Frontier Research Institute for Interdisciplinary Sciences
Tohoku University

Tetrodotoxin (TTX) is one of the most famous natural toxins as a pufferfish toxin. This toxin is a potent and highly selective blocker of voltage-gated sodium channels. In addition to pufferfish and other diverse marine organisms, TTX is also found in terrestrial amphibians such as newts. Owing to its unique structure, its strong pharmacological activity that can cause fatal food poisoning, and its broad distribution across taxonomically diverse organisms, TTX has been studied in multiple disciplines, including organic chemistry, biology, food safety science, chemical ecology, and neuroscience. Nevertheless, its origin and biosynthetic pathway have remained unresolved.

In this study, Associate Professor Yuta Kudo of the Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, led an international collaborative project with Shugo Horie (undergraduate student) and Professor Mari Yotsu-Yamashita of the Graduate School of Agricultural Science, Tohoku University, and Associate Professor Charles Hanifin of Utah State University. Kudo and co-workers discovered five new tetrodotoxin analogues from toxic newts and elucidated their chemical structures. By identifying these analogues that differ in oxidation state and stereochemical configuration, Kudo and co-workers were able to propose a biosynthetic pathway for terrestrial tetrodotoxin. Furthermore, the inhibitory activities of these newly identified analogues against voltage-gated sodium channels were evaluated, providing new insights into their structure–activity relationships.

The findings have been published online on February 4, 2026, in the Journal of Natural Products, a peer-reviewed journal of the American Chemical Society (ACS). The article is available as open access through Tohoku University’s APC support program.

 

 

Publication Details:
Title: Identification of Deoxy- and epi-Tetrodotoxin Analogues from the Newt Cynops ensicauda popei Suggests Stepwise Oxidation in Terrestrial Tetrodotoxin Biosynthesis 
Authors: Shugo Horie, Charles T. Hanifin, Yuko Cho, Keiichi Konoki, Mari Yotsu-Yamashita, and Yuta Kudo* (*corresponding author)
Journal: Journal of Natural Products
DOI: 10.1021/acs.jnatprod.5c01546
URL: https://doi.org/10.1021/acs.jnatprod.5c01546
 

 

Figure: Identification of novel tetrodotoxin analogues (2-6) enabled the proposal of a late-stage biosynthetic pathway