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.
authors: School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM, St. Andrews, Fife, Scotland KY16 9ST, UK.
authors: Linna
authors: L
authors: Zhou
authors: Hironori
authors: H
authors: Ishizaki
authors: Michaela
authors: M
authors: Spitzer
authors: Kerrie L
authors: KL
authors: Taylor
authors: Nicholas D
authors: ND
authors: Temperley
authors: Stephen L
authors: SL
authors: Johnson
authors: Paul
authors: P
authors: Brear
authors: Philippe
authors: P
authors: Gautier
authors: Zhiqiang
authors: Z
authors: Zeng
authors: Amy
authors: A
authors: Mitchell
authors: Vikram
authors: V
authors: Narayan
authors: Ewan M
authors: EM
authors: McNeil
authors: David W
authors: DW
authors: Melton
authors: Terry K
authors: TK
authors: Smith
authors: Mike
authors: M
authors: Tyers
authors: Nicholas J
authors: NJ
authors: Westwood
authors: E Elizabeth
authors: EE
authors: Patton
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008544:Melanocytes / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D009581:Nitrofurans / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D015027:Zebrafish / Q000196:embryology
chemical_list: D009581:Nitrofurans; D011994:Recombinant Proteins; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial