Gliotoxin inactivates alcohol dehydrogenase by either covalent modification or free radical damage mediated by redox cycling

Biochemical Pharmacology
P WaringQ H Lin

Abstract

The fungal metabolite gliotoxin shows selective toxicity to cells of the immune system and has been implicated in the aetiology of invasive aspergillosis. The related toxin sporidesmin is the causative agent of facial eczema in sheep. The toxicity of these compounds has been related to their ability to redox cycle intracellularly and thus produce damaging free radicals. These toxins are also potentially capable of forming mixed disulphides with thiol groups on proteins by virtue of their bridged disulphide structure. We show here that gliotoxin can inactivate horse liver alcohol dehydrogenase by either oxidative damage or covalent modification of thiol groups on the enzyme. Either Cys-281 or Cys-282 is selectively modified. Neither of these residues are at the active site. Covalent modification occurs in the absence of reducing agents such as dithiothreitol. In the presence of dithiothreitol no protection is observed and the rate of inactivation is enhanced although as expected no covalent modification occurs. Gliotoxin can therefore inhibit alcohol dehydrogenase by either pathway and this will depend on the availability of reducing agents such as glutathione and/or how readily the reactive oxygen species generated are removed.

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Citations

Sep 1, 2011·Analytical and Bioanalytical Chemistry·Carol DavisSean Doyle
Mar 10, 2006·Cell Biology and Toxicology·V AxelssonA Forsby
Aug 7, 2003·Toxicology and Applied Pharmacology·Katherine L MoermanPaul Waring
Dec 1, 1996·General Pharmacology·P Waring, J Beaver
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Jun 6, 2009·Antioxidants & Redox Signaling·Georg T Wondrak
Jul 15, 2009·Clinical Microbiology Reviews·Taylor R T Dagenais, Nancy P Keller
Oct 22, 2005·The Journal of Clinical Investigation·Stefan Fichtner-FeiglAtsushi Kitani
Mar 13, 2012·Fungal Genetics and Biology : FG & B·Stephen CarberrySean Doyle
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Oct 8, 2015·Environmental Microbiology·Daniel H ScharfPrasun K Mukherjee
Jun 5, 2007·Biochemical and Biophysical Research Communications·Hee Shim ChoiHo Jeong Kwon
Jan 21, 2015·Frontiers in Microbiology·Kevin J SheridanSean Doyle
Feb 3, 2006·Journal of Microbiological Methods·Olivier GrovelYves-François Pouchus
Oct 26, 2012·Chembiochem : a European Journal of Chemical Biology·Bo LiChristopher T Walsh
Mar 13, 2014·Angewandte Chemie·Tynchtyk Amatov, Ullrich Jahn
Aug 30, 2003·The Journal of Biological Chemistry·Paul H BernardoPaul Waring
Aug 6, 2013·Chemical Science·Nicolas BoyerMohammad Movassaghi
Nov 18, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yen-Chih ChenNiels Ringstad
Apr 29, 2021·Angewandte Chemie·Kirstin ScherlachEva M Huber
Apr 5, 2017·Chemical Reviews·Abraham J WaldmanEmily P Balskus
Jul 26, 2014·Journal of the American Chemical Society·Daniel H ScharfChristian Hertweck

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