ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species
- Authors
- 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., and Patton, E.E.
- ID
- ZDB-PUB-120802-7
- Date
- 2012
- Source
- Chemistry & Biology 19(7): 883-892 (Journal)
- Registered Authors
- Johnson, Stephen L., Patton, E. Elizabeth, Zeng, Zhiqiang
- Keywords
- none
- MeSH Terms
-
- Aldehyde Dehydrogenase/metabolism*
- Animals
- Dose-Response Relationship, Drug
- Humans
- Melanocytes/drug effects*
- Models, Molecular
- Molecular Structure
- Nitrofurans/chemistry
- Nitrofurans/pharmacology*
- Recombinant Proteins/metabolism
- Saccharomyces cerevisiae/drug effects*
- Saccharomyces cerevisiae/metabolism
- Species Specificity
- Structure-Activity Relationship
- Zebrafish/embryology
- PubMed
- 22840776 Full text @ Chem. Biol.
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.