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SEARCH FOR METABOLITES INFLUENCING CELLAR FUNCTION FROM AQUATIC INVERTEBRATES AND ANLYSIS OF THEIR MODES OF ACTION.

从水生无脊椎动物中寻找影响细胞功能的代谢物并分析其作用模式。

基本信息

批准号：
09306014
负责人：
FUSETANI Nobuhiro
金额：
$ 16.77万
依托单位：
THE UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 2000
项目状态：
已结题

项目摘要

A number of marine invertebrates including sponges, soft corals, and tunicates collected from various Japanese coasts has been tested for cytotoxicity against P388 leukemia cells, morphological changes-inducing activity in rat neuroblast 3Y1, inhititory activity against serine proteases, cystein proteases, metalloproteinases, and glycosidases. Isolation and structure elucidation of active constituents from promising specimens resulted in discovery of 71 new compounds, among which calmodulin-inhibiting alkaloids were included. Biological activity studies of new calyculin derivatives and those derived chemically from calyculin A led to important insights into the interaction of calyculins with protein phosphatases.Detailed analyses of modes of action of selective compounds obtained led to several inportant findings. Mycalolides/kabiramides bind to a different site of actin from those of cytochalasin D and latrunculin A.Bistheonellide A bind to G-actin in a molar ration of 1 : 2 to inhibit actin polymerization. Stellettamide A and related alkaloids induce contraction of smooth muscles which was found to be due to inhibition of phosphorylation of myosin light chain by inhibiting calmodulin. It was also found that discodermin A forms pores in biomembranes and that theonellamides A and F interact with dehydrogenases.In search for metabolites affecting development of echinoderm embryos, several active substances were isolated from sponges including ancorinoside A and rhopaloic acids. Jaspisin was found to inhibit selectively a hatching enzyme of sea urchin, a matrix endopeptidase. Finally, a simple system to detect inhibitors of protein phosphatases such as okadaic acid and calyculin A by using antibodies which differentiate specific phosphorylated amino acids in ANO39, an endoplasmic reticulum protein of sea urchin eggs.

从日本海岸采集的海绵、软珊瑚和被囊动物等多种海洋无脊椎动物对P388白血病细胞的细胞毒性、诱导大鼠神经母细胞3Y1形态学变化的活性、对丝氨酸蛋白酶、半胱氨酸蛋白酶、金属蛋白酶和糖苷酶的抑制活性进行了测试。从有希望的标本中分离和鉴定了71个新化合物，其中包括抑制钙调素的生物碱。新的calyculin衍生物和由calyculin A化学衍生的生物活性研究使我们对calyculin与蛋白磷酸酶的相互作用有了重要的认识。对所获得的选择性化合物的作用方式进行了详细的分析，得出了几个重要的发现。Mycalolides/kabiramide与细胞松弛素D和latrunculin a结合在肌动蛋白的不同位点上，双糖内酯a以1:2的摩尔比与g -肌动蛋白结合，抑制肌动蛋白聚合。星甲酰胺A及相关生物碱通过抑制钙调蛋白抑制肌球蛋白轻链磷酸化而引起平滑肌收缩。研究还发现，降脂素A在生物膜上形成孔洞，茶酰胺A和F与脱氢酶相互作用。为了寻找影响棘皮动物胚胎发育的代谢物，从海绵中分离出了几种活性物质，包括槐内酯A和蛇藿酸。发现茉莉素对海胆孵化酶基质内肽酶有选择性抑制作用。最后，我们建立了一个简单的系统，通过抗体区分海胆卵内质网蛋白ANO39中特定磷酸化的氨基酸，来检测蛋白质磷酸酶抑制剂，如冈田酸和花青素a。