A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism

Adam Roberts, Joanne Dunne, Stanley Scullion, Suzanne Norval, Alan Fairlamb (Lead / Corresponding author)

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Abstract

Trypanosomatid parasites are the infectious agents causing Chagas’ disease, visceral and cutaneous leishmaniasis and human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in susceptibility and resistance of Trypanosoma cruzi to benznidazole, a drug used to treat Chagas’ disease. Here we show that TcAKR and homologues in the related parasites T. brucei and Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox, fexinidazole) or bicyclic nitro-drugs such as PA824. 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 bio-activation 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 removal of toxic glyoxal. In addition, three of the four enzymes studied here display activity as prostaglandin F2α 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 F2α and 8-iso-prostaglandin F2α.
Original languageEnglish
Pages (from-to)2593-2610
Number of pages18
JournalBiochemical Journal
Volume475
Issue number16
Early online date25 Jul 2018
DOIs
Publication statusPublished - 29 Aug 2018

Keywords

  • Prostaglandin
  • isoprostane
  • parasite metabolism
  • Trypanosoma brucei
  • Trypanosoma cruzi
  • Leishmania
  • enzyme kinetics
  • ketoaldehydes
  • drug metabolism
  • benznidazole

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