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

doi:10.1016/j.chembiol.2012.05.017

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 journal › Article › peer-review

45 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 language	English
Pages (from-to)	883-892
Number of pages	10
Journal	Chemistry & Biology
Volume	19
Issue number	7
DOIs	https://doi.org/10.1016/j.chembiol.2012.05.017
Publication status	Published - 27 Jul 2012

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10.1016/j.chembiol.2012.05.017

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Zhou, L., Ishizaki, H., Spitzer, M., Taylor, K. L., Temperley, N. D., Johnson, S. L., Brear, P., Gautier, P., Zeng, Z., Mitchell, A., Narayan, V., McNeil, E. M., Melton, D. W., Smith, T. K., Tyers, M., Westwood, N. J., & 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

@article{6ac9dffd31ca405da0ac93b452918d71,

title = "ALDH2 mediates 5-nitrofuran activity in multiple species",

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.",

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

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doi = "10.1016/j.chembiol.2012.05.017",

language = "English",

volume = "19",

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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

PY - 2012/7/27

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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.

U2 - 10.1016/j.chembiol.2012.05.017

DO - 10.1016/j.chembiol.2012.05.017

M3 - Article

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SN - 1074-5521

VL - 19

SP - 883

EP - 892

JO - Chemistry & Biology

JF - Chemistry & Biology

IS - 7

ER -

ALDH2 mediates 5-nitrofuran activity in multiple species

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