Investigation of the origin and biosynthesis of the terrestrial tetrodotoxin based on the chemical and metagenome analyses

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21141
• Project/Area Number (Other): 18H05997 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0601:Agricultural chemistry and related fields
• Research Institution: Tohoku University
• Principal Investigator: Kudo Yuta 東北大学, 学際科学フロンティア研究所, 助教 (60824662)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: テトロドトキシン / 生合成 / 構造解析 / LC-MS / イモリ / 電位依存性ナトリウムチャネル / 生理活性 / グアニジン

Outline of Final Research Achievements

We performed the screening of new TTX-related compounds to collect information regarding the biosynthetic pathway of TTX. As the result, a new TTX analogue, 8-epimer of TTX (8-epiTTX), and new cyclic guanidino compounds (Cep-226A and more) were discovered from toxic newts. The structures of these compounds supported the proposed biosynthetic pathway of TTX, and provided further insights into the biosynthetic and shunt pathway of TTX in terrestrial organisms. In addition, the voltage-gated sodium ion channels (Nav) blocking activities of 8-epiTTX and other TTX analogues were evaluated by a cell-based assay. The results indicated that the equatorial C-8 hydroxy group in TTX is important for its interaction with the voltage-gated sodium ion channels. This finding is consistent with the previous study regarding the contribution of the equatorial hydroxy group at C-8 to the activity.

Free Research Field

天然物生命化学

Academic Significance and Societal Importance of the Research Achievements

テトロドトキシン (TTX) は、強力な毒性と複雑な分子構造を持ち、海洋と陸上の様々な生物に分布する興味深い神経毒であり、食中毒原因物質として重要である。長年研究対象となる一方で、自然界でどのようにTTXが生産されるか（生合成経路）は未解明であり、その解明には学術的・社会的な意義がある。本研究では有毒イモリより新規化合物を複数発見し、陸上におけるTTXの生合成経路への知見を深めることができた。新規化合物の生理活性試験により、TTXと電位依存性ナトリウムチャネルとの相互作用について理解を深めることができた。