Involvement of Sulfur in the Biosynthesis of Essential Metabolites in Pathogenic Fungi of Animals, Particularly Aspergillus spp.: Molecular and Therapeutic Implications

Traynor, Aimee M; Sheridan, Kevin J.; Jones, Gary W.; Calera, José Antonio; Doyle, Seán

doi:10.3389/fmicb.2019.02859

Cited by 32 publications

(30 citation statements)

References 90 publications

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“…This leads to depletion of intracellular GSH in animal cells, which itself can result in redox stress, or reactive oxygen species (ROS) [2] production. Secondly, and of equivalent or possibly greater relevance, is that this disulphide cleavage event results in the sudden intracellular presence of a zinc chelator, DTG, which can both chelate intracellular zinc and eject it from cellular zinc-metalloenzymes [3] – potentially disrupting intracellular zinc homeostasis and resulting in disrupted enzyme activity, respectively [4]. This nascent scenario, that it is DTG, rather than GT, which is the actual deleterious form of the natural product, merits serious consideration and may be related to the role of GT and related epipolythiodioxopiperazines in fungi and dithiolopyrrolones (DTPs; e.g.…”

Section: Introductionmentioning

confidence: 99%

At the metal–metabolite interface in Aspergillus fumigatus: towards untangling the intersecting roles of zinc and gliotoxin

et al. 2021

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Cryptic links between apparently unrelated metabolic systems represent potential new drug targets in fungi. Evidence of such a link between zinc and gliotoxin (GT) biosynthesis in Aspergillus fumigatus is emerging. Expression of some genes of the GT biosynthetic gene cluster gli is influenced by the zinc-dependent transcription activator ZafA, zinc may relieve GT-mediated fungal growth inhibition and, surprisingly, GT biosynthesis is influenced by zinc availability. In A. fumigatus, dithiol gliotoxin (DTG), which has zinc-chelating properties, is converted to either GT or bis-dethiobis(methylthio)gliotoxin (BmGT) by oxidoreductase GliT and methyltransferase GtmA, respectively. A double deletion mutant lacking both GliT and GtmA was previously observed to be hypersensitive to exogenous GT exposure. Here we show that compared to wild-type exposure, exogenous GT and the zinc chelator N,N,N′,N′-tetrakis(2-pyridinylmethyl)−1,2-ethanediamine (TPEN) inhibit A. fumigatus ΔgliTΔgtmA growth, specifically under zinc-limiting conditions, which can be reversed by zinc addition. While GT biosynthesis is evident in zinc-depleted medium, addition of zinc (1 µM) suppressed GT and activated BmGT production. In addition, secretion of the unferrated siderophore, triacetylfusarinine C (TAFC), was evident by A. fumigatus wild-type (at >5 µM zinc) and ΔgtmA (at >1 µM zinc) in a low-iron medium. TAFC secretion suggests that differential zinc-sensing between both strains may influence fungal Fe3+ requirement. Label-free quantitative proteomic analysis of both strains under equivalent differential zinc conditions revealed protein abundance alterations in accordance with altered metabolomic observations, in addition to increased GliT abundance in ΔgtmA at 5 µM zinc, compared to wild-type, supporting a zinc-sensing deficiency in the mutant strain. The relative abundance of a range of oxidoreductase- and secondary metabolism-related enzymes was also evident in a zinc- and strain-dependent manner. Overall, we elaborate new linkages between zinc availability, natural product biosynthesis and oxidative stress homeostasis in A. fumigatus.

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Section: Introductionmentioning

confidence: 99%

At the metal–metabolite interface in Aspergillus fumigatus: towards untangling the intersecting roles of zinc and gliotoxin

et al. 2021

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“…GT biosynthesis is linked to cellular oxidative stress in mammalian and fungal cells via a yet to be described mechanism (Davis et al, 2011;Struck et al, 2012;Amich et al, 2013;Sheridan et al, 2016;Traynor et al, 2019). In addition, GT self-protection is essential during GT biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

“…In A. fumigatus, a BGC on chromosome VI contains 13 gli genes responsible for GT biosynthesis and secretion (Dolan et al, 2015). GT biosynthesis is tightly regulated because it interferes with and depends on several cellular pathways that regulate sulfur metabolism [cysteine (Cys) and methionine (Met)], oxidative stress defenses [glutathione (GSH) and ergothioneine (EGT)], methylation [Sadenosylmethionine (SAM)], and iron metabolism (Fe-S clusters) (Davis et al,2011;Struck et al, 2012;Amich et al, 2013;Sheridan et al, 2016;Traynor et al, 2019). Regulation of GT biosynthesis involves numerous transcription factors (TFs), protein kinases, transcriptional and developmental regulators, regulators of G-protein signalling as well as chromatin modifying enzymes (Dolan et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Regulation of gliotoxin biosynthesis and protection in Aspergillus species

