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Antillatoxin
Antillatoxin (ATX) is a potent lipopeptide neurotoxin produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channels, which can cause cell depolarisation, NMDA-receptor overactivity, excess calcium influx and neuronal necrosis.
Antillatoxin is found in the venom of the marine cyanobacterium Lyngbya majuscula. The filamentous cyanobacterium grows on seagrass, macroalgae, and corals up to 30m deep in tropical and subtropical regions throughout the world.
The three dimensional NMR study of this toxin showed that it consists of a tripeptide glycine-N-methylvaline-alanine, a hydroxycarboxylic acid and a 9-t-butyl-6,8-dimethyl-6,8-diene attached to the C5 atom of the cyclic peptide backbone.
There are three known analogous structures of ATX which have different toxicity: antillatoxin B (8-demethyl-antillatoxin) and DH-ATX (8-demethyl-8,9-dihydro-antillatoxin), and various stereoisomers of antillatoxin A. These various structures have been found to be less toxic than antillatoxin A. Synthetic versions of antillatoxin have been produced with conformational variations of the lipophilic side chain. All of these structures drastically changed the toxins activity. Structures where the C7-C8=C9 bond angle was closer to 180o showed lower levels of toxicity in cell cultures. Structures that added a bulky side group to the C5 position also showed dramatic decreases in toxicity, including loss of activity.
The figure below shows the first total synthesis of antillatoxin by Yokokawa et al. in 1998. (2E,4E)-2,4,6,6-Tetramethyl-2,4-heptadien-1-ol was transformed using a stereoselective aldol reaction, followed by the addition of a triethylsilyl protecting group. This allowed for cleavage of the chiral auxiliary of the ester. TPAP oxidation followed by Still’s olefination and protonation leads to the lactone. After transformation into the phenylselenyl derivative, alkaline cleavage, allyl esterification and coupling with the tripeptide yields the ester. Oxidation leads to the linear product, which is transformed into antillatoxin by deprotection at the N and C terminals and macrolactimization with DPPA.
Antillatoxin is a sodium channel gating modifier with special efficacy in cells expressing rNav1.2, rNav1.4 and rNav1.5 α subunits. It is suggested that ATX preferentially binds to the voltage-gated sodium channel in the inactivated state. The specific site of interaction of this neurotoxin is not yet known, however there is an allosteric interaction between ATX and brevetoxin (PbTx) at site 5 of the α subunit, which indicates that the neurotoxin site for ATX is topologically close and/or conformationally coupled to neurotoxin site 5. Additionally, sites 1, 2, 3, 5 and 7 were ruled out as possible binding sites.
Changing the tert-butyl-substituted diene groups reduced toxicity, which proves that the twisted shape of these groups plays a critical role in the degree of neurotoxicity of ATX.
Antillatoxin activates voltage-gated sodium channels, thus increasing sodium influx into the cell. It is hypothesized that ATX creates the increase in sodium influx by altering the voltage-gating properties of the channel. The toxin might change the voltage dependence of inactivation or augment the rate of recovery from inactivation. The effect is concentration dependent, with similar potency for the rNav1.2, rNav1.4 and rNav1.5 α-subunit types of sodium channels.
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Antillatoxin
Antillatoxin (ATX) is a potent lipopeptide neurotoxin produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channels, which can cause cell depolarisation, NMDA-receptor overactivity, excess calcium influx and neuronal necrosis.
Antillatoxin is found in the venom of the marine cyanobacterium Lyngbya majuscula. The filamentous cyanobacterium grows on seagrass, macroalgae, and corals up to 30m deep in tropical and subtropical regions throughout the world.
The three dimensional NMR study of this toxin showed that it consists of a tripeptide glycine-N-methylvaline-alanine, a hydroxycarboxylic acid and a 9-t-butyl-6,8-dimethyl-6,8-diene attached to the C5 atom of the cyclic peptide backbone.
There are three known analogous structures of ATX which have different toxicity: antillatoxin B (8-demethyl-antillatoxin) and DH-ATX (8-demethyl-8,9-dihydro-antillatoxin), and various stereoisomers of antillatoxin A. These various structures have been found to be less toxic than antillatoxin A. Synthetic versions of antillatoxin have been produced with conformational variations of the lipophilic side chain. All of these structures drastically changed the toxins activity. Structures where the C7-C8=C9 bond angle was closer to 180o showed lower levels of toxicity in cell cultures. Structures that added a bulky side group to the C5 position also showed dramatic decreases in toxicity, including loss of activity.
The figure below shows the first total synthesis of antillatoxin by Yokokawa et al. in 1998. (2E,4E)-2,4,6,6-Tetramethyl-2,4-heptadien-1-ol was transformed using a stereoselective aldol reaction, followed by the addition of a triethylsilyl protecting group. This allowed for cleavage of the chiral auxiliary of the ester. TPAP oxidation followed by Still’s olefination and protonation leads to the lactone. After transformation into the phenylselenyl derivative, alkaline cleavage, allyl esterification and coupling with the tripeptide yields the ester. Oxidation leads to the linear product, which is transformed into antillatoxin by deprotection at the N and C terminals and macrolactimization with DPPA.
Antillatoxin is a sodium channel gating modifier with special efficacy in cells expressing rNav1.2, rNav1.4 and rNav1.5 α subunits. It is suggested that ATX preferentially binds to the voltage-gated sodium channel in the inactivated state. The specific site of interaction of this neurotoxin is not yet known, however there is an allosteric interaction between ATX and brevetoxin (PbTx) at site 5 of the α subunit, which indicates that the neurotoxin site for ATX is topologically close and/or conformationally coupled to neurotoxin site 5. Additionally, sites 1, 2, 3, 5 and 7 were ruled out as possible binding sites.
Changing the tert-butyl-substituted diene groups reduced toxicity, which proves that the twisted shape of these groups plays a critical role in the degree of neurotoxicity of ATX.
Antillatoxin activates voltage-gated sodium channels, thus increasing sodium influx into the cell. It is hypothesized that ATX creates the increase in sodium influx by altering the voltage-gating properties of the channel. The toxin might change the voltage dependence of inactivation or augment the rate of recovery from inactivation. The effect is concentration dependent, with similar potency for the rNav1.2, rNav1.4 and rNav1.5 α-subunit types of sodium channels.