The lipopeptide toxins anabaenolysin A and B target biological membranes in a cholesterol-dependent manner

Oftedal, Linn; Myhren, Lene Elisabeth; Jokela, Jouni; Gausdal, Gro; Sivonen, Kaarina; Døskeland, Stein Ove; Herfindal, Lars

doi:10.1016/j.bbamem.2012.07.015

Cited by 37 publications

(49 citation statements)

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“…Anabaenolysins may account for up to 0.1% of the dry weight of Anabaena strains (16). Anabaenolysins are able to permeabilize mammalian cells in a cholesterol-dependent manner and show more hemolytic potency than do the plant saponin digitonin and the bacterial cyclic peptide surfactin (17). In this study, we report the discovery of the anabaenolysin gene cluster and demonstrate that anabaenolysins exhibit antifungal activity.…”

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confidence: 89%

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Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria

Shishido

Jokela

Kolehmainen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cyclodextrins are cyclic oligosaccharides widely used in the pharmaceutical industry to improve drug delivery and to increase the solubility of hydrophobic compounds. Anabaenolysins are lipopeptides produced by cyanobacteria with potent lytic activity in cholesterolcontaining membranes. Here, we identified the 23-to 24-kb gene clusters responsible for the production of the lipopeptide anabaenolysin. The hybrid nonribosomal peptide synthetase and polyketide synthase biosynthetic gene cluster is encoded in the genomes of three anabaenolysin-producing strains of Anabaena. We detected previously unidentified strains producing known anabaenolysins A and B and discovered the production of new variants of anabaenolysins C and D. Bioassays demonstrated that anabaenolysins have weak antifungal activity against Candida albicans. Surprisingly, addition of the hydrophilic fraction of the whole-cell extracts increased the antifungal activity of the hydrophobic anabaenolysins. The fraction contained compounds identified by NMR as α-, β-, and γ-cyclodextrins, which undergo acetylation. Cyclodextrins have been used for decades to improve the solubility and bioavailability of many drugs including antifungal compounds. This study shows a natural example of cyclodextrins improving the solubility and efficacy of an antifungal compound in an ancient lineage of photosynthetic bacteria.natural products | bioactive compounds | hydroxyamino fatty acid | NRPS | PKS

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confidence: 89%

“…1). Isolated anabaenolysins are known to permeabilize mammalian cells, which contain cholesterol (17), and it could also make the ergosterol containing fungal cells permeable. The structure of these two sterols differs only by two double bonds and a methyl group.…”

Section: Significancementioning

confidence: 99%

Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria

Shishido

Jokela

Kolehmainen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…As one of the less explored cyanobacterial secondary metabolites, cyclic lipopeptides may be important due to their broad biological effects in various organisms, which also raises questions on their possible toxicity to humans [10], [11]. Thus far, approximately 80 structural variants derived from several core structures have been isolated from cyanobacteria.…”

Section: Introductionmentioning

confidence: 99%

A Hybrid Non-Ribosomal Peptide/Polyketide Synthetase Containing Fatty-Acyl Ligase (FAAL) Synthesizes the β-Amino Fatty Acid Lipopeptides Puwainaphycins in the Cyanobacterium Cylindrospermum alatosporum

et al. 2014

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A putative operon encoding the biosynthetic pathway for the cytotoxic cyanobacterial lipopeptides puwainphycins was identified in Cylindrospermum alatosporum. Bioinformatics analysis enabled sequential prediction of puwainaphycin biosynthesis; this process is initiated by the activation of a fatty acid residue via fatty acyl-AMP ligase and continued by a multidomain non-ribosomal peptide synthetase/polyketide synthetase. High-resolution mass spectrometry and nuclear magnetic resonance spectroscopy measurements proved the production of puwainaphycin F/G congeners differing in FA chain length formed by either 3-amino-2-hydroxy-4-methyl dodecanoic acid (4-methyl-Ahdoa) or 3-amino-2-hydroxy-4-methyl tetradecanoic acid (4-methyl-Ahtea). Because only one puwainaphycin operon was recovered in the genome, we suggest that the fatty acyl-AMP ligase and one of the amino acid adenylation domains (Asn/Gln) show extended substrate specificity. Our results provide the first insight into the biosynthesis of frequently occurring β-amino fatty acid lipopeptides in cyanobacteria, which may facilitate analytical assessment and development of monitoring tools for cytotoxic cyanobacterial lipopeptides.

