Isolation and Biological Activity of 9-epiTetrodotoxin and Isolation of Tb-242B, Possible Biosynthetic Shunt Products of Tetrodotoxin from Pufferfish
Isolation and Biological Activity of 9-epiTetrodotoxin and Isolation of Tb-242B, Possible Biosynthetic Shunt Products of Tetrodotoxin from Pufferfish
复制标题
河豚毒素可能的生物合成分流产物 9-epi 河豚毒素的分离和生物活性以及 Tb-242B 的分离
DOI：
10.1021/acs.jnatprod.2c00588
复制
发表时间：
2022
影响因子：
5.1
通讯作者：
Mari Yotsu-Yamashita
中科院分区：
文献类型：
--
作者：
Yuji Yaegashi;Yuta Kudo;Nozomi Ueyama;Ken-ichi Onodera;Yuko Cho;Keiichi Konoki;Mari Yotsu-Yamashita
河豚毒素(TTX，1)是一种在某些海洋生物和陆地生物中检测到的有效的电压门控钠通道阻滞剂。我们报道了一个新的TTX类似物9-epTTX(2)和一个与TTX相关的化合物TB-242B(4)，分别是从河豚Takifugu flavipterus和Dichotomyctere ocellatus中分离得到的。核磁共振分析表明，2以半乳糖和10，8-内酯的混合物形式存在，而其他已报道的TTX类似物通常以半乳糖和10，7-内酯的平衡混合物存在。化合物2和TTX在37℃的中性和酸性条件下孵育24小时不能相互转化，化合物4被鉴定为TB-242a(3)的9-异构体，先前报道可能是TTX的生物合成前体。在37℃的中性缓冲液中孵育7天，化合物4部分转化为3，而3在此条件下不转化为4。在几种含有TTX的海洋动物和一只蝾螈中检测到化合物2。小鼠经腹腔注射600毫微克的2,000毫克，没有表现出任何不良症状，这表明TTX中的C-9构型对其生物活性至关重要。根据结构预测，2和4可能是TTX生物合成的分流产物。
Tetrodotoxin (TTX,1) is a potent voltage-gated sodium channel blocker detected in certain marine and terrestrial organisms. We report here a new TTX analogue, 9-epiTTX (2), and a TTX-related compound, Tb-242B (4), isolated from the pufferfishTakifugu flavipterusandDichotomyctere ocellatus, respectively. NMR analysis suggested that2exists as a mixture of hemilactal and 10,8-lactone forms, whereas other reported TTX analogues are commonly present as an equilibrium mixture of hemilactal and 10,7-lactone forms. Compound2and TTX were confirmed not to convert to each other by incubation under neutral and acidic conditions at 37 °C for 24 h. Compound4was identified as the 9-epimer of Tb-242A (3), previously reported as a possible biosynthetic precursor of TTX. Compound4was partially converted to3by incubation in a neutral buffer at 37 °C for 7 days, whereas3was not converted to4under this condition. Compound2was detected in several TTX-containing marine animals and a newt. Mice injected with 600 ng of2by intraperitoneal injection did not show any adverse symptoms, suggesting that the C-9 configuration in TTX is critical for its biological activity. Based on the structures,2and4were predicted to be shunt products for TTX biosynthesis.