Brevetoxin-2, is a unique inhibitor of the C-terminal redox center of mammalian thioredoxin reductase-1

Toxicol Appl Pharmacol. 2017 Aug 15;329:58-66. doi: 10.1016/j.taap.2017.05.027. Epub 2017 May 25.

Abstract

Karenia brevis, the Florida red tide dinoflagellate produces a suite of neurotoxins known as the brevetoxins. The most abundant of the brevetoxins PbTx-2, was found to inhibit the thioredoxin-thioredoxin reductase system, whereas the PbTx-3 has no effect on this system. On the other hand, PbTx-2 activates the reduction of small disulfides such as 5,5'-dithio-bis-(2-nitrobenzoic acid) by thioredoxin reductase. PbTx-2 has an α, β-unsaturated aldehyde moiety which functions as an efficient electrophile and selenocysteine conjugates are readily formed. PbTx-2 blocks the inhibition of TrxR by the inhibitor curcumin, whereas curcumin blocks PbTx-2 activation of TrxR. It is proposed that the mechanism of inhibition of thioredoxin reduction is via the formation of a Michael adduct between selenocysteine and the α, β-unsaturated aldehyde moiety of PbTx-2. PbTx-2 had no effect on the rates of reactions catalyzed by related enzymes such as glutathione reductase, glutathione peroxidase or glutaredoxin.

Keywords: Brevetoxin; Karenia brevis; Thioredoxin; Thioredoxin reductase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Curcumin / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / toxicity*
  • Humans
  • Lipid Peroxidation / drug effects
  • Marine Toxins / toxicity*
  • Oxidation-Reduction
  • Oxocins / toxicity*
  • Protein Domains
  • Rats
  • Selenocysteine
  • Thioredoxin Reductase 1 / antagonists & inhibitors*
  • Thioredoxin Reductase 1 / chemistry
  • Thioredoxin Reductase 1 / metabolism
  • Time Factors

Substances

  • Enzyme Inhibitors
  • Marine Toxins
  • Oxocins
  • brevetoxin 2
  • Selenocysteine
  • TXNRD1 protein, human
  • Thioredoxin Reductase 1
  • Txnrd1 protein, rat
  • Curcumin