Transcription profiling of the Neurospora crassa response to a group of synthetic (thio)xanthones and a natural acetophenone

Gonçalves, A. Pedro; Silva, Nuno A.; Oliveíra, Carla; Kowbel, David; Glass, N. Louise; Kijjoa, Anake; Palmeira, Andreia; Sousa, Emı́lia; Pinto, Madalena; Videira, Arnaldo

doi:10.1016/j.gdata.2015.02.001

Cited by 6 publications

(10 citation statements)

References 26 publications

(51 reference statements)

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“…In Kluyveromyces lactis , a fungus more closely related to S. cerevisiae than to N. crassa , deletion of ERG6 (encoding C-24 sterol methyl transferase) can also activate the expression of the CDR4 homolog ( Konecna et al, 2016 ), providing another supporting evidence to the transcriptional activation induced by defects in ergosterol biosynthesis. Thus, the transcriptional induction of cdr4 in N. crassa by compounds, such as xanthone derivatives, might be caused by their inhibition on ergosterol biosynthesis ( Pinto et al, 2011 ; Pedro Gonçalves et al, 2015 ). Interestingly, DTT and avicel, which can induce ER stress, also activate the expression of cdr4 in N. crassa ( Coradetti et al, 2013 ; Fan et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles

Zhou

Wang

et al. 2018

Front. Microbiol.

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Fungi transcriptionally upregulate expression of azole efflux pumps and ergosterol biosynthesis pathway genes when exposed to antifungal agents that target ergosterol biosynthesis. To date, these transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol. Using an inducible promoter to regulate Neurospora crassa erg11, which encodes the major azole target, sterol 14α-demethylase, we were able to demonstrate that the CDR4 azole efflux pump can be transcriptionally activated by ergosterol biosynthesis inhibition even in the absence of azoles. By analyzing ergosterol deficient mutants, we demonstrate that the transcriptional responses by cdr4 and, unexpectedly, genes encoding ergosterol biosynthesis enzymes (erg genes) that are responsive to azoles, are not dependent on ergosterol depletion. Nonetheless, deletion of erg2, which encodes C-8 sterol isomerase, also induced expression of cdr4. Deletion of erg2 also induced the expression of erg24, the gene encoding C-14 sterol reductase, but not other tested erg genes which were responsive to erg11 inactivation. This indicates that inhibition of specific steps of ergosterol biosynthesis can result in different transcriptional responses, which is further supported by our results obtained using different ergosterol biosynthesis inhibitors. Together with the sterol profiles, these results suggest that the transcriptional responses by cdr4 and erg genes are associated with accumulation of specific sterol intermediate(s). This was further supported by the fact that when the erg2 mutant was treated with ketoconazole, upstream inhibition overrode the effects by downstream inhibition on ergosterol biosynthesis pathway. Even though cdr4 expression is associated with the accumulation of sterol intermediates, intra- and extracellular sterol analysis by HPLC-MS indicated that the transcriptional induction of cdr4 did not result in efflux of the accumulated intermediate(s). This study demonstrates, by detailed genetic and chemical analysis, that transcriptional responses by a major efflux pump and genes of the ergosterol biosynthesis pathway to ergosterol biosynthesis inhibitors can be independent of the presence of the drugs and are linked with the accumulation of ergosterol intermediate(s).

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Section: Discussionmentioning

confidence: 99%

Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles

Zhou

Wang

et al. 2018

Front. Microbiol.

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“…In 2020, to further explore the mode of action of 22 in cells, as well as other structure related(thio)xanthones with antitumor activity, the transcriptional response of the filamentous fungus Neurospora crassa to these compounds using high throughput RNA sequencing was evaluated. These compounds showed to induce genes which express ABC transporters in N. crassa , particularly atrb and cdr4, and to repress genes that are evocative of genes downregulated during oxidative stress [ 94 ].…”

Section: A Library Of Natural Mimetic Xanthones Looking For Biologmentioning

confidence: 99%

“…Furthermore, no significant differences were detected in the activity of the enantiomeric pairs towards P-gp [ 181 ]. Still concerning P-gp induction in other organisms, using high throughput RNA sequencing, the transcriptional response of the filamentous fungus Neurospora crassa to thioxanthone derivatives with antitumor activity ( 75 , 81 , and 86 ) revealed that there is an induction of ABC transporters in that fungus, particularly atrb and cdr4, which is a common consequence of the treatment with (thio)xanthones [ 94 ]. Moreover, a group of genes were downregulated by the tested thioxanthones during oxidative stress [ 94 ].…”

