2022
DOI: 10.1021/acschembio.2c00606
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Thermorubin Biosynthesis Initiated by a Salicylate Synthase Suggests an Unusual Conversion of Phenols to Pyrones

Abstract: Thermorubin is a tetracyclic naphthoisocoumarin natural product that demands investigation due to its novel mechanism of bacterial protein synthesis inhibition and its unusual structural features. In this work, we describe the identification of the biosynthetic cluster responsible for thermorubin from the sequenced Laceyella sacchari producer species and its confirmation via heterologous production in Escherichia coli. Based on an indepth annotation of the cluster, we propose a biosynthetic pathway that accoun… Show more

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Cited by 5 publications
(7 citation statements)
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“…The biosynthetic gene cluster of the tetracyclic naphthoisocoumarin natural product, thermorubin 30 , an inhibitor of bacterial protein synthesis, has been identified from Laceyella sacchari . 28 As well as validation of the thermorubin cluster through heterologous expression in E. coli , a thermostable salicylate synthase, TheO, responsible for early-stage biosynthesis of 2-hydroxybenzoic acid, was fully characterised. A family of cyclic thiazole- and thiazoline-rich non-ribosomal peptides, such as thiamyxin B 31 , have been isolated from the myxobacterial strain MCy9487 and have been found to have significant activity against RNA viruses.…”
mentioning
confidence: 99%
“…The biosynthetic gene cluster of the tetracyclic naphthoisocoumarin natural product, thermorubin 30 , an inhibitor of bacterial protein synthesis, has been identified from Laceyella sacchari . 28 As well as validation of the thermorubin cluster through heterologous expression in E. coli , a thermostable salicylate synthase, TheO, responsible for early-stage biosynthesis of 2-hydroxybenzoic acid, was fully characterised. A family of cyclic thiazole- and thiazoline-rich non-ribosomal peptides, such as thiamyxin B 31 , have been isolated from the myxobacterial strain MCy9487 and have been found to have significant activity against RNA viruses.…”
mentioning
confidence: 99%
“…17,50,83,84 During binning, contigs, and thus BGCs, may not be attributed to the correct MAG or as is more commonly the case not be attributed to any MAG. 78 While a BGC typically contains most or all of the biosynthetic enzymes, regulatory genes, resistance elements and transporters required for compound production, 85 unusual genes or gene arrangements including the use of genes that are not co-localised may occur 86,87 , which may further complicate correct attribution. The pipeline presented here allows facile processing of numerous datasets and facilitates selection of samples containing taxonomic groups and/or BGCs of interest based on relatively inexpensive shotgun sequencing.…”
Section: Discussionmentioning
confidence: 99%
“…The antibiotic thermorubin [122,123] begins with a singular salicyclic acid starter unit; after the inclusion of eleven acetates, it is hypothesized to cyclize to an all-carbon tetracycle [124]. Tailoring enzymes are predicted to oxidatively open one polyphenolic ring and reclose it as a lactone [125], which is the first potential example of the formation of this functional group not formed from the ACP-bound acetate. Chartreusin [126,127] and its related structures [128] show antibiotic and chemotherapeutic activity.…”
Section: Figurementioning
confidence: 99%
“…Oxytetracycline biosynthesis also relies on three cyclases, but they are not homologous to the tcm series: OxyK, which cyclizes the first ring [181]; OxyN, which cyclizes the second (and possibly the third ring, though this step may be spontaneous) [182]; and OxyH, an unusual CoA-ligase-like protein which forms the fourth ring [183]. Intriguingly, of the three predicted cyclases in the thermorubin cluster [125], two resemble the tcm/elm family while one resembles the oxy family, and the ordering is blended. This finding suggests that after establishing the controlling features of starter unit and length with minimal type II PKS cassettes, the mixing of engineered cyclases from various systems may enable the controlled creation of novel ring architectures.…”
Section: Aromatases and Cyclasesmentioning
confidence: 99%