Chen Wei, Tuladhar Anupama, Rolle Shantelle, Lai Yanhao, Rodriguez Del Rey Freddy, Zavala Cristian E, Liu Yuan, Rein Kathleen S
Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, FL 33199, United States.
Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, FL 33199, United States; Biomolecular Sciences Institute, School of Integrated Sciences and Humanity, Florida International University, 11200 SW 8th Street, Miami, FL 33199, United States.
Toxicol Appl Pharmacol. 2017 Aug 15;329:58-66. doi: 10.1016/j.taap.2017.05.027. Epub 2017 May 25.
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.
短裸甲藻，即造成佛罗里达赤潮的甲藻，会产生一系列被称为短裸甲藻毒素的神经毒素。其中含量最为丰富的短裸甲藻毒素PbTx-2，被发现可抑制硫氧还蛋白-硫氧还蛋白还原酶系统，而PbTx-3对该系统没有影响。另一方面，PbTx-2可激活硫氧还蛋白还原酶对诸如5,5'-二硫代双(2-硝基苯甲酸)等小分子二硫化物的还原作用。PbTx-2具有一个α,β-不饱和醛基部分，该部分作为一种高效亲电试剂，可轻易形成硒代半胱氨酸共轭物。PbTx-2可阻断抑制剂姜黄素对硫氧还蛋白还原酶（TrxR）的抑制作用，而姜黄素则可阻断PbTx-2对TrxR的激活作用。有人提出，抑制硫氧还蛋白还原的机制是通过硒代半胱氨酸与PbTx-2的α,β-不饱和醛基部分形成迈克尔加成物。PbTx-2对谷胱甘肽还原酶、谷胱甘肽过氧化物酶或谷氧还蛋白等相关酶催化的反应速率没有影响。
