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Here, we show that TcAKR and homologues in the related parasites Trypanosoma brucei and Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox and fexinidazole) or bicyclic nitro-drugs such as PA-824. Rather, these enzymes metabolise a variety of toxic ketoaldehydes, such as glyoxal and methylglyoxal, suggesting a role in cellular defence against chemical stress. UPLC-QToF\/MS analysis of benznidazole bioactivation by T. cruzi cell lysates confirms previous reports identifying numerous drug metabolites, including a dihydro-dihydroxy intermediate that can dissociate to form N-benzyl-2-guanidinoacetamide and glyoxal, a toxic DNA-glycating and cross-linking agent. Thus, we propose that TcAKR contributes to benznidazole resistance by the removal of toxic glyoxal. In addition, three of the four enzymes studied here display activity as prostaglandin F2\u03b1 synthases, despite the fact that there are no credible cyclooxygenases in these parasites to account for formation of the precursor PGH2 from arachidonic acid. Our studies suggest that arachidonic acid is first converted non-enzymatically in parasite lysates to (PGH2-like) regioisomers by free radical-mediated peroxidation and that AKRs convert these lipid peroxides into isoprostanes, including prostaglandin F2\u03b1 and 8-iso-prostaglandin F2\u03b1.<\/jats:p>","DOI":"10.1042\/bcj20180232","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T16:54:42Z","timestamp":1532537682000},"page":"2593-2610","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism"],"prefix":"10.1042","volume":"475","author":[{"given":"Adam J.","family":"Roberts","sequence":"first","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Dunne","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Scullion","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne","family":"Norval","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5134-0329","authenticated-orcid":false,"given":"Alan H.","family":"Fairlamb","sequence":"additional","affiliation":[{"name":"Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,8,29]]},"reference":[{"key":"2021112216543053500_BCJ-2018-0232C1","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1172\/JCI33945","article-title":"Kinetoplastids: related protozoan pathogens, different diseases","volume":"118","author":"Stuart","year":"2008","journal-title":"J. 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