Search for marine bioactive substances useful for studies of Ca^<2+> signal transductions

在这个研究项目中，我们研究了冲绳海洋生物的生物活性物质，以发现激活或抑制重要蛋白质活性的有用化合物，如Ca通道、Ca- atp酶、肌动球蛋白atp酶、钙调蛋白和蛋白激酶c。这些蛋白质在细胞内Ca^<2+>信号转导中起着至关重要的作用。角酰胺A是一种抑制肌浆网Ca^<2+>- atp酶活性的环状肽。作为肌动球蛋白atp酶的激活剂，ageliferins和oxysceptrin二聚体溴吡咯生物碱从Agelas属海绵中分离得到。来自于被囊动物的一种吡咯嘧啶生物碱——刚性蛋白，和来自海绵的一种环状肽——康巴胺，显示出钙调素的拮抗活性。从被囊动物硬丝瘤中分离到24元大环内酯类化合物，作为蛋白激酶C的激活剂。这些化合物的化学结构是在广泛的光谱数据的基础上阐明的。在这些化合物中，iejimalides C和D是特别独特的，因为这些大环内酯的一部分结构改变会导致对蛋白激酶C的作用从激活到抑制的变化。因此，我们期望Iejimalides C和D能成为了解蛋白激酶C的分子作用机制的有用工具。

In this research project we studied bioactive substances from Okinawan marine organisms to find useful compounds that activate or inhibit the activities of important proteins such as Ca-channel, Ca-ATPase, actomyosin ATPase, calmodulin, and protein kinase C. These proteins have crucial roles in intracellular Ca^<2+> signal transductions.Keramamide A, a cyclic peptide which inhibits the activity of sarcoplassic reticulum Ca^<2+>-ATPase, was obtained from a sponge Theonella sp. As actomyosin ATPase activators, ageliferins and oxysceptrin, dimeric bromopyrrole alkaloids, were isolated from sponges of the genus Agelas. Rigidin, a pyrrolopyrimidine alkaloid, from a tunicate Eudistoma cf. rigida, and konbamide, a cyclic peptide, from a sponge Theonella sp. exhibited calmodulin antagonistic activity. Iejimalides C and D, 24-membered macrolide sulfates, were isolated from a tunicate Eudistoma cf. rigida as protein kinase C activators. The chemical structures of These compounds were elucidated on the basis of extensive spectroscopic data.Among these compounds, iejimalides C and D are especially unique since structural change of a part of these macrolides induces a change of the effect against protein kinase C from activation to inhibition. Iejimalides C and D are therefore expected as a useful tool for understanding the molecular mechanism of action of protein kinase C.