Molecular Mechanism of Action for Particularly Potent Marine Biotoxins.

特别有效的海洋生物毒素的分子作用机制。

基本信息

项目摘要

Maitotoxin (MTX) was first discovered as one of the toxins responsible for ciguatera, a seafood poisoning caused by ingestion of coral reef fish. MTX has extremely potent bioactivities ; its toxicity is particularly worth noting, since its LD_<50>(50 ng/kg, mouse ip.) is exceeded only by a few proteinaceous toxins. MTX elicits Ca^<2+> influx in virtually all cells and tissues and this elevation in intracellular calcium concentration leads to secondary events ; e.g., phosphoinositide breakdown, arachidonic acid release, muscle contraction, and secretion of dopamine, norepinephrine, and insulin. Gangliosides GM1 and GM3 strongly inhibited MTX-induced Ca^<2+> influx in C6 cells. Their inhibitory potency was in the order GM1 (IC_<50>, ca. 2 μM)>GM3 (ca. 5 μM)>asialo-GM1 (ca. 20 μM). GM1 (3 μM) completely blocked MTX(30 nM)-induced Ca^<2+> influx in human erythrocyte ghosts. When C6 cells were pretreated with tunicamycin, an antibiotic which inhibits N-linked glycosylation, or concanavalin A, a lectin which exhibits high affinity for cell-surface oligosaccharides, MTX-induced Ca^<2+> influx was significantly potentiated. This suggests that removal of oligosaccharides from the cell surface by tunicamycin or capping of sugar chains on plasma membranes by concanavalin A can potentiate the action of MTX.Photoaffinity labeling experiment to identify MTX-binding protein was carried out with use of a daizirine-biotin conjugated reagent developed by Hatanaka. Some spots on 2D electrophoresis, corresponding to 2 KDa were eliminated by addition of an MTX inhibitor, brevetoxin-B.
Maitotoxin (MTX)最初被发现是导致雪卡毒素的毒素之一,雪卡毒素是一种因摄入珊瑚礁鱼类而引起的海产品中毒。甲氨蝶呤具有极强的生物活性;其毒性特别值得注意,因为其LD_<50>(50 ng/kg,小鼠体重)只有少数蛋白质类毒素超过。MTX在几乎所有细胞和组织中引起Ca^<2+>内流,细胞内钙浓度的升高导致继发性事件;例如,磷酸肌肽分解、花生四烯酸释放、肌肉收缩、多巴胺、去甲肾上腺素和胰岛素的分泌。神经节苷脂GM1和GM3强烈抑制mtx诱导的C6细胞Ca^<2+>内流。它们的抑制效价依次为GM1 (IC_<50>,约为2 μM)、>GM3(约为5 μM)、>asialo-GM1(约为20 μM)。GM1 (3 μM)完全阻断MTX(30 nM)诱导的Ca^<2+>内流。当用tunicamycin(一种抑制n -连接糖基化的抗生素)或concanavalin A(一种对细胞表面寡糖具有高亲和力的凝集素)预处理C6细胞时,mtx诱导的Ca^<2+>内流显著增强。这表明,tunicamycin从细胞表面去除寡糖或concanavalin A在质膜上盖上糖链可以增强MTX的作用。利用Hatanaka开发的daizirine-biotin偶联试剂进行了鉴定mtx结合蛋白的光亲和标记实验。通过添加MTX抑制剂brevetoxin-B,可以消除2D电泳上与2kda对应的一些点。

项目成果

期刊论文数量(31)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Konoki,K.: "Direct observation of binding between biotinylated okadaic acid and protein phosphatase 2A monitored by surface plasmon resonance."Tetrahedron Lett.. 40. 887-890 (1999)
Konoki,K.:“通过表面等离子共振监测生物素化的大田酸和蛋白磷酸酶 2A 之间的结合的直接观察。”Tetrahedron Lett.. 40. 887-890 (1999)
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村田道雄: "The Structure Elucidation and Biological Activities of High Molecular Weight Algal Toxins : Maitoroxin, Prymnesing and Zooxanthellatoxins."Nat.Prod.Rep.. 17. 293-316 (2000)
Michio Murata:“高分子量藻类毒素的结构阐明和生物活性:Maitroxin、Prymnesing 和Zooxanthellatoxins。Nat.Prod.Rep.. 17. 293-316 (2000)
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Murata, M.and Yasumoto, T.: "The structure elucidation and biological activities of high molecular weight algal toxins : maitotoxin, prymnesins and zooxanthellatoxins."Nat.Prod.Rep.. 17. 293-316 (2000)
Murata, M. 和 Yasumoto, T.:“高分子量藻类毒素的结构阐明和生物活性:麦毒毒素、紫草毒素和虫黄藻毒素。”Nat.Prod.Rep.. 17. 293-316 (2000)
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Keiichi Konoki: "Inhibition of maitotoxin-induced Ca^<2+> in fhex in rat glioma C6 cells by breretrcins and synthetic fragment of maitotoxin" Journal of Neurochemistry. 70. 409-416 (1998)
Keiichi Konoki:“布雷特菌素和麦芽毒素的合成片段对大鼠神经胶质瘤C6细胞中麦芽毒素诱导的Ca 2+ 的抑制”《神经化学杂志》。
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Konoki, K., Sugiyama, N., Murata, M., Tachibana, K., Hatanaka, Y.: "Development of biotin-Avidin technology to investigate okadaic acid-promoted cell signaling pathway."Tetrahedron. 56. 9003-9014 (2000)
Konoki, K.、Sugiyama, N.、Murata, M.、Tachibana, K.、Hatanaka, Y.:“开发生物素-亲和素技术来研究冈田酸促进的细胞信号传导途径。”四面体。
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MURATA Michio其他文献

MURATA Michio的其他文献

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{{ truncateString('MURATA Michio', 18)}}的其他基金

Dynamic conformation and domain structure of lipid molecules in model biomembranes
模型生物膜中脂质分子的动态构象和域结构
  • 批准号:
    16H06315
  • 财政年份:
    2016
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
Rapid conformational change results in attractive interactions between biomolecules
快速构象变化导致生物分子之间有吸引力的相互作用
  • 批准号:
    24651244
  • 财政年份:
    2012
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Structures and Functions of Membrane-Bound Biomolecules
膜结合生物分子的结构和功能
  • 批准号:
    18101010
  • 财政年份:
    2006
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
Structure of Molecular Assembles of Bioactive Natural Products Formed in Biomembranes
生物膜中形成的生物活性天然产物的分子组装结构
  • 批准号:
    15201048
  • 财政年份:
    2003
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Frontier in Structure Elucidation of Natural Products
天然产物结构解析前沿
  • 批准号:
    12045243
  • 财政年份:
    2000
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
Practical Configuration Analysis for Natural Products.
天然产物的实用构型分析。
  • 批准号:
    10554043
  • 财政年份:
    1998
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
Membrane Protein Recognition by Ladder-shaped Polyether Compounds
梯形聚醚化合物的膜蛋白识别
  • 批准号:
    08458171
  • 财政年份:
    1996
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Complete Structure Elucidation of Maitotoxin
麦芽毒素的完整结构解析
  • 批准号:
    06453211
  • 财政年份:
    1994
  • 资助金额:
    $ 6.02万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)

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    24790082
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