2-Hydroxysorangiadenosine: Structure and Biosynthesis of a Myxobacterial Sesquiterpene–Nucleoside

Abstract

Myxobacteria represent an under-investigated source for biologically active natural products featuring intriguing structural moieties with potential applications, e.g., in the pharmaceutical industry. Sorangiadenosine and the here-discovered 2-hydroxysorangiadenosine are myxobacterial sesquiterpene–nucleosides with an unusual structural moiety, a bicyclic eudesmane-type sesquiterpene. As the biosynthesis of these rare terpene–nucleoside hybrid natural products remains elusive, we investigated secondary metabolomes and genomes of several 2-hydroxysorangiadenosine-producing myxobacteria. We report the isolation and full structure elucidation of 2-hydroxysorangiadenosine and its cytotoxic and antibiotic activities and propose a biosynthetic pathway in the myxobacterium Vitiosangium cumulatum MCy10943T.

Development versus predation: Transcriptomic changes during the lifecycle of Myxococcus xanthus

“…These FA are responsible for maintaining membrane fluidity, and are involved in signaling during development and in biosynthesis of some secondary metabolites ( Bode et al, 2006b ; Li et al, 2013 ). M. xanthus can synthesize IV-CoA via leucine degradation, but also from 3-hydroxy-methyl-glutaryl-CoA (HMG_CoA) via an alternative system ( aib operon) from the mevalonate pathway ( Figure 3 ; Bode et al, 2009 ; Li et al, 2013 ; Okoth et al, 2020 ). As observed in Figure 3 , some genes of the Bkd/Esg complex (branched-chain α-keto acid dehydrogenase complex/E signal) involved in IV-CoA via leucine degradation are downregulated, but genes from the mevalonate pathway, including the aibC gene, which converts HMG-CoA into IV-CoA, are upregulated.…”

Bacterial Diterpene Synthases Prenylate Small Molecules

“… , Given their structural and functional similarities to TSs, it was not entirely surprising that the members of the UbiA family of enzymes were able to catalyze cyclization or prenylation reactions. At the outset of this study, TSs were not generally considered to be able to catalyze direct prenylation reactions, although there are a few known examples in natural product biosynthesis (see the discussion section) and there are proposals that a single TS may catalyze both cyclization and prenylation. , However, during manuscript preparation, a few fungal and plant sesqui- and di-TSs were reported to primarily prenylate indole …”

“…At the outset of this study, TSs were not generally considered to be able to catalyze direct prenylation reactions, although there are a few known examples in natural product biosynthesis (see the discussion section) and there are proposals that a single TS may catalyze both cyclization and prenylation. 3,16 However, during manuscript preparation, a few fungal and plant sesqui-and di-TSs were reported to primarily prenylate indole. 17 Here, we report our discovery that a previously uncharacterized di-TS is capable of efficiently catalyzing both diterpene cyclization and the prenylation of small molecules.…”

Structure Elucidation and Biosynthesis of Nannosterols A and B, Myxobacterial Sterols from Nannocystis sp. MNa10993

“…For evaluation of antibacterial and antifungal activities of compounds 1 and 2 , E. coli DSM 1116 T , E. coli JW0451-2 ( acrB -efflux pump deletion mutant of E. coli BW25113), P. aeruginosa PA14, B. subtilis DSM10 T , M. smegmatis DSM 43756, S. aureus Newman, C. albicans DSM 1665, and M. hiemalis DSM 2656 were assayed using the microbroth dilution assay as described previously . These strains present a representative selection of bacterial and fungal microorganisms to evaluate biological activity of natural products.…”

“…For evaluation of antibacterial and antifungal activities of compounds 1 and 2 , E. coli DSM 1116 T , E. coli JW0451-2 ( acrB -efflux pump deletion mutant of E. coli BW25113), P. aeruginosa PA14, B. subtilis DSM10 T , M. smegmatis DSM 43756, S. aureus Newman, C. albicans DSM 1665, and M. hiemalis DSM 2656 were assayed using the microbroth dilution assay as described previously. 54 These strains present a representative selection of bacterial and fungal microorganisms to evaluate biological activity of natural products. Cytotoxic activity of compounds was determined using HepG2 hepatocellular carcinoma cells seeded at 6 × 10 3 cells per well of 96-well plates in 180 μL of complete medium and treated with test compounds in serial dilution after 2 h of equilibration.…”