Chemistry and biochemistry of saxitoxin analogues and tetrodotoxin.
Chemistry and biochemistry of saxitoxin analogues and tetrodotoxin.
复制标题
石房蛤毒素类似物和河豚毒素的化学和生物化学。
DOI：
10.1111/j.1749-6632.1986.tb15558.x
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发表时间：
1986
影响因子：
5.2
通讯作者：
Shimizu,Y
中科院分区：
文献类型：
--
作者：
Shimizu,Y
石房蛤毒素及其类似物在涉及钠通道的神经生理学实验中的重要性怎么强调都不过分。1976年，我们首次报道了新蛤蚌毒素类似物的分离，gonyautoxin-I，11，111 '，随后报道了新蛤蚌毒素，gonyautoxin-IV，V，VL 2。从那时起，作者的团队和其他人从各种来源分离出了总共十几种毒素（图1;见参考文献。3和4以及其中的参考文献）。这些新的毒素添加到药理学探针的库存提供了新的见解石房蛤毒素和河豚毒素在可兴奋膜的作用机制。例如，Kao及其同事提出，石房蛤毒素和河豚毒素衍生物中两个氧基团和胍基的排列是毒素结合的关键结构特征。清水还通过比较新分离的毒素与石房蛤毒素和河豚毒素中官能团的空间排列，指出了与经典”塞子”模型相关的结构问题，并提出了一个简单的三点连接的”盖子”模型。（图2）：另一方面，解释了新衍生物的实验数据，以显示在C-位的水合酮之间形成半缩酮或半氨基缩酮。12的石房蛤毒素和受体部位的亲核基团。这种与受体共价结合的可能性一直是讨论的主题，因为石房蛤毒素的结构被证明具有水合酮结构。“与这种模型相关的一个困难似乎是在河豚毒素衍生物中缺乏类似的缩酮形成位点。的确，在C-4位的半氨基缩醛或在C-10位的原酸酯可以形成类似的键，但它们相对于C-2位的必需胍的位置与石房蛤毒素衍生物中的位置有很大不同，除非该位点上的不同亲核基团参与河豚毒素结合。共价结合模型在解释12（OH）-二氢石房蛤毒素的活性时也可能存在困难，因为它抑制了缩酮的形成。'.~无论如何，关于这个问题的讨论将继续下去。下文讨论了毒素的一些理化性质，这些性质可用于解释神经生理学实验数据。
The importance of saxitoxin and its analogues in neurophysiological experiments involving sodium channels cannot be overstated. In 1976, we first reported the isolation of new saxitoxin analogues, gonyautoxin-I, 11, 111,'and subsequently neosaxitoxin, gonyautoxin-IV, V, VL2 Since then a total of more than a dozen toxins have been isolated from various sources by the author's group and others (FIG. 1; see refs. 3 and 4 and references therein). The addition of those new toxins to the inventory of pharmacological probes has provided new insights into the mechanism of action of saxitoxin and tetrodotoxin in excitable membranes. Kao and co-workers, for example, suggested that the arrangement of two oxygen groups and guanidinium moiety in both saxitoxin and tetrodotoxin derivatives is the critical structural feature for the toxin binding.'" Shimizu also pointed out structural problems associated with the classical" plug" model'by comparing the spatial arrangements of functional groups in the newly isolated toxin with those of saxitoxin and tetrodotoxin, and proposed a" lid" model with a simple three-point attachment to the proximity of sodium channels (FIG. 2): s' Stricharz, on the other hand, interpreted experimental data for the new derivatives to show the formation of hemiketal or hemiaminoketal between the hydrated ketone at C-12 of saxitoxin and a nucleophilic group at the receptor site.'The possibility of such covalent bonding to the receptor has been a subject of discussion since the structure of saxitoxin was shown to possess a hydrated ketone structure." A difficulty associated with such a model seems to be the absence of a comparable ketal formation site in tetrodotoxin derivatives. It is true that either hemiaminoacetal at C-4 or orthoester at C-10 could form a similar bond, but their locations relative to the essential guanidinium at C-2 are considerably different from that in saxitoxin derivatives, unless a different nucleophilic group at the site is involved in tetrodotoxin binding. The covalent binding model also may present a difficulty in explaining the activity observed with 12 (0H)-dihydrosaxitoxin," for which the ketal formation is pr~ hibited.~~'.~ At any rate discussion on this subject will continue. Some physicochemical properties of the toxins that may serve for the interpretation of the neurophysiological experimental data are discussed below.