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

• Published in: Toxicology and applied pharmacology Vol. 329; pp. 58 - 66
• Main Authors: Chen, Wei, Tuladhar, Anupama, Rolle, Shantelle, Lai, Yanhao, Rodriguez del Rey, Freddy, Zavala, Cristian E., Liu, Yuan, Rein, Kathleen S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2017
• Subjects: Animals; Brevetoxin; Cell Line; Cell Survival - drug effects; Curcumin - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - toxicity; Humans; Karenia brevis; Lipid Peroxidation - drug effects; Marine Toxins - toxicity; Oxidation-Reduction; Oxocins - toxicity; Protein Domains; Rats; Selenocysteine; Thioredoxin; Thioredoxin reductase; Thioredoxin Reductase 1 - antagonists & inhibitors; Thioredoxin Reductase 1 - chemistry; Thioredoxin Reductase 1 - metabolism; Time Factors; DTNB; FAD; SOD; IAC; SNAr; GR; Thioredoxin; Grx; Thioredoxin reductase; Karenia brevis; GPx; Brevetoxin; BSA; FT-ICR; HRMS; PbTx; ROS; ESI; Sec or U; Trx; TCEP; TrxR
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2017.05.027

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. [Display omitted] •Brevetoxin (PbTx-2) inhibits thioredoxin reduction by thioredoxin reductase.•Brevetoxin (PbTx-2) activates DTNB reduction by thioredoxin reductase.•Brevetoxin (PbTx-2) reacts with the active site selenocysteine of thioredoxin reductase.•Brevetoxin (PbTx-2) competes with curcumin for the active site of thioredoxin reductase.