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“…In addition to dysfunction of hepatic lipemic‐oxidative injury and suppression of resolution response, abnormal lipid metabolism is another manifestation of triton‐1339‐induced acute hyperlipidemia (Ramakrishnan et al, ) and liver injury (Cao et al, ). Specifically, in our case, triton‐1339W‐suppressed expression of Cyp7a1 , Abca1 , and Abcg5/8 , indicating abnormal bile acid metabolism including suppression of cholesterol efflux and catabolism, and suppression in Ldlr , Pcsk9 , Cd36 , and Sra1 , which are genes for hepatic lipid absorption, could lead to disorder of lipid metabolism and product of lipopeptite toxin in liver (Oftedal et al, ). In our experiment, transcriptional change of lipid metabolism suggests high content of serum lipid is partially caused by impaired reversal cholesterol transport.…”

Section: Discussionmentioning

confidence: 68%

Tanshinol A Ameliorates Triton‐1339W‐Induced Hyperlipidemia and Liver Injury in C57BL/6J Mice by Regulating mRNA Expression of Lipemic‐Oxidative Injury Genes

Yuxing²,

Huang³

et al. 2020

Lipids

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Tanshinol A, which is derived from a traditional Chinese herbal Radix Salviae Miltiorrhizae is indicative of a hypolipidemic candidate. Therefore, we aim to validate its hypolipidemic activity of tanshinol A and explore its mechanism in triton‐1339W‐induced hyperlipidemic mice model, which possess multiply pathogenesis for endogenous lipid metabolism disorder. Experimental hyperlipidemia mice are treated with or without tanshinol A (i.g. 40, 20, 10 mg/kg), and blood and liver tissue were collected for validating its hypolipidemic and hepatic protective effect, and hepatic mRNA expression profile, which was associated with lipid metabolism dysfunction and liver injury, was detected by RT‐qPCR. As results show, triton‐1339W‐induced abnormal of serum TC, TAG, HDL‐C, LDL‐C, SOD, MDA, GOT, and GPT is remarkably attenuated by tanshinol A. In pathological experiment, triton‐1339W‐induced hepatocellular ballooning degeneration, irregular central vein congestion, and inflammation infiltration are alleviated by tanshinol A. Correspondingly, hepatic mRNA expression of Atf4, Fgf21, Vldlr, Nqo1, Pdk4, and Angptl4, which are genes regulating lipemic‐oxidative injury, are significantly increased by tanshinol A by 2~6 fold. Abcg5, Cd36, and Apob, which are responsible for cholesterol metabolism, are mildly upregulated. Noticeably, triton‐1339W‐suppressed expressions of Ptgs2/Il10, which are genes responsible for acute inflammation resolution in liver injury, are remarkably increased by tanshinol A. Conclusively, tanshinol A exerted hypolipidemic effect and hepatoprotective effect through restoring triton‐1339W‐suppressed mRNA expression, which may be involved in Atf4/Fgf21/Vldlr and Ptgs2/Il‐10 signaling pathways.

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The lipopeptide toxins anabaenolysin A and B target biological membranes in a cholesterol-dependent manner

Cited by 37 publications

References 38 publications

Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria

Antifungal activity improved by coproduction of cyclodextrins and anabaenolysins in Cyanobacteria

A Hybrid Non-Ribosomal Peptide/Polyketide Synthetase Containing Fatty-Acyl Ligase (FAAL) Synthesizes the β-Amino Fatty Acid Lipopeptides Puwainaphycins in the Cyanobacterium Cylindrospermum alatosporum

Tanshinol A Ameliorates Triton‐1339W‐Induced Hyperlipidemia and Liver Injury in C57BL/6J Mice by Regulating mRNA Expression of Lipemic‐Oxidative Injury Genes

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