Spiro Bicyclic Guanidino Compounds from Pufferfish: Possible Biosynthetic Intermediates of Tetrodotoxin in Marine Environments

Nozomi Ueyama, Keita Sugimoto, Yuta Kudo, Ken Ichi Onodera, Yuko Cho, Keiichi Konoki, Toshio Nishikawa, Mari Yotsu-Yamashita

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Tetrodotoxin (TTX, 1) is a potent neurotoxin that is widely found in both terrestrial and marine animals; however, the biosynthetic pathway and genes for TTX have not yet been elucidated. Previously, we proposed that TTX originated from a monoterpene; this hypothesis was based on the structures of cyclic guanidino compounds that are commonly found in toxic newts. However, these compounds have not been detected in marine organisms. Instead, a series of deoxy analogues of TTX were found in toxic marine animals; thus, we further screened for TTX-related compounds in marine animals. Herein, we report seven novel spiro bicyclic guanidino compounds 2–8 that were isolated from the pufferfish Tetraodon biocellatus. In compounds 2–5 and 7–8, a six-membered cyclic guanidino amide is spiro-fused with 2,4-dimethyl cyclohexane, whereas in compound 6, the same cyclic guanidino amide is spiro-fused with 2,3,5-trimethylcyclopentane. Compounds 2–5 and 7–8 have the same carbon skeleton and relative configuration as TTX. Thus, we proposed that compounds 2–8 are biosynthetic intermediates of TTX in marine environments. TTX could be biosynthetically derived from compound 7 via intermediates 2–5 through several oxidations, amide hydrolysis, and formation of the hemiaminal and lactone found in 5,6,11-trideoxyTTX, the major TTX analogue, whereas compounds 6 and 8 might be shunt products. LC-MS analysis confirmed the wide distribution of compounds 2, 3, or both in TTX-containing marine animals, namely pufferfish, crab, octopus, and flatworm, but compounds 2–8 were not detected in newts.

Original languageEnglish
Pages (from-to)7250-7258
Number of pages9
JournalChemistry - A European Journal
Volume24
Issue number28
DOIs
Publication statusPublished - 2018 May 17

Keywords

  • biosynthesis
  • natural products
  • spiro guanidino compounds
  • structure elucidation
  • tetrodotoxin

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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