text: Brevetoxins share the common backbone structure of polyketides, but there are several methyl and oxygen groups that are not typical of a traditional polyketide synthesis. Labelling studies identifying the origin of the various carbon atoms have shown that the biosynthesis of brevetoxins greatly deviates from the polyketide synthetic pathway.
  From the labelling experiments of Brevetoxin-B (BTX-B), a 50-carbon molecule, 16 carbon signals were enhanced by [1-C13] acetate, 30 signals were enhanced by [2-C13] acetate, and 4 carbon signals were enhanced by [methyl-C13] methionine. Furthermore, 14 intact acetate units were identified with a fifteenth two carbon unit with a weak possibility of being an acetate unit. It is clear based on the oxygen locations of BTX-B that this molecule could not be produced using a traditional polyketide synthetic pathway. Attention was turned to the citric acid cycle to solve the problem. Acetate can be used in the polyketide synthetic pathway or modified by the citric acid cycle. Intermediate products of this cycle can then be reintroduced to the polyketide synthetic pathway, resulting in the addition of atypical carbon units. Previous studies of the citric acid pathway revealed three and four carbon units that can potentially explain the atypical condensation and oxidation pattern seen in BTX-B. That being said, there is currently no explanation as to why this particular pattern is favored.
  All these things considered, a proposed biosynthetic pathway for brevetoxin class compounds begins with a traditional polyketide synthesis that has the potential to incorporate larger carbon units originating from acetate modified by the citric acid cycle.  After the carbon backbone is synthesized, oxidation produces the necessary epoxides that lead to the closure of the multi-ring system. It is unclear if methyl groups as seen in BTX-B are added after cyclization or during the modification of the polyketide metabolites, but it is clear that methyl groups can originate from sources outside of acetate such as S-adenosylmethionine.