page_title: Brevetoxin
section_title: Biosynthesis
hierarchical_section_title: Brevetoxin / Biosynthesis
caption_attribution_description: English: Oxidation and ring closure leading to BTX-B, starting from the basic carbon backbone
context_page_description: Brevetoxin, or brevetoxins, are a suite of cyclic polyether compounds produced naturally by a species of dinoflagellate known as Karenia brevis. Brevetoxins are neurotoxins that bind to voltage-gated sodium channels in nerve cells, leading to disruption of normal neurological processes and causing the illness clinically described as neurotoxic shellfish poisoning.
  Although brevetoxins are most well-studied in K. brevis, they are also found in other species of Karenia and at least one large fish kill has been traced to brevetoxins in Chattonella.
  Other Brevetoxins:
  Brevetoxin-5: like PbTx-3, but acetylated hydroxyl group in position 38.
  Brevetoxin-6: like PbTx-2, but double bond 27-28 is epoxidated.
  Brevetoxin-B was synthesized in 1995 by K. C. Nicolaou and coworkers in 123 steps with 91% average yield and in 2004 in a total of 90 steps with an average 93% yield for each step.
  K. C. Nicolaou and coworkers reported their synthesis of Brevetoxin-1 in 1998. In 2009, Michael Crimmins and co-workers reported their synthesis of Brevetoxin-1 as well.
context_section_description: 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.
caption: Proposed pathway for brevetoxin-B
exif: {}