Castro

Moraes

Colabardini

et al. 2021

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Aspergillus fumigatus causes a range of human and animal diseases collectively known as aspergillosis. A. fumigatus possesses and expresses a range of genetic determinants of virulence, which facilitate colonisation and disease progression, including the secretion of mycotoxins. Gliotoxin (GT) is the best studied A. fumigatus mycotoxin with a wide range of known toxic effects that impair human immune cell function. GT is also highly toxic to A. fumigatus and this fungus has evolved self-protection mechanisms that include (i) the GT efflux pump GliA, (ii) the GT neutralising enzyme GliT, and (iii) the negative regulation of GT biosynthesis by the bis -thiomethyltransferase GtmA. The transcription factor (TF) RglT is the main regulator of GliT and this GT protection mechanism also occurs in the non-GT producing fungus A. nidulans . However, A. nidulans does not encode GtmA and GliA. This work aimed at analysing the transcriptional response to exogenous GT in A. fumigatus and A. nidulans , two distantly related Aspergillus species, and to identify additional components required for GT protection in Aspergillus species. RNA-sequencing shows a highly different transcriptional response to exogenous GT with the RglT-dependent regulon also significantly differing between A. fumigatus and A. nidulans . However, we were able to observe homologues whose expression pattern was similar in both species (43 RglT-independent and 12 RglT-dependent). Screening of an A. fumigatus deletion library of 484 transcription factors (TFs) for sensitivity to GT identified 15 TFs important for GT self-protection. Of these, the TF KojR, which is essential for kojic acid biosynthesis in Aspergillus oryzae , was also essential for GT biosynthesis in A. fumigatus and for GT protection in A. fumigatus , A. nidulans , and A. oryzae . KojR regulates rglT and gliT expression in Aspergillus spp. Together, this study identified conserved components required for GT protection in Aspergillus species.

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“…This A. fumigatus-specific G-rich region may contribute to some unknown gliotoxin expression pattern that contributes to A. fumigatus virulence or the lack of disease caused by other closely related Aspergillus species. metR encodes a bZIP DNA binding protein required for sulfur metabolism in A. fumigatus and whose gene expression is regulated by LaeA, a major regulator of secondary metabolism (Jain et al, 2018. Pertaining to A. fumigatus virulence, sulfur assimilation plays key roles in oxidative stress response and gliotoxin biosynthesis (Traynor et al, 2019). Recent efforts have identified differences in the transcriptional profiles of A. fumigatus and relatives in response to exogenous gliotoxin, highlighting the pathways relating sulfur assimilation and gliotoxin production (de Castro et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Extensive sequence divergence of non-coding regions between Aspergillus fumigatus, a major fungal pathogen of humans, and its relatives

Brown

Mead

Steenwyk

et al. 2021

Preprint

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Invasive aspergillosis is a deadly fungal disease; more than 400,000 patients are infected worldwide each year and the mortality rate can be as high as 50-95%. Of the ∼450 species in the genus Aspergillus only a few are known to be clinically relevant, with the major pathogen Aspergillus fumigatus being responsible for ∼50% of all invasive mold infections. Genomic comparisons of A. fumigatus to other Aspergillus species have historically focused on protein-coding regions. However, most A. fumigatus genes, including those that modulate its virulence, are also present in non-pathogenic close relatives of A. fumigatus. Our hypothesis is that differential gene regulation – mediated through the non-coding regions upstream of genes’ transcription start sites – contributes to A. fumigatus pathogenicity. To begin testing this, we compared non-coding regions up to 500 base pairs upstream of the first codon of single-copy orthologous genes from the two A. fumigatus reference strains Af293 and A1163 and eight closely related Aspergillus section Fumigati species. We found that non-coding regions showed extensive sequence variation and lack of homology across species. By examining the evolutionary rates of both protein-coding and non-coding regions in a subset of orthologous genes with highly conserved non-coding regions across the phylogeny, we identified 418 genes, including 25 genes known to modulate A. fumigatus virulence, whose non-coding regions exhibit a different rate of evolution in A. fumigatus. Examination of sequence alignments of these non-coding regions revealed numerous instances of insertions, deletions, and other types of mutations of at least a few nucleotides in A. fumigatus compared to its close relatives. These results show that closely related Aspergillus species that vary greatly in their pathogenicity exhibit extensive non-coding sequence variation and identify numerous changes in non-coding regions of A. fumigatus genes known to contribute to virulence.

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Involvement of Sulfur in the Biosynthesis of Essential Metabolites in Pathogenic Fungi of Animals, Particularly Aspergillus spp.: Molecular and Therapeutic Implications

Cited by 32 publications

References 90 publications

At the metal–metabolite interface in Aspergillus fumigatus: towards untangling the intersecting roles of zinc and gliotoxin

At the metal–metabolite interface in Aspergillus fumigatus: towards untangling the intersecting roles of zinc and gliotoxin

Regulation of gliotoxin biosynthesis and protection in Aspergillus species

Extensive sequence divergence of non-coding regions between Aspergillus fumigatus, a major fungal pathogen of humans, and its relatives

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