1.D.114. The Pore-forming and Na+ Channel-interacting Ladder-shaped Polyether (LPE) Family
Ladder-shaped polyether compounds, represented by brevetoxins, ciguatoxins, maitotoxin, and prymnesins, are thought to possess high affinity for transmembrane proteins. As a model compound of ladder-shaped polyethers, Mori et al. 2005 adopted desulfated yessotoxin and examined its interaction with glycopholin A, a membrane protein known to form dimers and higher oligomers. Desulfated yessotoxin interacts with the transmembrane α-helix so as to induce the dissociation of glycopholin oligomers when examined by SDS and PFO gel electrophoresis. Thus. ladder-shaped polyethers interact with transmembrane helices. Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, it is also the largest nonpolymeric natural product known (Nicolaou et al. 2008). The molecular determinants of brevetoxin binding to voltage-gated sodium channels have been studied (Konoki et al. 2019).
Brevetoxins, involved in the 'red tide' as well as shellfish poisoning, bind to cell membranes and membrane proteins. Brevetoxin B (BTX-B) interacts specifically with neuronal sodium channels and induces selective ion movements across lipid bilayers through transmembrane BTX self-assemblies (Matile et al. 1996). The active BTX-B complex in lipid bilayers is a cyclic, transmembrane , self-assembly, consisting of antiparallel aligned BTX molecules that mediate selective ion movement through membranes. The differences in pore formation mechanisms between BTX derivatives may be reflected in differences in pore formation by natural BTX variants, perhaps explaining their varying levels of toxicity (Matile et al. 1996). Some of these compounds may function by a carrier mechanism rather than a pore-type mechanism, and therefore, they are also listed under in TC Family 2.B.5.
Diarrhetic poisoning by bivalve molluscs, diarrhetic shellfish poisoning, is due to consumption of mussels containing biotoxins produced by some Dinoflagellates. Toxic effects of yessotoxin (YTX) include morphological alterations of mitochondria from heart and liver. YTX opens the permeability transition pore (PTP) of the inner mitochondrial membrane at nanomolar concentrations, dependent on calcium, and it induces membrane depolarization (Bianchi et al. 2004). YTX exerts different in vitro activities, such as changes of intracellular calcium and cyclic AMP levels, alteration of cytoskeletal and adhesion molecules, and caspases activation (Tubaro et al. 2010).
The generalized reaction catalyzed by these pore-forming compounds is:
ion (in) ⇋ ion (out)