Biosynthetic Studies of Brevetoxins, Potent Neurotoxins Produced by the Dinoflagellate Gymnodinium breve

Article abstract of DOI:10.1021/ja00198a039

Blooms of the dinoflegellate Gymnodinium breve (Ptychodiscus brevis) commonly known as "red tide" have led to massive fish kills, mollusk contamination, and human food intoxications along the Florida coast and the Gulf of Mexico.The toxins from G. breve responsible for these phenomena are the brevetoxins (BTX's), a group of potent neurotoxins with polycyclic trans-fused ether rings which presumably depolarize the sodium channels of the excitable membranes.BTX-B, C50H70O14, the first of these neurotoxins whose structure was elucidated, has an unprecedented structure consisting of 6/6/6/7/7/6/6/8/6/6/6 ether rings trans-fused in a ladder-like manner.Another member of these toxins, BTX-A, C49H70O13, has another remarkable structure consisting of trans-fused 5/8/6/7/9/6/6/6 ether rings.Although the carbon skeletons of BTX-B and BTX-A are different, both consist of a single carbon chain that is polyoxygenated with methyl substituent groups.This is consistent with polyketide biosynthesis, i.e., condensation of acetate units with the methyl groups originating from either S-adenosylmethionine or propionate.Labeling experiments using sodium <1-(13)C>- and <2-(13)C>acetate and methionine demonstrate that the labeling patterns of BTX-B and BTX-A are similar and that the biosynthesis of brevetoxins is not of simple polyketide origin.These labeling studies suggest that the citric acid cycle is involved in the biosynthetis of BTX-B and BTX-A, the degree of its involvement being unusually high.Furthermore, CO2 participates in a unique manner in the biosynthesis of C-1 of BTX-B and BTX-A.