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ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species.

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

School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM, St. Andrews, Fife, Scotland KY16 9ST, UK.

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.

Chem. Biol. 2012;19(7):883-92.

Pubmed ID: 22840776

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