Dual effectiveness of Alternaria but not Fusarium mycotoxins against human topoisomerase II and bacterial gyrase.
Type II DNA-topoisomerases (topo II) play a crucial role in the maintenance of DNA topology. Previously, fungi of the Alternaria genus were found to produce mycotoxins that target human topo II. These results implied the question why a fungus should produce secondary metabolites that target a human enzyme. In the current work, the homology between human topo II and its bacterial equivalent, gyrase, served as basis to study a potential dual inhibition of both enzymes by mycotoxins. A total of 15 secondary metabolites produced by fungi of the genera Alternaria and Fusarium were assessed for their impact on topo II of human and bacterial origin in the decatenation and the supercoiling assay, respectively. In line with the theory of dual topo II inhibition, six of the tested Alternaria mycotoxins were active against both enzymes, the dibenzo-α-pyrones alternariol (AOH) and alternariol monomethyl ether (AME), as well as the perylene-quinones altertoxin I (ATX I) and II (ATX II), alterperylenol (ALP) and stemphyltoxin III (STTX III). The Alternaria metabolites altersetin (ALN), macrosporin (MAC), altenusine (ALS) and pyrenophorol (PYR) impaired the function of human topo II, but did not show any effect on gyrase. The potency to inhibit topo II activity declined in the row STTX III (initial inhibitory concentration 10 µM) > AOH (25 µM) = AME (25 µM) = ALS (25 µM) = ATX II (25 µM) > ALN (50 µM) = ATX I (50 µM) > ALP (75 µM) = PYR (75 µM) > MAC (150 µM). Inhibition of gyrase activity was most pronounced for AOH and AME (initial inhibitory concentration 10 µM) followed by ATX II (25 µM) > ATX I = ALP = STTX III (50 µM). In contrast, none of the investigated Fusarium mycotoxins deoxynivalenol (DON), fumonisin B1, fusarin C and moniliformin, as well as the Alternaria metabolite tentoxin, had any impact on the activity of neither human nor bacterial topo II.
Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, 1090, Vienna, Austria.
Katharina
K
Jarolim
Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, 1090, Vienna, Austria.
Giorgia
G
Del Favero
Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354, Freising, Germany.
Doris
D
Ellmer
Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354, Freising, Germany.
Timo D
TD
Stark
Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, 85354, Freising, Germany.
Thomas
T
Hofmann
Department IFA-Tulln, University of Natural Resources and Life Sciences Vienna (BOKU), 3430, Tulln, Austria.
Michael
M
Sulyok
Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, 48149, Münster, Germany.
Hans-Ulrich
HU
Humpf
Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, 1090, Vienna, Austria. doris.marko@univie.ac.at.
Doris
http://orcid.org/0000-0001-6568-2944
D
Marko
D000528:Alternaria / Q000378:metabolism*; D027081:DNA Gyrase / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005670:Fusarium / Q000378:metabolism*; D006801:Humans; D009183:Mycotoxins / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D064210:Secondary Metabolism; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*
D009183:Mycotoxins; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II
Alternaria; Fusarium; Gyrase; Mycotoxins; Topoisomerase II
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