Evidence for an enantioselective pumiliotoxin 7-hydroxylase in dendrobatid poison frogs of the genus Dendrobates
Evidence for an enantioselective pumiliotoxin 7-hydroxylase in dendrobatid poison frogs of the genus Dendrobates
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DOI：
10.1073/pnas.1834430100
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发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Cover, JF
中科院分区：
文献类型：
--
作者：
Daly, JW;Garraffo, HM;Cover, JF
树蛙毒蛙很容易将饮食中的生物碱积累到皮肤中，这些化合物可以作为针对捕食者的化学防御。节肢动物似乎是十氢喹啉 (DHQ)、几种齐嗪、七彩霉素、螺吡咯里西啶、普米里奥毒素 (PTX) 和别奥普米里奥毒素 (aPTX) 的来源。将DHQ iso-223F和PTX (+)-251D喂给树蛙属Dendrobates、Epipedobates和Phyllobates属的毒蛙。这两种生物碱在皮肤中积累时没有变化，除了三种树突状动物外，其中大约80%的积累的PTX (+)-251D被立体选择性羟基化为aPTX (+)-267A。当喂食 Dendrobates auratus 时，非天然对映体 PTX (-)-251D 可以有效积累，但不会被羟基化。 IPTX 251D 的对映体及其去甲基类似物是由 N-Boc 保护的 (-)- 和 (+)-脯氨酸甲酯合成的。 PTX (+)-251D 和 aPTX (+)-267A 均被证明对小鼠具有强效惊厥作用，其中 (+)-267A 的毒性大约是 (+)-251D 的 5 倍。两种生物碱在注射部位均产生痛觉过敏。非天然的 PTX (-)-251D 对小鼠没有造成明显的影响。因此，pumiliotoxin 7-羟化酶的进化发展将为Dendrobates属的青蛙提供一种增强摄入的PTX的抗捕食者效力的方法。
Dendrobatid poison frogs readily accumulate alkaloids from diet into skin, where such compounds serve as a chemical defense against predators. Arthropods seem to be the source of decahydroquinolines (DHQs), several izidines, coccinellines, spiropyrrolizidines, pumiliotoxins (PTXs), and allopumiliotoxins (aPTXs). A DHQ iso-223F, and PTX (+)-251D were fed to poison frogs of the dendrobatid genera Dendrobates, Epipedobates, and Phyllobates. The two alkaloids were accumulated in skin unchanged except for the three species of Dendrobates, where approximate to80% of accumulated PTX (+)-251D was stereoselectively hydroxylated to aPTX (+)-267A. The unnatural enantiomer PTX (-)-251D was accumulated efficiently when fed to Dendrobates auratus, but was not hydroxylated. The enantiomers of IPTX 251D and their desmethyl analogs were synthesized from N-Boc-protected (-)- and (+)-proline methyl esters. Both PTX (+)-251D and aPTX (+)-267A proved to be potent convulsants in mice, with (+)-267A being approximate to5-fold more toxic than (+)-251D. Both alkaloids were hyperalgesic at the site of injection. The unnatural PTX (-)-251D caused no overt effect in mice. Thus, the evolutionary development of a pumiliotoxin 7-hydroxylase would have provided frogs of the genus Dendrobates with a means of enhancing the antipredator potency of ingested PTXs.