Glionitrin B, a Cancer Invasion Inhibitory Diketopiperazine Produced by Microbial Coculture

Park, Hyun Bong; Kim, Young-Joo; Park, Jin-Soo; Yang, Hyun Ok; Lee, Kang Ro; Kwon, Hak Cheol

doi:10.1021/np200563x

Cited by 56 publications

(49 citation statements)

References 29 publications

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“…Methylation can play an essential role in bioactivity and bioavailability of NPs. [49][50][51] Since there are not many examples of stand-alone methyltransferases in NRP biosyntheses, one could speculate that interrupted A domains are the most efficient way to regiospecifically methylate amino acid-like building blocks in NRPs. Therefore, it is important to further investigate and better understand interrupted A domains functionally and structurally for combinatorial biosynthesis of methylated NRPs.…”

Section: Resultsmentioning

confidence: 99%

A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

Lundy

Mori

2020

RSC Chem. Biol.

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Section: Resultsmentioning

confidence: 99%

A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

Lundy

Mori

2020

RSC Chem. Biol.

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“…To our best knowledge, this is the first example of methylthio-substituted cytochalasans. Methythio-substitution usually occurs in diketopiperazine derivatives of fungi and is derived from reductive methylation of disulfide linkage [ 22 ]. As for the biosynthesis of the methylthiol group in 1 and 2 , methanethiol etherification reaction is a possible pathway because of existence of methioninase in Aspergillus sp [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

Methylthio-Aspochalasins from a Marine-Derived Fungus Aspergillus sp.

et al. 2014

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Two novel aspochalasins, 20-β-methylthio-aspochalsin Q (named as aspochalasin V), (1) and aspochalasin W (2), were isolated from culture broth of Aspergillus sp., which was found in the gut of a marine isopod Ligia oceanica. The structures were determined on the basis of NMR and mass spectral data analysis. This is the first report about methylthio-substituted aspochalasin derivatives. Cytotoxicity against the prostate cancer PC3 cell line and HCT116 cell line was assayed using the MTT method. Apochalasin V showed moderate activity at IC50 values of 30.4 and 39.2 μM, respectively.

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“…This indicates that no enzymatic reaction takes place. For many ETPs a biologically inactive bisthiomethylated derivate is known [ 18 , 66 , 67 ], showing no toxicity anymore [ 68 ]. Furthermore, in case of gliotoxin it is shown that the methylated compound strongly suppresses the biosynthesis of gliotoxin [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

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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Glionitrin B, a Cancer Invasion Inhibitory Diketopiperazine Produced by Microbial Coculture

Cited by 56 publications

References 29 publications

A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

A thorough analysis and categorization of bacterial interrupted adenylation domains, including previously unidentified families

Methylthio-Aspochalasins from a Marine-Derived Fungus Aspergillus sp.

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

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