title: The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker.
abstract: Bufonid anurans of the genus Atelopus contain both steroidal bufadienolides and various guanidinium alkaloids of the tetrodotoxin class. The former inhibit sodium-potassium ATPases, whereas the latter block voltage-dependent sodium channels. The structure of one guanidinium alkaloid, zetekitoxin AB, has remained a mystery for over 30 years. The structure of this alkaloid now has been investigated with a sample of approximately 0.3 mg, purified from extracts obtained decades ago from the Panamanian golden frog Atelopus zeteki. Detailed NMR and mass spectral analyses have provided the structure and relative stereochemistry of zetekitoxin AB and have revealed that it is an analog of saxitoxin. The proposed structure is characterized by richness of heteroatoms (C16H25N8O12S) and contains a unique 1,2-oxazolidine ring-fused lactam, a sulfate ester, and an N-hydroxycarbamate moiety. Zetekitoxin AB proved to be an extremely potent blocker of voltage-dependent sodium channels expressed in Xenopus oocytes. The IC50 values were 280 pM for human heart channels, 6.1 pM for rat brain IIa channels, and 65 pM for rat skeletal muscle channels, thus being roughly 580-, 160-, and 63-fold more potent at these channels than saxitoxin.
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan. myama@biochem.tohoku.ac.jp
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Yong H
authors.initials: YH
authors.lastname: Kim
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
authors.forename: Gaurav
authors.initials: G
authors.lastname: Choudhary
authors.forename: Arnold
authors.initials: A
authors.lastname: Pfahnl
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Oshima
authors.forename: John W
authors.initials: JW
authors.lastname: Daly
mesh_terms: D000818:Animals; D002025:Bufonidae; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D012530:Saxitoxin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D012879:Skin Physiological Phenomena; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D014982:Xenopus laevis
chemical_list: D026941:Sodium Channel Blockers; C487810:zetekitoxin AB; D012530:Saxitoxin