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Volume 167, Issue 11

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

Abstract

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 is emerging. Expression of some genes of the GT biosynthetic gene cluster 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 , dithiol gliotoxin (DTG), which has zinc-chelating properties, is converted to either GT or -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 ,,′,′-tetrakis(2-pyridinylmethyl)−1,2-ethanediamine (TPEN) inhibit ΔΔ 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 wild-type (at >5 µM zinc) and Δ (at >1 µM zinc) in a low-iron medium. TAFC secretion suggests that differential zinc-sensing between both strains may influence fungal Fe 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 Δ 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 .

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): BGC , fungal drug targets , gliotoxin , nutritional immunity , quantitative proteomics and zinc
Funding
This study was supported by the:
  • Science Foundation Ireland (Award Infrastructure Award 12/RI/2346(3))
    • Principle Award Recipient: SeanDoyle
  • National University of Ireland, Maynooth (Award John and Pat Hume Scholarship)
    • Principle Award Recipient: AimeeM. Traynor
  • Ministerio de Ciencia e Innovación (Award PID2019-110994RB-I00)
    • Principle Award Recipient: JoséA. Calera
© 2021 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2021-11-05
2024-04-26
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At the metal–metabolite interface in Aspergillus fumigatus: towards untangling the intersecting roles of zinc and gliotoxin
Microbiology 167, 001106 (2021); https://doi.org/10.1099/mic.0.001106
/content/journal/micro/10.1099/mic.0.001106
/content/journal/micro/10.1099/mic.0.001106
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