The ergot alkaloid gene cluster: Functional analyses and evolutionary aspects

Lorenz, Nicole; Haarmann, Thomas; Pažoutová, Sylvie; Jung, Manfred; Tudzynski, Paul

doi:10.1016/j.phytochem.2009.05.023

Cited by 71 publications

(67 citation statements)

References 69 publications

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“…The global transcription factor is not deacetylated by FfHda1 prior to binding; however, whether either another HDAC is involved in this process or the transcription factor can bind in the acetylated state or is not subject to acetylation in the first place remains to be elucidated. A similar hypothesis was proposed for the unexpected downregulation of alkaloid biosynthesis in C. purpurea or deoxynivalenol production in A. nidulans (77,78).…”

Section: Discussionsupporting

confidence: 72%

Two Histone Deacetylases, FfHda1 and FfHda2, Are Important for Fusarium fujikuroi Secondary Metabolism and Virulence

Studt

Schmidt

Jahn

et al. 2013

Appl Environ Microbiol

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Histone modifications are crucial for the regulation of secondary metabolism in various filamentous fungi. Here we studied the involvement of histone deacetylases (HDACs) in secondary metabolism in the phytopathogenic fungus Fusarium fujikuroi, a known producer of several secondary metabolites, including phytohormones, pigments, and mycotoxins. Deletion of three Zn 2؉ -dependent HDAC-encoding genes, ffhda1, ffhda2, and ffhda4, indicated that FfHda1 and FfHda2 regulate secondary metabolism, whereas FfHda4 is involved in developmental processes but is dispensable for secondary-metabolite production in F. fujikuroi. Single deletions of ffhda1 and ffhda2 resulted not only in an increase or decrease but also in derepression of metabolite biosynthesis under normally repressing conditions. Moreover, double deletion of both the ffhda1 and ffhda2 genes showed additive but also distinct phenotypes with regard to secondary-metabolite biosynthesis, and both genes are required for gibberellic acid (GA)-induced bakanae disease on the preferred host plant rice, as ⌬ffhda1 ⌬ffhda2 mutants resemble the uninfected control plant. Microarray analysis with a ⌬ffhda1 mutant that has lost the major HDAC revealed differential expression of secondarymetabolite gene clusters, which was subsequently verified by a combination of chemical and biological approaches. These results indicate that HDACs are involved not only in gene silencing but also in the activation of some genes. Chromatin immunoprecipitation with the ⌬ffhda1 mutant revealed significant alterations in the acetylation state of secondary-metabolite gene clusters compared to the wild type, thereby providing insights into the regulatory mechanism at the chromatin level. Altogether, manipulation of HDAC-encoding genes constitutes a powerful tool to control secondary metabolism in filamentous fungi.

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Section: Discussionsupporting

confidence: 72%

Two Histone Deacetylases, FfHda1 and FfHda2, Are Important for Fusarium fujikuroi Secondary Metabolism and Virulence

Studt

Schmidt

Jahn

et al. 2013

Appl Environ Microbiol

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“…Lp1), synthesize lysergic acid-based alkaloids in which the D ring of the ergoline nucleus is unsaturated between carbons 9 and 10 and carbon 17 is highly oxidized (Fig. 1) (4,10,11). Ergot alkaloidproducing fungi in the Trichocomaceae, such as the opportunistic human pathogen Aspergillus fumigatus, produce clavine-based derivatives in which the D ring is saturated and carbon 17 remains reduced as a methyl group (12,13).…”

mentioning

confidence: 99%

“…All known genes involved in ergot alkaloid synthesis (eas genes) in both A. fumigatus and the Clavicipitaceae have been found in clusters (Fig. 2) (11,(18)(19)(20)(21)(22)(23)(24). The roles of many genes in eas clusters have been determined by gene knockout or by expression of coding sequences in Escherichia coli.…”

mentioning

confidence: 99%

Heterologous Expression of Lysergic Acid and Novel Ergot Alkaloids in Aspergillus fumigatus

Robinson

Panaccione

2014

Appl Environ Microbiol

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Different lineages of fungi produce distinct classes of ergot alkaloids. Lysergic acid-derived ergot alkaloids produced by fungi in the Clavicipitaceae are particularly important in agriculture and medicine. The pathway to lysergic acid is partly elucidated, but the gene encoding the enzyme that oxidizes the intermediate agroclavine is unknown. We investigated two candidate agroclavine oxidase genes from the fungus Epichloë festucae var. lolii ؋ Epichloë typhina isolate Lp1 (henceforth referred to as Epichloë sp. Lp1), which produces lysergic acid-derived ergot alkaloids. Candidate genes easH and cloA were expressed in a mutant strain of the mold Aspergillus fumigatus, which typically produces a subclass of ergot alkaloids not derived from agroclavine or lysergic acid. Candidate genes were coexpressed with the Epichloë sp. Lp1 allele of easA, which encodes an enzyme that catalyzed the synthesis of agroclavine from an A. fumigatus intermediate; the agroclavine then served as the substrate for the candidate agroclavine oxidases. Strains expressing easA and cloA from Epichloë sp. Lp1 produced lysergic acid from agroclavine, a process requiring a cumulative six-electron oxidation and a double-bond isomerization. Strains that accumulated excess agroclavine (as a result of Epichloë sp. Lp1 easA expression in the absence of cloA) metabolized it into two novel ergot alkaloids for which provisional structures were proposed on the basis of mass spectra and precursor feeding studies. Our data indicate that CloA catalyzes multiple reactions to produce lysergic acid from agroclavine and that combining genes from different ergot alkaloid pathways provides an effective strategy to engineer important pathway molecules and novel ergot alkaloids.

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“…It was shown that the "phosphate" effect acts on transcriptional level; i.e., expression of EAS genes is induced by lowering the phosphate level [ 58 ]. Lorenz et al [ 59 ] presented evidence that epigenetic processes are involved in EAS gene regulation: Inhibitors of histone acetyl transferases induced EAS under non-inducing conditions in strain P1. This leads to the assumption that overexpression of histone deacetylases could overrule the inhibiting effect mediated by histone acetyl transferases.…”

Section: Biosynthesis and Molecular Genetics Of Ergot Alkaloidsmentioning

confidence: 99%