Extending the Salinilactone Family

Schlawis, Christian; Harig, Tim; Ehlers, Stephanie; Guillén-Matus, Dulce; Creamer, Kaitlin E.; Jensen, Paul R.; Schulz, Stefan

doi:10.1002/cbic.201900764

Cited by 11 publications

(14 citation statements)

References 30 publications

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“…As noted, the flavin-dependent oxidoreductase spt8 (Fig. S1) was unique to the Salinispora spt BGC, yet has no proposed function in salinipostin [68] or salinilactone [66, 67] biosynthesis. Similarly, some Streptomyces spt -like BGCs did not contain spt2 (AMP-ligase) and spt4 (acyl carrier protein) homologues, which are proposed to help load and carry the R 2 aliphatic sidechain during salinipostin biosynthesis, respectively [68].…”

Section: Resultsmentioning

confidence: 99%

“…The spt BGC has been linked to the production of both the salinipostins A-K [63,64,68], Sal-GBL1 and Sal-GBL2 [68], and the salinilactones A-H [66,67], which share structural similarities to the A-factor family of γ-butyrolactone signalling molecules. Additionally, Salinispora arenicola and Salinispora pacifica produce two additional AHLs that have yet to be linked to their biosynthetic origins [102].…”

Section: Discussionmentioning

confidence: 99%

“…γ-Butyrolactones represent an important class of signalling molecules produced by Actinobacteria (). The salinipostins, salinilactones, Sal-GBL1 and Sal-GBL2 were recently reported from the marine actinomycete genus Salinispora [64, 66–68], and bear structural similarities to previously characterized actinomycete γ-butyrolactones. Linkage between the biosynthesis of these compounds and the γ-butyrolactone synthase Spt9 encoded by the salinipostin spt BGC led us to more broadly explore the potential for signalling molecule production by assessing the distribution of this protein among sequenced bacterial genomes.…”

Section: Discussionmentioning

confidence: 99%

“…Two γ-butyrolactones, Sal-GBL1 and Sal-GBL2, were also recently characterized from multiple Salinispora strains [68]. The Sal-GBLs, salinilactones A-H and salinipostins A-K all share a bicyclic lactone motif and are proposed to originate from the same spt BGC [63,[66][67][68] (Fig. S1).…”

Section: Impact Statementmentioning

confidence: 99%

“…Salinipostin biosynthesis was linked to the spt gene cluster via a knockout of the afsA homologue spt9 in Salinispora tropica CNB-440, which resulted in the elimination of salinipostin production [63]. Subsequently, eight volatile bicyclic lactones, salinilactones A – H, were isolated and characterized from Salinispora arenicola CNS-205 [66, 67]. Two γ-butyrolactones, Sal-GBL1 and Sal-GBL2, were also recently characterized from multiple Salinispora strains [68].…”

Section: Introductionmentioning

confidence: 99%

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Phylogenetic analysis of the salinipostin γ-butyrolactone gene cluster uncovers new potential for bacterial signalling-molecule diversity

et al. 2021

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Bacteria communicate by small-molecule chemicals that facilitate intra- and inter-species interactions. These extracellular signalling molecules mediate diverse processes including virulence, bioluminescence, biofilm formation, motility and specialized metabolism. The signalling molecules produced by members of the phylum Actinobacteria generally comprise γ-butyrolactones, γ-butenolides and furans. The best-known actinomycete γ-butyrolactone is A-factor, which triggers specialized metabolism and morphological differentiation in the genus Streptomyces . Salinipostins A–K are unique γ-butyrolactone molecules with rare phosphotriester moieties that were recently characterized from the marine actinomycete genus Salinispora . The production of these compounds has been linked to the nine-gene biosynthetic gene cluster (BGC) spt. Critical to salinipostin assembly is the γ-butyrolactone synthase encoded by spt9. Here, we report the surprising distribution of spt9 homologues across 12 bacterial phyla, the majority of which are not known to produce γ-butyrolactones. Further analyses uncovered a large group of spt-like gene clusters outside of the genus Salinispora , suggesting the production of new salinipostin-like diversity. These gene clusters show evidence of horizontal transfer and location-specific recombination among Salinispora strains. The results suggest that γ-butyrolactone production may be more widespread than previously recognized. The identification of new γ-butyrolactone BGCs is the first step towards understanding the regulatory roles of the encoded small molecules in Actinobacteria.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Impact Statementmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phylogenetic analysis of the salinipostin γ-butyrolactone gene cluster uncovers new potential for bacterial signalling-molecule diversity

et al. 2021

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Activity‐Based Protein Profiling Identifies Protein Disulfide‐Isomerases as Target Proteins of the Volatile Salinilactones

Jerye,

Lüken,

Steffen

et al. 2024

Advanced Science

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The salinilactones, volatile marine natural products secreted from Salinispora arenicola, feature a unique [3.1.0]‐lactone ring system and cytotoxic activities through a hitherto unknown mechanism. To find their molecular target, an activity‐based protein profiling with a salinilactone‐derived probe is applied that disclosed the protein disulfide‐isomerases (PDIs) as the dominant mammalian targets of salinilactones, and thioredoxin (TRX1) as secondary target. The inhibition of protein disulfide‐isomerase A1 (PDIA1) and TRX1 is confirmed by biochemical assays with recombinant proteins, showing that (1S,5R)‐salinilactone B is more potent than its (1R,5S)‐configured enantiomer. The salinilactones bound covalently to C53 and C397, the catalytically active cysteines of the isoform PDIA1 according to tandem mass spectrometry. Reactions with a model substrate demonstrated that the cyclopropyl group is opened by an attack of the thiol at C6. Fluorophore labeling experiments showed the cell permeability of a salinilactone‐BODIPY (dipyrrometheneboron difluoride) conjugate and its co‐localization with PDIs in the endoplasmic reticulum. The study is one of the first to pinpoint a molecular target for a volatile microbial natural product, and it demonstrates that salinilactones can achieve high selectivity despite their small size and intrinsic reactivity.

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