title: Cyclic Guanidine Compounds from Toxic Newts Support the Hypothesis that Tetrodotoxin is Derived from a Monoterpene.
abstract: The biosynthesis of tetrodotoxin (TTX), a potent neurotoxin consisting of a 2,4-dioxaadamantane skeleton and a guanidine moiety, is an unsolved problem in natural product chemistry. Recently, the first C5-C10 directly bonded TTX analogue, 4,9-anhydro-10-hemiketal-5-deoxyTTX, was obtained from toxic newts and its carbon skeleton suggested a possible monoterpene origin. On the basis of this hypothesis, screening of predicted biosynthetic intermediates of TTX was performed using two MS-guided methods. Herein, five novel cyclic guanidine compounds from toxic newts are reported which commonly contain a cis-fused bicyclic structure including a six-membered cyclic guanidine. These structures could be biosynthetically derived from geranyl guanidine through oxidation, cyclization, and/or isomerization steps. LC-MS analysis confirmed the widespread distribution of the five novel compounds in toxic newt species. These results support the hypothesis that TTX is derived from a monoterpene.
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kudo
authors.affiliation: Tama Laboratory, Japan Food Research Laboratories, 6-11-10 Nagayama, Tama-shi, Tokyo, 206-0025, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yasumoto
authors.affiliation: Institute of Legal Medicine, University of Frankfurt, Kennedyallee 104, 60596, Frankfurt, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Mebs
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Konoki
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai, Miyagi, 981-8555, Japan. myama@biochem.tohoku.ac.jp.
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D006146:Guanidines / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D039821:Monoterpenes / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D012455:Salamandridae / Q000378:metabolism*; D013237:Stereoisomerism; D013779:Tetrodotoxin / Q000031:analogs & derivatives* / Q000096:biosynthesis
chemical_list: D001643:Bridged Bicyclo Compounds; D006146:Guanidines; D039821:Monoterpenes; D013779:Tetrodotoxin
keywords: biosynthesis; mass spectrometry; natural products; structure elucidation; tetrodotoxin