ALDH2 mediates 5-nitrofuran activity in multiple species

Linna Zhou, Hironori Ishizaki, Michaela Spitzer, Kerrie L Taylor, Nicholas D Temperley, Stephen L Johnson, Paul Brear, Philippe Gautier, Zhiqiang Zeng, Amy Mitchell, Vikram Narayan, Ewan M McNeil, David W Melton, Terry K. Smith, Mike Tyers, Nicholas J Westwood, E Elizabeth Patton

    Research output: Contribution to journalArticle

    23 Citations (Scopus)

    Abstract

    Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of prodrugs widely used to treat bacterial and trypanosome infections, but despite relative specificity, 5-nitrofurans often cause serious toxic side effects in people. Here, we use yeast and zebrafish, as well as human in vitro systems, to assess the biological activity of 5-nitrofurans, and we identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5-nitrofuran anti-trypanosome prodrug, is dependent on zebrafish Aldh2 and is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5-nitrofuran treatment.
    Original languageEnglish
    Pages (from-to)883-892
    Number of pages10
    JournalChemistry & Biology
    Volume19
    Issue number7
    DOIs
    Publication statusPublished - 27 Jul 2012

    Fingerprint

    Nitrofurans
    Trypanosomiasis
    Prodrugs
    Zebrafish
    Nifurtimox
    Pharmaceutical Preparations
    Aldehyde Dehydrogenase
    Poisons
    Drug Design
    Bioactivity
    Bacterial Infections
    Yeast
    Toxicity
    Yeasts
    Substrates

    Cite this

    Zhou, L., Ishizaki, H., Spitzer, M., Taylor, K. L., Temperley, N. D., Johnson, S. L., ... Patton, E. E. (2012). ALDH2 mediates 5-nitrofuran activity in multiple species. Chemistry & Biology, 19(7), 883-892. https://doi.org/10.1016/j.chembiol.2012.05.017
    Zhou, Linna ; Ishizaki, Hironori ; Spitzer, Michaela ; Taylor, Kerrie L ; Temperley, Nicholas D ; Johnson, Stephen L ; Brear, Paul ; Gautier, Philippe ; Zeng, Zhiqiang ; Mitchell, Amy ; Narayan, Vikram ; McNeil, Ewan M ; Melton, David W ; Smith, Terry K. ; Tyers, Mike ; Westwood, Nicholas J ; Patton, E Elizabeth. / ALDH2 mediates 5-nitrofuran activity in multiple species. In: Chemistry & Biology. 2012 ; Vol. 19, No. 7. pp. 883-892.
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    abstract = "Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of prodrugs widely used to treat bacterial and trypanosome infections, but despite relative specificity, 5-nitrofurans often cause serious toxic side effects in people. Here, we use yeast and zebrafish, as well as human in vitro systems, to assess the biological activity of 5-nitrofurans, and we identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5-nitrofuran anti-trypanosome prodrug, is dependent on zebrafish Aldh2 and is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5-nitrofuran treatment.",
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    Zhou, L, Ishizaki, H, Spitzer, M, Taylor, KL, Temperley, ND, Johnson, SL, Brear, P, Gautier, P, Zeng, Z, Mitchell, A, Narayan, V, McNeil, EM, Melton, DW, Smith, TK, Tyers, M, Westwood, NJ & Patton, EE 2012, 'ALDH2 mediates 5-nitrofuran activity in multiple species', Chemistry & Biology, vol. 19, no. 7, pp. 883-892. https://doi.org/10.1016/j.chembiol.2012.05.017

    ALDH2 mediates 5-nitrofuran activity in multiple species. / Zhou, Linna; Ishizaki, Hironori; Spitzer, Michaela; Taylor, Kerrie L; Temperley, Nicholas D; Johnson, Stephen L; Brear, Paul; Gautier, Philippe; Zeng, Zhiqiang; Mitchell, Amy; Narayan, Vikram; McNeil, Ewan M; Melton, David W; Smith, Terry K.; Tyers, Mike; Westwood, Nicholas J; Patton, E Elizabeth.

    In: Chemistry & Biology, Vol. 19, No. 7, 27.07.2012, p. 883-892.

    Research output: Contribution to journalArticle

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    T1 - ALDH2 mediates 5-nitrofuran activity in multiple species

    AU - Zhou, Linna

    AU - Ishizaki, Hironori

    AU - Spitzer, Michaela

    AU - Taylor, Kerrie L

    AU - Temperley, Nicholas D

    AU - Johnson, Stephen L

    AU - Brear, Paul

    AU - Gautier, Philippe

    AU - Zeng, Zhiqiang

    AU - Mitchell, Amy

    AU - Narayan, Vikram

    AU - McNeil, Ewan M

    AU - Melton, David W

    AU - Smith, Terry K.

    AU - Tyers, Mike

    AU - Westwood, Nicholas J

    AU - Patton, E Elizabeth

    N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.

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    N2 - Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of prodrugs widely used to treat bacterial and trypanosome infections, but despite relative specificity, 5-nitrofurans often cause serious toxic side effects in people. Here, we use yeast and zebrafish, as well as human in vitro systems, to assess the biological activity of 5-nitrofurans, and we identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5-nitrofuran anti-trypanosome prodrug, is dependent on zebrafish Aldh2 and is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5-nitrofuran treatment.

    AB - Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of prodrugs widely used to treat bacterial and trypanosome infections, but despite relative specificity, 5-nitrofurans often cause serious toxic side effects in people. Here, we use yeast and zebrafish, as well as human in vitro systems, to assess the biological activity of 5-nitrofurans, and we identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5-nitrofuran anti-trypanosome prodrug, is dependent on zebrafish Aldh2 and is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5-nitrofuran treatment.

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    VL - 19

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    EP - 892

    JO - Chemistry & Biology

    JF - Chemistry & Biology

    SN - 1074-5521

    IS - 7

    ER -

    Zhou L, Ishizaki H, Spitzer M, Taylor KL, Temperley ND, Johnson SL et al. ALDH2 mediates 5-nitrofuran activity in multiple species. Chemistry & Biology. 2012 Jul 27;19(7):883-892. https://doi.org/10.1016/j.chembiol.2012.05.017