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Cell Chem Biol. 2019 Jan 17. pii: S2451-9456(19)30001-7. doi: 10.1016/j.chembiol.2019.01.001. [Epub ahead of print]

Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase.

Author information

1
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
2
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute (HKI), 07745 Jena, Germany.
3
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
4
Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute (HKI), 07745 Jena, Germany.
5
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute (HKI), 07745 Jena, Germany.
6
Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy.
7
Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
8
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute (HKI), 07745 Jena, Germany; Friedrich-Schiller-University Jena, 07743 Jena, Germany.
9
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute (HKI), 07745 Jena, Germany; Friedrich-Schiller-University Jena, 07743 Jena, Germany.
10
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.

Abstract

The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4H). Here, we identified gliotoxin as inhibitor of LTA4H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models. Gliotoxin failed to inhibit the formation of other eicosanoids and the aminopeptidase activity of the bifunctional LTA4H. Suppression of LTB4 formation by gliotoxin required the cellular environment and/or reducing conditions, and only the reduced form of gliotoxin inhibited LTA4H activity. Conclusively, gliotoxin suppresses the biosynthesis of the potent neutrophil chemoattractant LTB4 by direct interference with LTA4H thereby impairing neutrophil functions in invasive aspergillosis.

KEYWORDS:

Aspergillus fumigatus; gliotoxin; invasive aspergillosis; leukotriene; leukotriene A(4) hydrolase; neutrophils

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