Bridged Epipolythiodiketopiperazines from <i>Penicillium raciborskii</i>, an Endophytic Fungus of <i>Rhododendron tomentosum</i> Harmaja

Kajula, Marena; Ward, Joshua; Turpeinen, Ari; Tejesvi, Mysore V.; Hokkanen, Juho; Tolonen, Ari; Häkkänen, Heikki; Picart, Pere; Ihalainen, Janne A.; Sahl, Hans‐Georg; Pirttilä, Anna Maria; Mattila, Sampo

doi:10.1021/np500822k

Cited by 49 publications

(40 citation statements)

References 36 publications

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“…Epithiodiketopiperazines with 1,2-oxazadecaline moiety are rare in nature. To date, only eleven such compounds have been reported [ 1 , 2 , 3 , 4 ]. Structural differences in compounds of this class consist in N -methylation, C-4–C-5-epoxidation [ 5 , 6 ] and substituent at C-5.…”

Section: Introductionmentioning

confidence: 99%

Pretrichodermamides D–F from a Marine Algicolous Fungus Penicillium sp. KMM 4672

et al. 2016

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Three new epidithiodiketopiperazines pretrichodermamides D–F (1–3), together with the known N-methylpretrichodermamide B (4) and pretrichodermamide С (5), were isolated from the lipophilic extract of the marine algae-derived fungus Penicillium sp. KMM 4672. The structures of compounds 1–5 were determined based on spectroscopic methods. The absolute configuration of pretrichodermamide D (1) was established by a combination of modified Mosher′s method, NOESY data, and biogenetic considerations. N-Methylpretrichodermamide B (5) showed strong cytotoxicity against 22Rv1 human prostate cancer cells resistant to androgen receptor targeted therapies.

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Section: Introductionmentioning

confidence: 99%

Pretrichodermamides D–F from a Marine Algicolous Fungus Penicillium sp. KMM 4672

et al. 2016

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“…In order to evaluate the characteristic fragmentation behavior of ETPs with the used mass spectrometer, gliotoxin was used as reference compound. In this analytical procedure metabolites with a diketopiperazine (DKP) backbone and at least one sulfur bridge first show a neutral loss of both sulfur atoms and later the opening of the DKP ring, as already described in literature [ 35 – 37 ]. Based on this information every new peak in the mutant strain which was not present in the wild-type was analyzed by HRMS n .…”

Section: Resultsmentioning

confidence: 94%

The Epipolythiodiketopiperazine Gene Cluster in Claviceps purpurea: Dysfunctional Cytochrome P450 Enzyme Prevents Formation of the Previously Unknown Clapurines

et al. 2016

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Claviceps purpurea is an important food contaminant and well known for the production of the toxic ergot alkaloids. Apart from that, little is known about its secondary metabolism and not all toxic substances going along with the food contamination with Claviceps are known yet. We explored the metabolite profile of a gene cluster in C. purpurea with a high homology to gene clusters, which are responsible for the formation of epipolythiodiketopiperazine (ETP) toxins in other fungi. By overexpressing the transcription factor, we were able to activate the cluster in the standard C. purpurea strain 20.1. Although all necessary genes for the formation of the characteristic disulfide bridge were expressed in the overexpression mutants, the fungus did not produce any ETPs. Isolation of pathway intermediates showed that the common biosynthetic pathway stops after the first steps. Our results demonstrate that hydroxylation of the diketopiperazine backbone is the critical step during the ETP biosynthesis. Due to a dysfunctional enzyme, the fungus is not able to produce toxic ETPs. Instead, the pathway end-products are new unusual metabolites with a unique nitrogen-sulfur bond. By heterologous expression of the Leptosphaeria maculans cytochrome P450 encoding gene sirC, we were able to identify the end-products of the ETP cluster in C. purpurea. The thioclapurines are so far unknown ETPs, which might contribute to the toxicity of other C. purpurea strains with a potentially intact ETP cluster.

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“…To determine the suitability of Mo-catalyzed oxidation for the identification of sulfur compounds, methanol solutions of several known microbial compounds containing sulfur, such as outovirin A [17], nanaomycin K [18], and lactacystin [19,20] ( Figure S1), were oxygenated with (NH 4 ) 6 Mo 7 O 24 •4H 2 O and 30% H 2 O 2 . After 6 h of shaking at room temperature, both non-oxidized and oxidation samples were analyzed by LC/MS.…”

Section: Resultsmentioning

confidence: 99%

Screening for Sulfur Compounds by Molybdenum-Catalyzed Oxidation Combined with Liquid Chromatography-Mass Spectrometry

et al. 2020

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The molybdenum (Mo)-catalyzed oxidation of sulfide under neutral conditions yields sulfone. This reaction proceeds more smoothly than olefin epoxidation and primary or secondary alcohol oxidation. In this study, Mo-catalyzed oxidation was used to screen for sulfur compounds (named “MoS-screening”) in microbial broths by liquid chromatography-mass spectrometry (LC/MS). To demonstrate proof-of-concept, known sulfur microbial compounds were successfully identified from a mixture of non-sulfur microbial compounds as sulfinyl or sulfonyl products of Mo-catalyzed oxidation. Then our MoS-screening method was used to screen 300 samples of microbial broth for sulfur compounds. One of the identified compounds was a kitasetaline-containing N-acetyl cysteine moiety produced by an actinomycete strain. These results demonstrate the potential of MoS-screening in the search for new sulfur compounds from microbial sources.

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Bridged Epipolythiodiketopiperazines from Penicillium raciborskii, an Endophytic Fungus of Rhododendron tomentosum Harmaja

Cited by 49 publications

References 36 publications

Pretrichodermamides D–F from a Marine Algicolous Fungus Penicillium sp. KMM 4672

Pretrichodermamides D–F from a Marine Algicolous Fungus Penicillium sp. KMM 4672

The Epipolythiodiketopiperazine Gene Cluster in Claviceps purpurea: Dysfunctional Cytochrome P450 Enzyme Prevents Formation of the Previously Unknown Clapurines

Screening for Sulfur Compounds by Molybdenum-Catalyzed Oxidation Combined with Liquid Chromatography-Mass Spectrometry

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