saxitoxin and chiriquitoxin

Bioactive marine natural products occur only rarely in nonmarine sources. The converse also is true. Divergent evolutionary pathways for the biosynthesis of bioactive secondary metabolites seem to be the rule. Marine biosynthetic pathways lead to a wide variety of different structural classes, among which polyethers, macrolides, terpenes, unusual amino acids/peptides, and alkaloids are notable. Nonmarine biosynthetic pathways also lead to a similar wide variety of structural classes. However, the structures are usually quite different from the marine analogues. The alkaloids of plants are notable, but again there appears little convergence between the marine and nonmarine alkaloids. However, tetrodotoxin, a remarkable, highly polar, marine alkaloid, does occur in various amphibians. The occurrence and possible origin of tetrodotoxin and congeners, including chiriquitoxin, and of the saxitoxin analogue zetekitoxin in amphibians are reviewed.

Topics: Alkaloids; Amphibian Venoms; Animals; Fish Venoms; Marine Toxins; Molecular Structure; Quinazolines; Saxitoxin; Tetrodotoxin; Toxins, Biological

Major toxins from skin extracts of 18 specimens of six Atelopus toad species collected in Panama were analyzed. Chiriquitoxin was identified using (1)H NMR in A. limosus and A. glyphus for the first time. Zetekitoxin in A. zeteki and tetrodotoxin in A. varius, A. chiriquiensis and A. zeteki were identified again. Furthermore, A. certus was suggested to contain a water-soluble toxin other than tetrodotoxin.

Topics: Animals; Biological Assay; Bufonidae; Chromatography, Liquid; Complex Mixtures; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Mice; Panama; Saxitoxin; Skin; Species Specificity; Spectrometry, Fluorescence; Spectrometry, Mass, Electrospray Ionization; Tetrodotoxin; Toxins, Biological

Chiriquitoxin (CqTX) from the Costa Rican frog Atelopus chiriquensis differs from tetrodoxin (TTX) only in that a glycine residue replaces a methylene hydrogen of the C-11 hydroxymethyl function. On the voltage-clamped frog skeletal muscle fiber, in addition to blocking the sodium channel and unrelated to such an action, CqTX also slows the activation of the fast potassium current in approximately 40% of the muscle fiber population. At pH 7.25, CqTX is as potent as TTX in blocking the sodium channel, with an ED50 of 3.8 nM. Its ED50's at pH 6.50 and 8.25 are 6.8 and 2.3 nM, contrasted with 3.8 and 4.3 nM for TTX. These differences are attributable to changes in the chemical states in the glycine residue. The equipotency of CqTX with TTX at pH 7.25 is explainable by an intramolecular salt bridge between the amino and carboxyl groups of the glycine function, all other surface groups in TTX and CqTX being the same. From available information on these groups and those in saxitoxin (STX), the TTX/STX binding site is deduced to be in a pocket 9.5 A wide, 6 A high, and 5 A deep. The glycine residue of CqTX probably projects out of the entrance to this pocket. Such a view of the binding site could also account for the actions of STX analogues, including the C-11 sulfated gonyautoxins and the 21-sulfocarbamoyl analogues. In the gonyautoxins the sulfate groups are equivalently placed as the glycine in CqTX, whereas in the sulfocarbamoyl toxins the sulfate groups extend the carbamoyl side-chain, leading to steric hinderance to productive binding.

Topics: Amphibian Proteins; Animals; Bufonidae; Carrier Proteins; Hydrogen-Ion Concentration; In Vitro Techniques; Muscle Contraction; Muscles; Potassium Channels; Saxitoxin; Sodium Channels; Tetrodotoxin

Chiriquitoxin is a new, natural analog of tetrodotoxin, differing only in having the -CH2OH on C-6 replaced with an unidentified group of 104 mass units. On isolated frog sartorius muscle fibers, chiriquitoxin is equipotent with tetrodotoxin in blocking the Na+ channel, as shown by their identical dose-response relations on the maximum rate of rise of the action potential. Chiriquitoxin additionally interferes with some K+ channels, as shown by a slowed repolarization of the action potential, a reduced steady-state membrane conductance in current-clamped fibers, and a reduced K+ current in point-voltage-clamped fibers. The effects of chiriquitoxin on the Na+ and K+ channels are apparently exerted by the same molecule because high concentration of tetrodotoxin can either prevent or reverse the effects of chiriquitoxin on the K+ channel. Therefore, the receptor for tetrodotoxin-chiriquitoxin is probably not located inside the Na+ channel, but is on the outside surface of the membrane close to the orifice of the Na+ channel. The results also suggest that the Na+ and K+ channels are probably not randomly distributed throughout the membrane, but occur in clusters with some definite spatial relation to each other. From the structure of tetrodotoxin and a presumed structure of chiriquitoxin, the Na+ and K+ channels are estimated to be separated from each other by not less than 5 nor much more than 15A. The receptor for saxitoxin may be different, but partially overlapping with that for tetrodotoxin-chiriquitoxin.

Topics: Action Potentials; Animals; Binding, Competitive; Ion Channels; Saxitoxin; Tetrodotoxin