is a group of hybrid isoprenoid-indole alkaloids, produced solely by members of the Subsection V cyanobacterial strains. This family broadly includes the hapalindoles, welwitindolinones, fisherindoles and ambiguines amongst others, all of which have an isonitrile- or isothiocyanate-containing indole alkaloid skeleton, with a cyclized isoprene unit. The hapalindoles are diversified into the welwitindolinones, fischerindoles and ambiguines through the employment of tailoring oxygenase, methyltransferase and prenyltransferase enzymes. We compare the genetic basis for the biosynthesis of this diverse group of natural products and identify key early biosynthetic intermediates.ResultsWhole genome sequencing of freshwater and terrestrial cyanobacteria Westiella intricata UH strain HT-29-1, Hapalosiphon welwitschii UH strain IC-52-3, Fischerella ambigua UTEX 1903 and Fischerella sp. ATCC 43239 led to the identification of a candidate hapalindole-type gene cluster in each strain. These were compared with the recently published ambiguine and welwitindolinone gene clusters and four unpublished clusters identified within publicly available genomes. We present detailed comparative bioinformatic analysis of the gene clusters and the biosynthesis of a pivotal indole-isonitrile intermediate resulting in both cis and trans geometrical isomers. Enzyme analyses and metabolite extractions from two hapalindole-producing Fischerella strains indicate the presence of cis and trans indole-isonitriles as biosynthetic intermediates in the early steps of the pathway.ConclusionsInterestingly, the organization of the welwitindolinone gene cluster is conserved in all producing strains but distinct from the hapalindole and ambiguine clusters. Enzymatic assays using WelI1 and WelI3 from Westiella intricata UH strain HT-29-1 demonstrated the ability to catalyze the formation of both cis and trans geometrical isomers when using a cell lysate. The enzymatic and metabolic characterization of both cis and trans indole-isonitrile intermediates implies conservation of their stereochemical integrity towards members of the ambiguine and welwitindolinone products. In summary, we present data that supports a unified biosynthetic pathway towards hapalindoles in nine individual species of cyanobacteria. Diversification of the pathway occurs later through the employment of specialized enzymatic steps towards fischerindoles, ambiguines and welwitindolinones.

Dataset Information

Hapalindole/Ambiguine Biogenesis Is Mediated by a Cope Rearrangement, C-C Bond-Forming Cascade.

Publications

Hapalindole/Ambiguine Biogenesis Is Mediated by a Cope Rearrangement, C-C Bond-Forming Cascade.

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