Boronated tartrolon antibiotic produced by symbiotic cellulose-degrading bacteria in shipworm gills

Elshahawi, Sherif I.; Trindade-Silva, Amaro E.; Hanora, Amro; Han, Andrew; Flores, Malem; Vizzoni, Vinicius Figueiredo; Schrago, Carlos G.; Soares, Carlos A. G.; Concepción, Gisela P.; Distel, Daniel L.; Schmidt, Eric W.; Haygood, Martha G.

doi:10.1073/pnas.1213892110

Cited by 98 publications

(120 citation statements)

References 61 publications

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“…The mechanism by which this occurs is currently unknown. It has been proposed that secondary metabolites produced by gill endosymbionts such as T. turnerae may be translocated to the caecum and contribute to suppression of microbial growth [24]. Siderophores may also play a role in suppression of microbial growth in the caecum.…”

Section: Discussionmentioning

confidence: 99%

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Turnerbactin, a Novel Triscatecholate Siderophore from the Shipworm Endosymbiont Teredinibacter turnerae T7901

et al. 2013

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Shipworms are marine bivalve mollusks (Family Teredinidae) that use wood for shelter and food. They harbor a group of closely related, yet phylogenetically distinct, bacterial endosymbionts in bacteriocytes located in the gills. This endosymbiotic community is believed to support the host's nutrition in multiple ways, through the production of cellulolytic enzymes and the fixation of nitrogen. The genome of the shipworm endosymbiont Teredinibacter turnerae T7901 was recently sequenced and in addition to the potential for cellulolytic enzymes and diazotrophy, the genome also revealed a rich potential for secondary metabolites. With nine distinct biosynthetic gene clusters, nearly 7% of the genome is dedicated to secondary metabolites. Bioinformatic analyses predict that one of the gene clusters is responsible for the production of a catecholate siderophore. Here we describe this gene cluster in detail and present the siderophore product from this cluster. Genes similar to the entCEBA genes of enterobactin biosynthesis involved in the production and activation of dihydroxybenzoic acid (DHB) are present in this cluster, as well as a two-module non-ribosomal peptide synthetase (NRPS). A novel triscatecholate siderophore, turnerbactin, was isolated from the supernatant of iron-limited T. turnerae T7901 cultures. Turnerbactin is a trimer of N-(2,3-DHB)-L-Orn-L-Ser with the three monomeric units linked by Ser ester linkages. A monomer, dimer, dehydrated dimer, and dehydrated trimer of 2,3-DHB-L-Orn-L-Ser were also found in the supernatant. A link between the gene cluster and siderophore product was made by constructing a NRPS mutant, TtAH03. Siderophores could not be detected in cultures of TtAH03 by HPLC analysis and Fe-binding activity of culture supernatant was significantly reduced. Regulation of the pathway by iron is supported by identification of putative Fur box sequences and observation of increased Fe-binding activity under iron restriction. Evidence of a turnerbactin fragment was found in shipworm extracts, suggesting the production of turnerbactin in the symbiosis.

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Section: Discussionmentioning

confidence: 99%

“…Analysis of T. turnerae 's genome also reveals nine gene clusters predicted to code for secondary metabolites, constituting nearly 7% of its genome. One of the nine gene clusters was recently reported to synthesize an antibacterial compound in the tartrolon family [24].…”

Section: Introductionmentioning

confidence: 99%

Turnerbactin, a Novel Triscatecholate Siderophore from the Shipworm Endosymbiont Teredinibacter turnerae T7901

et al. 2013

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“…We have previously reported a method to predict biosynthetic products of trans-AT PKS by examining the phylogeny of ketosynthase (KS) domains 22 , which catalyze polyketide chain elongation. This approach, validated for diverse polyketides 26,[32][33][34][35] , is based on a correlation of KS phylogeny with the structure of the incoming substrates close to the thioester terminus 22,32 . On this basis, prediction of the mis PKS product returned an almost perfect match for swinholideand misakinolide-type compounds (Fig.…”

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confidence: 99%

Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms

et al. 2015

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Actin-targeting macrolides comprise a large, structurally diverse group of cytotoxins isolated from remarkably dissimilar micro- and macroorganisms. In spite of their disparate origins and structures, many of these compounds bind actin at the same site and exhibit structural relationships reminiscent of modular, combinatorial drug libraries. Here we investigate biosynthesis and evolution of three compound groups: misakinolides, scytophycin-type compounds and luminaolides. For misakinolides from the sponge Theonella swinhoei WA, our data suggest production by an uncultivated 'Entotheonella' symbiont, further supporting the relevance of these bacteria as sources of bioactive polyketides and peptides in sponges. Insights into misakinolide biosynthesis permitted targeted genome mining for other members, providing a cyanobacterial luminaolide producer as the first cultivated source for this dimeric compound family. The data indicate that this polyketide family is bacteria-derived and that the unusual macrolide diversity is the result of combinatorial pathway modularity for some compounds and of convergent evolution for others.

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“…1). To prepare boron-containing biomolecules, living organisms produce small molecules that spontaneously react with boric acid available in the environment 15,16 . While this non-enzymatic method for capturing boron is sufficient for an organism’s survival, it is limited to a substrate’s inherent affinity towards boric acid, and lacks tunability and generality for synthetic biology applications.…”

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confidence: 99%

Genetically programmed chiral organoborane synthesis

Kan

Huang

Gumulya

et al. 2017

Nature

260

213

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Summary paragraph Recent advances in enzyme engineering and design have expanded nature’s catalytic repertoire to functions that are new to biology1–3. Yet only a subset of these engineered enzymes can function in living systems4–7. Finding enzymatic pathways that forge chemical bonds not found in biology is particularly difficult in the cellular environment, as this hinges on the discovery not only of new enzyme activities but also reagents that are simultaneously sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution, and generalisation of a fully genetically-encoded platform for producing chiral organoboranes in bacteria. Escherichia coli harbouring wild-type cytochrome c from Rhodothermus marinus8 (Rma cyt c) were found to form carbon–boron bonds in the presence of borane-Lewis base complexes, through carbene insertion into B–H bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram scale biosynthesis, offering up to 15300 turnovers, 6100 h–1 turnover frequency, 99:1 enantiomeric ratio (e.r.), and 100% chemoselectivity. The enantio-preference of the biocatalyst could also be switched to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace which rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than that of known chiral catalysts for the same class of transformation9–11. This tunable method for manipulating boron in cells opens a whole new world of boron chemistry in living systems.

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Boronated tartrolon antibiotic produced by symbiotic cellulose-degrading bacteria in shipworm gills

Cited by 98 publications

References 61 publications

Turnerbactin, a Novel Triscatecholate Siderophore from the Shipworm Endosymbiont Teredinibacter turnerae T7901

Turnerbactin, a Novel Triscatecholate Siderophore from the Shipworm Endosymbiont Teredinibacter turnerae T7901

Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms

Genetically programmed chiral organoborane synthesis

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