Section: A Library Of Natural Mimetic Xanthones Looking For Biologmentioning

confidence: 99%

“…Still concerning P-gp induction in other organisms, using high throughput RNA sequencing, the transcriptional response of the filamentous fungus Neurospora crassa to thioxanthone derivatives with antitumor activity ( 75 , 81 , and 86 ) revealed that there is an induction of ABC transporters in that fungus, particularly atrb and cdr4, which is a common consequence of the treatment with (thio)xanthones [ 94 ]. Moreover, a group of genes were downregulated by the tested thioxanthones during oxidative stress [ 94 ]. While screening for potential P-gp inhibitors that increased the accumulation of known P-gp substrate Rh123, some of the tested thioxanthones caused the opposite effect, decreasing the Rh123 accumulation ratio.…”

Section: A Library Of Natural Mimetic Xanthones Looking For Biologmentioning

confidence: 99%

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From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones

et al. 2021

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This work reviews the contributions of the corresponding author (M.M.M.P.) and her research group to Medicinal Chemistry concerning the isolation from plant and marine sources of xanthone derivatives as well as their synthesis, biological/pharmacological activities, formulation and analytical applications. Although her group activity has been spread over several chemical families with relevance in Medicinal Chemistry, the main focus of the investigation and research has been in the xanthone family. Xanthone derivatives have a variety of activities with great potential for therapeutic applications due to their versatile framework. The group has contributed with several libraries of xanthones derivatives, with a variety of activities such as antitumor, anticoagulant, antiplatelet, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective, antioxidant, and multidrug resistance reversal effects. Besides therapeutic applications, our group has also developed xanthone derivatives with analytical applications as chiral selectors for liquid chromatography and for maritime application as antifouling agents for marine paints. Chemically, it has been challenging to afford green chemistry methods and achieve enantiomeric purity of chiral derivatives. In this review, the structures of the most significant compounds will be presented.

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“…6 ). Gene expression data for putative Pth11-related GPCRs was mined from publically available datasets, including experiments of GSE65311 [ 30 ] and GSE49597 [ 31 ] for biotic stress, GSE37886 [ 32 ], GSE21908 [ 33 ], and GSE33683 [ 34 ] for invasive plant infection, and GSE43006 [ 35 ], GSE53040 [ 36 ], GSE42692 [ 37 ], and GSE46155 [ 38 ] for nutritional stress. RNA-seq data for H. oryzae were also used to study the invasive infection of plants by H. oryzae [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Genome-wide comparative analysis of putative Pth11-related G protein-coupled receptors in fungi belonging to Pezizomycotina

et al. 2017

BMC Microbiol

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BackgroundG-protein coupled receptors (GPCRs) are the largest family of transmembrane receptors in fungi, where they play important roles in signal transduction. Among them, the Pth11-related GPCRs form a large and divergent protein family, and are only found in fungi in Pezizomycotina. However, the evolutionary process and potential functions of Pth11-related GPCRs remain largely unknown.ResultsTwenty genomes of fungi in Pezizomycotina covering different nutritional strategies were mined for putative Pth11-related GPCRs. Phytopathogens encode much more putative Pth11-related GPCRs than symbionts, saprophytes, or entomopathogens. Based on the phylogenetic tree, these GPCRs can be divided into nine clades, with each clade containing fungi in different taxonomic orders. Instead of fungi from the same order, those fungi with similar nutritional strategies were inclined to share orthologs of putative Pth11-related GPCRs. Most of the CFEM domain-containing Pth11-related GPCRs, which were only included in two clades, were detected in phytopathogens. Furthermore, many putative Pth11-related GPCR genes of phytopathogens were upregulated during invasive plant infection, but downregulated under biotic stress. The expressions of putative Pth11-related GPCR genes of saprophytes and entomopathogens could be affected by nutrient conditions, especially the carbon source. The gene expressions revealed that Pth11-related GPCRs could respond to biotic/abiotic stress and invasive plant infection with different expression patterns.ConclusionOur results indicated that the Pth11-related GPCRs existed before the diversification of Pezizomycotina and have been gained and/or lost several times during the evolutionary process. Tandem duplications and trophic variations have been important factors in this evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-017-1076-5) contains supplementary material, which is available to authorized users.

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Transcription profiling of the Neurospora crassa response to a group of synthetic (thio)xanthones and a natural acetophenone

Cited by 6 publications

References 26 publications

Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles

Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles

From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones

Genome-wide comparative analysis of putative Pth11-related G protein-coupled receptors in fungi belonging to Pezizomycotina

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