ReferenceID 3847
Interaction of adenanthin with glutathione and thiol enzymes: selectivity for thioredoxin reductase and inhibition of peroxiredoxin recycling
Free Radic Biol Med
The diterpenoid, adenanthin, represses tumor growth and prolongs survival in mouse promyelocytic leukemia models (Liu et al., Nat. Chem. Biol. 8, 486, 2012). It was proposed that this was done by inactivating peroxiredo
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- Reference Id
- 3847
- Evidence Id
- 20437
- Core Evidence Id
- 20437
- Source Reference Id
- 973
- Herb2 Reference Id
- HBREF001684
- Subject Paper Key
- HBIN014672_25289458
- Pubmed Id
- 25289458
- Doi
- 10.1016/j.freeradbiomed.2014.09.025
- Paper Title
- Interaction of adenanthin with glutathione and thiol enzymes: selectivity for thioredoxin reductase and inhibition of peroxiredoxin recycling
- Paper Abstract
- The diterpenoid, adenanthin, represses tumor growth and prolongs survival in mouse promyelocytic leukemia models (Liu et al., Nat. Chem. Biol. 8, 486, 2012). It was proposed that this was done by inactivating peroxiredoxins (Prxs) 1 and 2 through the formation of an adduct specifically on the resolving Cys residue. We confirmed that adenanthin underwent Michael addition to isolated Prx2, thereby inhibiting oxidation to a disulfide-linked dimer. However, contrary to the original report, both the peroxidatic and the resolving Cys residues could be derivatized. Glutathione also formed an adenanthin adduct, reacting with a second-order rate constant of 25±5 M(-1) s(-1). With 50 M adenanthin, the peroxidatic and resolving Cys of Prx2 reacted with half-times of 7 and 40 min, respectively, compared with 10 min for GSH. When erythrocytes or Jurkat T cells were treated with adenanthin, we saw no evidence for a reaction with Prxs 1 or 2. Instead, adenanthin caused time- and concentration-dependent loss of GSH followed by dimerization of the Prxs. Prxs undergo continuous oxidation in cells and are normally recycled by thioredoxin reductase and thioredoxin. Our results indicate that Prx reduction was inhibited. We observed rapid inhibition of purified thioredoxin reductase (half-time 5 min with 2 M adenanthin) and in cells, thioredoxin reductase was much more sensitive than GSH and loss of both preceded accumulation of oxidized Prxs. Thus, adenanthin is not a specific Prx inhibitor, and its reported antitumor and anti-inflammatory effects are more likely to involve more general inhibition of thioredoxin and/or glutathione redox pathways.
- Journal
- Free Radic Biol Med
- Publish Year
- 2014
- Experiment Subject
- rythrocytes or jurkat t cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Interaction of adenanthin with glutathione and thiol enzymes: selectivity for thioredoxin reductase and inhibition of peroxiredoxin recycling
- Bilingual Status
- semi_complete