Algal Toxin Goniodomin A Binds Potassium Ion Selectively to Yield a Conformationally Altered Complex with Potential Biological Consequences.
Algal Toxin Goniodomin A Binds Potassium Ion Selectively to Yield a Conformationally Altered Complex with Potential Biological Consequences.
复制标题
DOI：
10.1021/acs.jnatprod.9b01094
复制
发表时间：
2020-04-24
影响因子：
5.1
通讯作者：
Harris, Thomas M.
中科院分区：
文献类型：
--
作者：
Tainter, Craig J.;Schley, Nathan D.;Harris, Constance M.;Stec, Donald F.;Song, Anna K.;Balinski, Andrzej;May, Jody C.;McLean, John A.;Reece, Kimberly S.;Harris, Thomas M.
海洋毒素性腺素A （GDA）是一种多环大环内酯，含有螺缩醛和三个环醚作为大环主链的一部分。GDA由三种双鞭毛藻亚历山大属产生，它们的大量繁殖与“赤潮”有关，赤潮分布广泛，对海洋生物造成重大危害。GDA的毒性归因于结构蛋白的丝状肌动蛋白群的稳定，但其结合的结构基础尚不清楚。日本的研究人员利用假定的高取代大环内酯环的刚性，通过核磁共振耦合常数和noe确定了相对的构型和构象；通过降解将绝对构型分配给与合成材料比较的片段。我们通过x射线晶体学证实了GDA的绝对结构和构象的广泛特征，但发现GDA与碱金属离子络合，尽管其中两个杂环朝外。这样的排列可能会削弱GDA形成冠醚型多齿配合物的能力。在金属离子浸渍硅胶板的薄层色谱和电喷雾质谱分析中，GDA对K+、Rb+和Cs+的偏好高于Li+和Na+。利用四[五氟苯基]硼酸钾（KBArF20）形成的GDA的K+配合物进行核磁共振研究，发现大环内酯环的构象发生了重大变化。这些观察结果反驳了先前关于环刚性的假设。化学位移、偶联常数和noe的变化表明，除了f环之外，K+还参与了大部分分子的反应。分子力学模拟表明，K+形成了一个七配位配合物，包括OA、OB、OC、OD、OE以及C-26和C-27羟基。我们推测，在海洋动物中，由于GDA在生理ph下带负电荷，K+与GDA的络合在静电上稳定了GDA与丝状肌动蛋白的络合。GDA也可能导致钾通过细胞膜渗漏。这项研究提供了对GDA的结构特征和化学特征的深入了解，这些特征和化学特征可能是与GDA产生的藻华相关的重大生态破坏的原因。
The marine toxin goniodomin A (GDA) is a polycyclic macrolide containing a spiroacetal and three cyclic ethers as part of the macrocycle backbone. GDA is produced by three species of the Alexandrium genus of dinoflagellates, blooms of which are associated with “red tides”, which are widely dispersed and can cause significant harm to marine life. The toxicity of GDA has been attributed to stabilization of the filamentous form of the actin group of structural proteins, but the structural basis for its binding is not known. Japanese workers, capitalizing on the assumed rigidity of the heavily substituted macrolide ring, assigned the relative configuration and conformation by relying on NMR coupling constants and NOEs; the absolute configuration was assigned by degradation to a fragment that was compared with synthetic material. We have confirmed the absolute structure and broad features of the conformation by X-ray crystallography but have found GDA to complex with alkali metal ions in spite of two of the heterocyclic rings facing outward. Such an arrangement would have been expected to impair the ability of GDA to form a crown-ether-type multidentate complex. GDA shows preference for K+, Rb+, and Cs+ over Li+ and Na+ in determinations of relative affinities by TLC on metal-ion-impregnated silica gel plates and by electrospray mass spectrometry. NMR studies employing the K+ complex of GDA, formed from potassium tetrakis[pentafluorophenyl]borate (KBArF20), reveal a major alteration of the conformation of the macrolide ring. These observations argue against the prior assumption of rigidity of the ring. Alterations in chemical shifts, coupling constants, and NOEs indicate the involvement of most of the molecule other than ring F. Molecular mechanics simulations suggest K+ forms a heptacoordinate complex involving OA, OB, OC, OD, OE, and the C-26 and C-27 hydroxy groups. We speculate that complexation of K+ with GDA electrostatically stabilizes the complex of GDA with filamentous actin in marine animals due to the protein being negatively charged at physiological pH. GDA may also cause potassium leakage through cell membranes. This study provides insight into the structural features and chemistry of GDA that may be responsible for significant ecological damage associated with the GDA-producing algal blooms.
登录
查看更多内容
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
3.6
作者：
Gottlieb, HE;Kotlyar, V;Nudelman, A
通讯作者：
Nudelman, A
影响因子：
6.6
作者：
Anderson DM;Alpermann TJ;Cembella AD;Collos Y;Masseret E;Montresor M
通讯作者：
Montresor M
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
6.1
作者：
Hooft RW;Straver LH;Spek AL
通讯作者：
Spek AL