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

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Pyruvaldehyde
Isoprostanes
Glyoxal
Metabolism
Prostaglandins
Dinoprost
Poisons
Parasites
Prostaglandin H2
Chagas Disease
Trypanosoma cruzi
Prostaglandin-Endoperoxide Synthases
Arachidonic Acid
Nifurtimox
Pharmaceutical Preparations
African Trypanosomiasis
Leishmania donovani
Cutaneous Leishmaniasis
Visceral Leishmaniasis
Lipid Peroxides

Keywords

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

Cite this

@article{52e6e5a877f7496b867d610367b6b603,
title = "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 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.",
keywords = "Prostaglandin, isoprostane, parasite metabolism, Trypanosoma brucei, Trypanosoma cruzi, Leishmania, enzyme kinetics, ketoaldehydes, drug metabolism, benznidazole",
author = "Adam Roberts and Joanne Dunne and Stanley Scullion and Suzanne Norval and Alan Fairlamb",
note = "This work was supported by a grant from the Welcome Trust (079838) with additional co-funding from the Wellcome Trust / Bill and Melinda Gates Foundation (OPP1066891)",
year = "2018",
month = "8",
day = "29",
doi = "10.1042/BCJ20180232",
language = "English",
volume = "475",
pages = "2593--2610",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press",
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TY - JOUR

T1 - A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism

AU - Roberts, Adam

AU - Dunne, Joanne

AU - Scullion, Stanley

AU - Norval, Suzanne

AU - Fairlamb, Alan

N1 - This work was supported by a grant from the Welcome Trust (079838) with additional co-funding from the Wellcome Trust / Bill and Melinda Gates Foundation (OPP1066891)

PY - 2018/8/29

Y1 - 2018/8/29

N2 - 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.

AB - 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.

KW - Prostaglandin

KW - isoprostane

KW - parasite metabolism

KW - Trypanosoma brucei

KW - Trypanosoma cruzi

KW - Leishmania

KW - enzyme kinetics

KW - ketoaldehydes

KW - drug metabolism

KW - benznidazole

U2 - 10.1042/BCJ20180232

DO - 10.1042/BCJ20180232

M3 - Article

VL - 475

SP - 2593

EP - 2610

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 16

ER -