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

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 the 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 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 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.

• Authors: Adam J Roberts, Joanne Dunne, Paul Scullion, Suzanne Norval, Alan H Fairlamb
• Journal: The Biochemical journal (Biochem J) Vol. 475 Issue 16 Pg. 2593-2610 (08 30 2018) ISSN: 1470-8728 [Electronic] England
• PMID: 30045874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Author(s).

Chemical References

• Isoprostanes
• Protozoan Proteins
• 8-epi-prostaglandin F2alpha
• Pyruvaldehyde
• Dinoprost
• Aldo-Keto Reductases

Topics

• Aldo-Keto Reductases (genetics, metabolism)
• Dinoprost (analogs & derivatives, genetics, metabolism)
• Isoprostanes (genetics, metabolism)
• Leishmania donovani (genetics, metabolism)
• Protozoan Proteins (genetics, metabolism)
• Pyruvaldehyde (metabolism)
• Trypanosoma brucei brucei (genetics, metabolism)
• Trypanosoma cruzi (genetics, metabolism)