ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species
| Autor: | Mike Tyers, E. Elizabeth Patton, Stephen L. Johnson, Amy Mitchell, Nicholas D Temperley, Linna Zhou, Zhiqiang Zeng, Vikram Narayan, Hironori Ishizaki, Philippe Gautier, Michaela Spitzer, Terry K. Smith, Paul Brear, Kerrie L. Taylor, Ewan M. McNeil, Nicholas J. Westwood, David W. Melton |
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| Přispěvatelé: | University of St Andrews. School of Chemistry, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. School of Biology, University of St Andrews. EaSTCHEM |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Nitrofurans Clinical Biochemistry Aldehyde dehydrogenase Pharmacology Biochemistry 0302 clinical medicine Drug Discovery QD Nitrofuran Zebrafish media_common 0303 health sciences Molecular Structure Aldehyde Dehydrogenase Mitochondrial 030302 biochemistry & molecular biology Biological activity General Medicine Prodrug Recombinant Proteins 3. Good health 030220 oncology & carcinogenesis Melanocytes Molecular Medicine medicine.drug Drug medicine.drug_class media_common.quotation_subject Saccharomyces cerevisiae Biology Article 03 medical and health sciences Structure-Activity Relationship Species Specificity medicine Animals Humans Nifurtimox Molecular Biology 030304 developmental biology ALDH2 Dose-Response Relationship Drug Correction Aldehyde Dehydrogenase biology.organism_classification QD Chemistry biology.protein |
| Zdroj: | 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 and Biology, vol. 19, no. 7, pp. 883-892 . https://doi.org/10.1016/j.chembiol.2012.05.017 Chemistry & Biology Cell Chemical Biology Zhou, L, Ishizaki, H, Spitzer, M, Marie, 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 and Biology, vol. 19, no. 7, pp. 883-892 . https://doi.org/10.1016/j.chembiol.2012.05.017 |
| Popis: | Summary 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. Graphical Abstract Highlights ► Zebrafish provide a viable assay for the biological toxicity of 5-nitrofurans ► ALDH2 inhibitors prevent 5-nitrofuran toxicity in zebrafish and yeast ► Genetic dependence on ALDH2 for 5-nitrofuran toxicity in zebrafish and yeast systems ► 5-Nitrofurans bind to and are substrates of human ALDH2 5-nitrofurans are antibiotics activated by pathogen specific enzymes, however, less is known about what happens in the host. Zhou et al. identify aldehyde dehydrogenase 2 as a 5-nitrofuran activating enzyme that has implications for managing some of the toxicity associated with 5-nitrofuran treatment. |
| Databáze: | OpenAIRE |
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