Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure–activity relationships

Bohnert, Markus; Nützmann, Hans-Wilhelm; Schroeckh, Volker; Horn, Fabian; Dahse, Hans‐Martin; Brakhage, Axel A.; Hoffmeister, Dirk

doi:10.1016/j.phytochem.2014.05.009

Cited by 47 publications

(65 citation statements)

References 30 publications

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“…Although certain brown-rot basidiomycetes have been shown to produce protoilludane-type sesquiterpenoids, this is the first time an STS generating a protoilludene scaffold from brownrot fungi has been identified. Because protoilludene is a key intermediate for a wide variety of bioactive sesquiterpenoids (Hirota et al, 2003;Reina et al, 2004;Wang et al, 2006;Bohnert et al, 2014), there is strong interest in exploring biosynthetic machineries including P450s. We have previously isolated 184 full-length cDNA of Number [a] Chemical shifts, ppm PpCYPs, which is a large library that included 70-80% of the total P450s in P. placenta (Ide et al, 2012).…”

Section: Ppcyps Responsible For Metabolism Of Protoilludane-type Sesqmentioning

confidence: 99%

Insight into metabolic diversity of the brown‐rot basidiomycete Postia placenta responsible for sesquiterpene biosynthesis: semi‐comprehensive screening of cytochrome P450 monooxygenase involved in protoilludene metabolism

Ichinose

Kitaoka

2018

Microbial Biotechnology

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SummaryA wide variety of sesquiterpenoids have been isolated from basidiomycetes, and their bioactive properties have attracted significant attention in an effort to understand biosynthetic machineries. As both sesquiterpene synthases and cytochrome P450 monooxygenases play key roles in the diversification of sesquiterpenoids, it is important to widely and mutually understand their biochemical properties. In this study, we performed genome‐wide annotation and functional characterization of sesquiterpene synthases from the brown‐rot basidiomycete Postia placenta. Using RT‐PCR, we isolated 16 sesquiterpene synthases genes as full‐length cDNAs. Heterologous expression revealed that the sesquiterpene synthases could produce a series of sesquiterpene scaffolds with distinct metabolic profiles. Based on metabolic studies, we identified 25 sesquiterpene scaffolds including Δ6‐protoilludene produced by the sesquiterpene synthases. In particular, a protoilludene synthase from the brown‐rot basidiomycete was characterized for the first time. Furthermore, we conducted a semi‐comprehensive functional screening of cytochrome P450 monooxygenases from P. placenta to elucidate biosynthetic machineries involved in metabolisms of Δ6‐protoilludene. Coexpression of protoilludene synthase and 184 isoforms of cytochrome P450 monooxygenases enabled the identification of CYP5344B1, CYP5348E1 and CYP5348J3, which catalysed the hydroxylation reaction of Δ6‐protoilludene to produce Δ6‐protoilludene‐8‐ol and Δ6‐protoilludene‐5‐ol. Furthermore, structural isomers of Δ7‐protoilludene‐6‐ol were obtained from incubation of Δ6‐protoilludene‐8‐ol in acidic culture medium.

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Section: Ppcyps Responsible For Metabolism Of Protoilludane-type Sesqmentioning

confidence: 99%

Insight into metabolic diversity of the brown‐rot basidiomycete Postia placenta responsible for sesquiterpene biosynthesis: semi‐comprehensive screening of cytochrome P450 monooxygenase involved in protoilludene metabolism

Ichinose

Kitaoka

2018

Microbial Biotechnology

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“…However, in the case of the melleolides, the physiological reason for introducing a chlorine atom is unclear. Available studies on structure-activity relationships do not support strongly changed bioactivity through chlorination (8,9,20). Hence, a role in detoxification of melleolides through halogenation also cannot be assumed, and the reason why A. mellea secures chlorination of its toxic natural products to the degree described here remains elusive.…”

Section: Discussionmentioning

confidence: 82%

“…1) moiety esterified to a tricyclic sesquiterpene (protoilludane) alcohol. The melleolides are intriguing, as they show two distinct structure-activity relationships for their cytotoxic and antifungal bioactivities (8). Phytotoxic activities have also been established (9,10).…”

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confidence: 99%

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

Wick

Heine

Lackner

et al. 2016

Appl Environ Microbiol

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The basidiomycetous tree pathogen Armillaria mellea (honey mushroom) produces a large variety of structurally related antibiotically active and phytotoxic natural products, referred to as the melleolides. During their biosynthesis, some members of the melleolide family of compounds undergo monochlorination of the aromatic moiety, whose biochemical and genetic basis was not known previously. This first study on basidiomycete halogenases presents the biochemical in vitro characterization of five flavin-dependent A. mellea enzymes (ArmH1 to ArmH5) that were heterologously produced in Escherichia coli. We demonstrate that all five enzymes transfer a single chlorine atom to the melleolide backbone. A 5-fold, secured biosynthetic step during natural product assembly is unprecedented. Typically, flavin-dependent halogenases are categorized into enzymes acting on free compounds as opposed to those requiring a carrier-protein-bound acceptor substrate. The enzymes characterized in this study clearly turned over free substrates. Phylogenetic clades of halogenases suggest that all fungal enzymes share an ancestor and reflect a clear divergence between ascomycetes and basidiomycetes.

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“…Sesquiterpene aryl esters from Armillaria sp. were already found to possess antibacterial [10,16], antifungal [28] and cytotoxic [29,30] effects and to inhibit the growth of lettuce [25]. Inhibition of degranulation of RBL-2H3 cells was observed for the first time in A. ostoyae, and all purified compounds were also isolated from the mycelium of A. ostoyae for the first time.…”

Section: Discussionmentioning

confidence: 96%

Untitled

2017

PMIO

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IntroductionDuring our investigations of biologically active fungi, Armillaria ostoyae (Romagn.) Herink [1], a basidiomycete belonging to the family Physalacriaceae, came into focus, as it affected degranulation in RBL-2H3 cells. The species is commonly known as edible mushroom, but it also occurs as a devastating pathogen of various tree species causing serious economic losses in forestry all over the world [2]. The mechanisms of host infection as well as hostpathogen interactions have been studied intensively [3][4][5][6][7]. In addition, Armillaria mushrooms attract a wider interest, for instance, as the worldʼs biggest living organism [8] or as a producer of bioluminescence [9]. A broad variety of antibacterial and cytotoxic sesquiterpene aryl esters were isolated from the genus Armillaria, especially Armillaria mellea [10][11][12][13][14][15][16][17][18][19][20], but also Armillaria novae-zelandiae [21] and Armillaria tabescens [22]. In this manuscript, degranulation inhibiting effects of extracts from fruiting bodies and cultivated mycelium as well as bioactivity-guided isolation of compounds from the mycelium of A. ostoyae are described. Degranulation is the process in which cells release secretory products stored in secretory granules by exocytosis. It is an important feature of many immune cells, e.g., for release of mediators [23]. Inhibition of degranulation can result in the blocking of inflammatory or allergic reactions.

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Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure–activity relationships

Cited by 47 publications

References 30 publications

Insight into metabolic diversity of the brown‐rot basidiomycete Postia placenta responsible for sesquiterpene biosynthesis: semi‐comprehensive screening of cytochrome P450 monooxygenase involved in protoilludene metabolism

Insight into metabolic diversity of the brown‐rot basidiomycete Postia placenta responsible for sesquiterpene biosynthesis: semi‐comprehensive screening of cytochrome P450 monooxygenase involved in protoilludene metabolism

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

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