Conservation of the genes for HC-toxin biosynthesis in Alternaria jesenskae

Wight, Wanessa D; Labuda, Román; Walton, Jonathan D.

doi:10.1186/1471-2180-13-165

Cited by 37 publications

(31 citation statements)

References 46 publications

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“…Another common feature of these gene clusters is the presence of a rather atypical bANK-type TF (ToxE and Aps2/Apf2) containing both a basic DNA-binding domain and four ankyrin repeats. ToxE/Aps2/Apf2-like TFs with reasonable amino acid identity and structure were recently also found in the genomes of Pyrenophora tritici-repentis , Setosophaeria turcica and Glomerella cingulata , and in all cases the TF-encoding genes are adjacent to four-module NRPS genes [61]. The DNA binding motifs for ToxE in C. carbonum (5′-ATCTCNCGNA-3′; [55]) and Apf2 in F. fujikuroi (5′-TGACGTGA-3′; this work) differ despite the high sequence similarity in the basic DNA binding and ankyrin domains of both TFs.…”

Section: Discussionmentioning

confidence: 90%

Apicidin F: Characterization and Genetic Manipulation of a New Secondary Metabolite Gene Cluster in the Rice Pathogen Fusarium fujikuroi

et al. 2014

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The fungus F. fujikuroi is well known for its production of gibberellins causing the ‘bakanae’ disease of rice. Besides these plant hormones, it is able to produce other secondary metabolites (SMs), such as pigments and mycotoxins. Genome sequencing revealed altogether 45 potential SM gene clusters, most of which are cryptic and silent. In this study we characterize a new non-ribosomal peptide synthetase (NRPS) gene cluster that is responsible for the production of the cyclic tetrapeptide apicidin F (APF). This new SM has structural similarities to the known histone deacetylase inhibitor apicidin. To gain insight into the biosynthetic pathway, most of the 11 cluster genes were deleted, and the mutants were analyzed by HPLC-DAD and HPLC-HRMS for their ability to produce APF or new derivatives. Structure elucidation was carried out be HPLC-HRMS and NMR analysis. We identified two new derivatives of APF named apicidin J and K. Furthermore, we studied the regulation of APF biosynthesis and showed that the cluster genes are expressed under conditions of high nitrogen and acidic pH in a manner dependent on the nitrogen regulator AreB, and the pH regulator PacC. In addition, over-expression of the atypical pathway-specific transcription factor (TF)-encoding gene APF2 led to elevated expression of the cluster genes under inducing and even repressing conditions and to significantly increased product yields. Bioinformatic analyses allowed the identification of a putative Apf2 DNA-binding (“Api-box”) motif in the promoters of the APF genes. Point mutations in this sequence motif caused a drastic decrease of APF production indicating that this motif is essential for activating the cluster genes. Finally, we provide a model of the APF biosynthetic pathway based on chemical identification of derivatives in the cultures of deletion mutants.

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Section: Discussionmentioning

confidence: 90%

Apicidin F: Characterization and Genetic Manipulation of a New Secondary Metabolite Gene Cluster in the Rice Pathogen Fusarium fujikuroi

et al. 2014

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“…Most fungal species seem to be resistant to HDACi, though mechanisms of resistance have only rarely been reported , and some even make their own. Examples include the linear polyketide depudecin and the cyclic tetrapeptides HC‐toxin , and Trapoxin . Another fungal HDACi, apicidin (a cyclic tetrapeptide made by Fusarium spp.)…”

Section: Hdaci Are Natural Products That Can Kill or Manipulate Compementioning

confidence: 99%

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Halsall

Turner

2016

BioEssays

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Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers.Also see the video abstract here.

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“…A well-known example is the interspecific horizontal transfer of the ToxA effector gene from P. nodorum to Pyrenophora tritici-repentis , resulting in the emergence of the tan-spot disease on wheat ( Friesen et al, 2006 ). HGT of whole or partial SM gene clusters have also been proposed ( Patron et al, 2007 ; Slot and Rokas, 2011 ; Wight et al, 2013 ). In a more extreme example, horizontal transfer of whole supernumerary chromosomes containing HST biosynthetic gene clusters has been proposed to confer pathogenicity to different pathotypes of Alternaria alternata ( Akagi et al, 2009 ; Mehrabi et al, 2011 ).…”

Section: Genome Evolutionary Dynamics Of Sm Biosynthetic Genes In Funmentioning

confidence: 99%

“…Interspecific comparative genomic analysis identified HC-toxin gene cluster is present in another maize pathogen Setosphaeria turcica ( Condon et al, 2013 ). Interestingly, the HC-toxin gene cluster is also present in another plant-associated fungus, Alternaria jesenskae , which does not appear to be pathogenic to most plants ( Wight et al, 2013 ). Comparative phylogenomic analysis of NRPS genes among plant pathogens has also revealed that some NRPS genes have undergone recombination and modular rearrangement ( Bushley and Turgeon, 2010 ).…”

Section: Genome Evolutionary Dynamics Of Sm Biosynthetic Genes In Funmentioning

confidence: 99%

A chemical ecogenomics approach to understand the roles of secondary metabolites in fungal cereal pathogens

Chooi

Solomon

2014

Front. Microbiol.

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Secondary metabolites (SMs) are known to play important roles in the virulence and lifestyle of fungal plant pathogens. The increasing availability of fungal pathogen genome sequences and next-generation genomic tools have allowed us to survey the SM gene cluster inventory in individual fungi. Thus, there is immense opportunity for SM discovery in these plant pathogens. Comparative genomics and transcriptomics have been employed to obtain insights on the genetic features that enable fungal pathogens to adapt in individual ecological niches and to adopt the different pathogenic lifestyles. Here, we will discuss how we can use these tools to search for ecologically important SM gene clusters in fungi, using cereal pathogens as models. This ecological genomics approach, combined with genome mining and chemical ecology tools, is likely to advance our understanding of the natural functions of SMs and accelerate bioactive molecule discovery.

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Conservation of the genes for HC-toxin biosynthesis in Alternaria jesenskae

Abstract: Background: HC-toxin, a cyclic tetrapeptide, is a virulence determinant for the plant pathogenic fungus Cochliobolus carbonum. It was recently discovered that another fungus, Alternaria jesenskae, also produces HC-toxin.

Cited by 37 publications

References 46 publications

Apicidin F: Characterization and Genetic Manipulation of a New Secondary Metabolite Gene Cluster in the Rice Pathogen Fusarium fujikuroi

Apicidin F: Characterization and Genetic Manipulation of a New Secondary Metabolite Gene Cluster in the Rice Pathogen Fusarium fujikuroi

Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

A chemical ecogenomics approach to understand the roles of secondary metabolites in fungal cereal pathogens

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