Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster

Abstract

Significance Actinomycetes produce many clinically useful drugs, especially antibiotics and anticancer agents. Rare actinomycetes are known to produce bioactive molecules but they remain underexplored compared to more common Streptomyces spp . Natural molecules having piperazate building blocks are often bioactive, and genome analyses previously indicated the rare actinomycete Lentzea flaviverrucosa DSM 44664 may encode for the production of such molecules. To discover these from complex fermentation mixtures, we devised and employed a targeted metabolomic approach that revealed petrichorin A, an unusual heterodimeric biaryl-cyclohexapeptide. Its structure was determined by using multi-dimensional nuclear magnetic resonance, theoretical calculations, and strain mutagenesis, and its biosynthesis implicated an atypical cytochrome p450 heterodimerization event. Petrichorin A demonstrated potent cytotoxicity, highlighting heterodimeric-biaryls as interesting features for future drug design.

A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif

“…34-36). These long-distance NOE observations only arise from the correct configuration of 7, which could provide an experimental dataset in comparison with calculated diastereomers generated from computational modelling approaches that have been used in other structurally complex peptides [21][22][23] . However, due to the high content of modified residues in these systems it is difficult to obtain accurate force fields and so less accurate potentials must be used.…”

Chemical Stability of Petrichorins

“…Compared with 3 , the symmetric homodimer petrichorin B ( 2 ) was relatively stable. We believe that the left hemisphere ( 5 , not detected) of compound 1 , which is exactly the same as the right and left hemispheres of 2 , is stable.…”

“…In our recent efforts to discover unique biologically active compounds from underexploited rare actinomycetes, we identified three piperazyl cyclopeptides, namely, petrichorins A−C (1-3) (Figure 1), from Lentzea f laviverrucosa DSM 44664. 1 These compounds, especially petrichorin A (1), showed potent antiproliferative activity, with IC 50 values at the nanomolar level. Petrichorin A (1) is an unsymmetrical heterodimer, petrichorin B (2) is a symmetrical homodimer, and petrichorin C (3) is a hexamino acid monomer comprised of one-half of 1.…”

“…In our recent efforts to discover unique biologically active compounds from underexploited rare actinomycetes, we identified three piperazyl cyclopeptides, namely, petrichorins A–C ( 1 - 3 ) (Figure ), from Lentzea flaviverrucosa DSM 44664 . These compounds, especially petrichorin A ( 1 ), showed potent antiproliferative activity, with IC 50 values at the nanomolar level.…”

Insights into the Multisymmetric Tailoring of Julichrome Compounds by the Oxygenases JuiN and JuiO: Enzymatic Processing around the Biaryl C–C Axis

“…The means to generate biaryl analogues via enzymatic modifications of the biaryl core are thus urgently needed. In addition, substrate recognition mechanisms are of great interest since symmetric modifications following C−C axis formation need to be precisely coordinated with respect to A small amount of intermediate julichrome Q 3-8 (8) was deacetylated and oxidized into a minor product julichrome Q 3-5 (2). Julichrome Q 8-8 ( 5) is air-oxidated into quinoid to form intermediates Q 1-8 ( 6) and Q 1-1 (7).…”