Formation of 1,3‐Cyclohexanediones and Resorcinols Catalyzed by a Widely Occuring Ketosynthase

Fuchs, Sebastian W.; Bozhüyük, Kenan A. J.; Kresovic, Darko; Grundmann, Florian; Dill, Veronica; Brachmann, Alexander O.; Waterfield, Nicholas R.; Bode, Helge B.

doi:10.1002/anie.201210116

Cited by 77 publications

(96 citation statements)

References 23 publications

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“…Additionally, the anabolic chain elongation reaction of DarB converting myristoyl-CoA to β-ketopalmitoyl-CoA was not detectable, supporting the biosynthetic pathway including fatty acid catabolism intermediates. In agreement with this previously unknown cyclization reaction catalyzed by DarB, this KS class represents a new branch of the KS phylogenetic tree (Fuchs et al 2013).…”

Section: Biosynthesis Of Dialkylresorcinolssupporting

confidence: 77%

“…Based on these results it was not clear whether the DAR precursors origin from de novo biosynthesis by the DAR enzymes, fatty acid anabolism (ACP bound intermediates) or fatty acid catabolism (beta-oxidation of coenzyme A bound intermediates). To target this question darBC from Chitinophaga pinensis was expressed in E. coli, and the formation of 2,5-dialkylcyclohexane-1,3-diones (CHD) and 4-carboxy-derivatives was detected (Fuchs et al 2013). As darA was additionally expressed, no CHDs or 4-carboxyCHDs could be detected anymore, instead the corresponding DAR derivative was formed.…”

Section: Biosynthesis Of Dialkylresorcinolsmentioning

confidence: 99%

“…Although in one case even a combination of DarAs and DarBs from different organism still resulted in DAR production, the substrate specificity was defined by DarB. In a homology model of DarB from C. pinensis, Pseudomonas chlororaphis, and Photorhabdus asymbiotica, the mode of action was investigated in more detail (Fuchs et al 2013). Like other KS, the active site shows a catalytic triad (Cys-His-Asn), which is responsible for the covalent binding of the intermediate at the Cys residue.…”

Section: Biosynthesis Of Dialkylresorcinolsmentioning

confidence: 99%

“…The genes for DAR biosynthesis have been found in more than 100 genomes from taxonomically distinct bacteria (Fuchs et al 2013;Brameyer et al 2015) and their biosynthetic products have been studied from different organisms. In general, the genes for DarA, DarB, and DarC cluster together, with a strongly conserved arrangement of the genes in all reported DAR-clusters.…”

Section: Occurrence Of Dar Biosynthesis Genesmentioning

confidence: 99%

“…Using transposon mutagenesis, they also identified the involved biosynthesis gene cluster (BGC) and characterized it by heterologous expression in Escherichia coli. In 2013, we were then able to fully elucidate the enzymatic basics for the DAR biosynthesis (Fuchs et al 2013). …”

Section: Introductionmentioning

confidence: 99%

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Biosynthesis and function of bacterial dialkylresorcinol compounds

Schöner

Kresovic

Bode

2015

Appl Microbiol Biotechnol

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This review summarizes the research of bacterially produced dialkylresorcinols (DARs). We will give an overview about the DAR-related research during the last 40 years. Furthermore, a brief introduction into the class of ketosynthases (KS) and examples of these enzymes which show a deviation to the usual catalytic activity is given. One of these is DarB, which is involved in the DAR biosynthesis. The clustering and distribution of the DAR biosynthesis gene clusters (BGC), that has been identified in more than 100 genomes from taxonomically distinct bacteria, is discussed regarding the structures of the biosynthetic products from these BGCs. Finally, the biological activities of described DARs are summarized and possible methods for the detection and structure elucidation of DARs are given.

