Structures of N-Hydroxy-Type Tetrodotoxin Analogues and Bicyclic Guanidinium Compounds Found in Toxic Newts
Structures of N-Hydroxy-Type Tetrodotoxin Analogues and Bicyclic Guanidinium Compounds Found in Toxic Newts
复制标题
毒蝾螈中N-羟基型河豚毒素类似物和双环胍化合物的结构
DOI：
10.1021/acs.jnatprod.0c00623
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发表时间：
2020
影响因子：
5.1
通讯作者：
Mari Yotsu-Yamashita*
中科院分区：
文献类型：
--
作者：
Yuta Kudo;Charles T. Hanifin;Yuichi Kotaki;Mari Yotsu-Yamashita*
河豚毒素（TTX，1）是一种广泛存在于海洋和陆地后生动物体内的神经毒素，其生物合成机制至今尚未完全阐明。一个重要的问题是确定与TTX生物合成途径相关的中间体和分流产物。本研究通过筛选和鉴定短尾蝾螈（Cynops ensicauda popei）和Taricha granulosa中新的TTX相关化合物来研究TTX的生物合成。质谱（MS）引导的筛选在蝾螈中发现了两种新的N-羟基TTX类似物：1-羟基-8-epiTTX（2）和1-羟基-8-epi-5，11-dideoxyTTX（3，以前报道为1-羟基-5，11-dideoxyTTX）。我们从3经N-OH还原制得了一种新的类似物8-epi-5，11-dideoxyTTX（4），并证实了4在T中的存在。使用亲水相互作用液相色谱法（HILIC）-LCMS测定颗粒。Cynops和Tarichas中存在的8-epi-type TTX类似物支持陆生TTX的分支生物合成途径，其产生6-和8-差向异构体。此外，新的双环胍化合物Tgr-238（5）和Tgr-240（6）被鉴定为我们提出的TTX生物合成途径的推定分流产物。使用NMR对另一种双环化合物Cep-228 A（7）进行结构分析。基于5 - 7及其类似物的结构，我们提出了陆地TTX生物合成的分流和代谢途径的模型。
The biosynthesis of tetrodotoxin (TTX,1), a potent neurotoxin widely distributed in marine and terrestrial metazoans, remains unresolved. A significant issue has been identifying intermediates and shunt products associated with the biosynthetic pathway of TTX. We investigated TTX biosynthesis by screening and identifying new TTX-related compounds fromCynops ensicauda popeiandTaricha granulosa. Mass spectrometry (MS)-guided screening identified two newN-hydroxy TTX analogues in newts: 1-hydroxy-8-epiTTX (2) and 1-hydroxy-8-epi-5,11-dideoxyTTX (3, previously reported as 1-hydroxy-5,11-dideoxyTTX). We prepared a new analogue, 8-epi-5,11-dideoxyTTX (4), from3viaN-OH reduction and confirmed the presence of4inT. granulosausing hydrophilic interaction liquid chromatography (HILIC)-LCMS. The presence of 8-epi-type TTX analogues in bothCynopsandTarichasupports a branched biosynthetic pathway of terrestrial TTX, which produces 6- and 8-epimers. In addition, new bicyclic guanidinium compounds Tgr-238 (5) and Tgr-240 (6) were identified as putative shunt products of our proposed TTX biosynthesis pathway. A structural analysis of Cep-228A (7), another bicyclic compound, was performed using NMR. Based on the structures of5–7and their analogues, we propose a model of the shunt and metabolic pathways of the terrestrial TTX biosynthesis.