Aestuaramides, a Natural Library of Cyanobactin Cyclic Peptides Resulting from Isoprene-Derived Claisen Rearrangements
ABSTRACT We report 12 cyanobactin cyclic peptides, the aestuaramides, from the cultivated cyanobacterium Lyngbya aestuarii. We show that aestuaramides are synthesized enzymatically as reverse O-prenylated tyrosine ethers that subsequently undergo a Claisen rearrangement to produce forward C-prenylated tyrosine. These results reveal that a nonenzymatic Claisen rearrangement dictates isoprene regiochemistry in a natural system. They also reveal one of the mechanisms that organisms use to generate structurally diverse compound libraries starting from simple ribosomal peptide pathways (RiPPs).
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ABSTRACT: Heterocycle-containing cyclic peptides are promising scaffolds for the pharmaceutical industry but their chemical synthesis is very challenging. A new universal method has been devised to prepare these compounds by using a set of engineered marine-derived enzymes and substrates obtained from a family of ribosomally produced and post-translationally modified peptides called the cyanobactins. The substrate precursor peptide is engineered to have a non-native protease cleavage site that can be rapidly cleaved. The other enzymes used are heterocyclases that convert Cys or Cys/Ser/Thr into their corresponding azolines. A macrocycle is formed using a macrocyclase enzyme, followed by oxidation of the azolines to azoles with a specific oxidase. The work is exemplified by the production of 17 macrocycles containing 6–9 residues representing 11 out of the 20 canonical amino acids.Angewandte Chemie International Edition 01/2014; 53(51). DOI:10.1002/anie.201408082 · 11.34 Impact Factor
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ABSTRACT: Filamentous cyanobacteria of the genus Phormidium have been rarely studied for their chemical diversity. For the first time, the cultivable Phormidium autumnale was shown to produce a prenylated cyclic peptide named autumnalamide (1). The structure of this peptide was fully determined after a deep exploration of the spectroscopic data, including NMR and HRMS. Interestingly, a prenyl moiety was located on the guanidine end of the arginine amino acid. The absolute configurations of most amino acids were assessed using enantioselective GC/MS analysis, with (13)C NMR modeling being used for the determination of d-arginine and d-proline. The effects of 1 on sodium and calcium fluxes were studied in SH-SY5Y and hNav 1.6 HEK cells. When the Ca2+ influx was stimulated by thapsigargin, strong inhibition was observed in the presence of 1. As a consequence, this compound may act by disrupting the normal calcium uptake of this organelle, inducing the opening of the mitochondrial permeability transition pore, which results in the indirect blockade of store-operated channels.Journal of Natural Products 09/2014; 77(10). DOI:10.1021/np500374a · 3.95 Impact Factor
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ABSTRACT: Aromatic prenyltransferases are an actively-mined enzymatic class whose biosynthetic repertoire is growing. Indole prenyltransferases catalyze the formation of a diverse set of prenylated tryptophan and diketopiperazines leading to the formation of fungal toxins with prolific biological activities. At a fundamental level, the mechanism of C4-prenylation of L-Tryptophan recently has surfaced to engage a debate between a "direct" electrophilic alkylation mechanism (for wt DMATS and FgaPT2) versus an indole C3-C4 "Cope" rearrangement followed by rearomatization (for mutant FgaPT2). Herein we provide the first series of regioselectively tunable conditions for a Cope rearrangement between C3 to C4 position. Biomimetic conditions are reported that effect a [3,3] sigmatropic shift whose two-step process is interrogated for intramolecularity and rate-limiting general base-promoted mechanism. Solvent polarity serves a crucial role in changing the regioselectivity resulting in sole [1,3] shifts under decalin. An intermolecular variant is also reported that effectively prenylates the C3 position of L-Tryptophan resulting in products that mimic the structures accessed by bacterial indole prenyltransferases. We report an elaborate investigation that includes screening various substituents and measuring steric and electronic effects, stereoselectivity and with synthetically useful transformations.The Journal of Organic Chemistry 09/2014; 79(21). DOI:10.1021/jo501651z · 4.64 Impact Factor