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Section: Biosynthesis Of Dialkylresorcinolssupporting

confidence: 77%

Section: Biosynthesis Of Dialkylresorcinolsmentioning

confidence: 99%

Section: Biosynthesis Of Dialkylresorcinolsmentioning

confidence: 99%

Section: Occurrence Of Dar Biosynthesis Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biosynthesis and function of bacterial dialkylresorcinol compounds

Schöner

Kresovic

Bode

2015

Appl Microbiol Biotechnol

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Biosynthesis‐Assisted Structural Elucidation of the Bartolosides, Chlorinated Aromatic Glycolipids from Cyanobacteria

et al. 2015

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The isolation of the bartolosides, unprecedented cyanobacterial glycolipids featuring aliphatic chains with chlorine substituents and C-glycosyl moieties, is reported. Their chlorinated dialkylresorcinol (DAR) core presented a major structural-elucidation challenge. To overcome this, we discovered the bartoloside (brt) biosynthetic gene cluster and linked it to the natural products through in vitro characterization of the DAR-forming ketosynthase and aromatase. Bioinformatic analysis also revealed a novel potential halogenase. Knowledge of the bartoloside biosynthesis constrained the DAR core structure by defining key pathway intermediates, ultimately allowing us to determine the full structures of the bartolosides. This work illustrates the power of genomics to enable the use of biosynthetic information for structure elucidation. Keywordsbiosynthesis; cyanobacteria; dialkylresorcinol; glycolipids; structure elucidation As ancient photoautotrophs, cyanobacteria have a differentiated ecophysiology among prokaryotes [1] that is abundantly reflected in their secondary metabolite diversity. [2] We have explored the chemical diversity of an in-house culture collection of cyanobacteria [3] and herein report the discovery of four unusual secondary metabolites and the use of biosynthesis in their structure elucidation.Examination of a fractionated crude organic extract from the filamentous cyanobacterium Nodosilinea sp. LEGE 06102 led to the 1 H NMR spectroscopy guided isolation of bartoloside A (1, 2.0 mg; Figure 1a). Intriguingly, analogous metabolites, namely bartolosides B, C, and D (2, 5.6 mg; 3, 0.7 mg; and 4, 0.3 mg; Figure 1b), were isolated through bioassay-guided fractionation of a crude extract of Synechocystis salina LEGE 06155, a unicellular, free-living cyanobacterium found at the same beach as the bartoloside A producer. [4] These cyanobacterial strains are morphologically and phylogenetically distant (Figure 1; see also the Supporting Information, Figure S1). Together with their geographical co-occurrence, this observation may suggest pathway acquisition by horizontal gene transfer.Initial structural-elucidation efforts focused on the most abundant metabolites (1 and 2). A combination of 1 H, 13 C, HSQC, HMBC and COSY data revealed a dialkylresorcinol (DAR) scaffold in both compounds (Supporting Information, S7-S39). D-Xylose and L-rhamnose were O-linked to the aromatic rings in 1 and 2, respectively (Figure 2a, see also Figure S33). The DAR scaffold in 2 was further decorated with a xylose residue C-linked to the C4 position (Figure 2a). To the best of our knowledge, this is the first report of a cyanobacterial C-glycoside.The two alkyl substituents on the resorcinol ring accounted for 25 and 27 carbon atoms in 1 and 2, respectively. Considering the HR-ESI-MS derived molecular formulae (C 36 H 62 Cl 2 O 6 for 1 and C 44 H 76 Cl 2 O 10 for 2) and NMR-based partial structures, these groups had to be linear. Overlapping 1 H and 13 C resonances for the two chlorinated methine groups and their corre...

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Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics

Park

Goddard

et al. 2020

Angewandte Chemie

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Tapinarof is as tilbene drug that is used to treat psoriasis and atopic dermatitis,a nd is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases.It is produced by the gammaproteobacterial Photorhabdus genus,w hicht hus represents am odel to probe tapinarof structural and functional transformations.W es howt hat Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that acupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers.O ne dimer has activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistantE nterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to ac yclopropane-bridge-containing hexacyclic framework that exhibits activity against Mycobacterium. These dimers lacke fficacy in ac olitis mouse model, whereas the monomer reduces disease symptoms.

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Formation of 1,3‐Cyclohexanediones and Resorcinols Catalyzed by a Widely Occuring Ketosynthase

Cited by 77 publications

References 23 publications

Biosynthesis and function of bacterial dialkylresorcinol compounds

Biosynthesis and function of bacterial dialkylresorcinol compounds

Biosynthesis‐Assisted Structural Elucidation of the Bartolosides, Chlorinated Aromatic Glycolipids from Cyanobacteria

Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics

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