BIOSYNTHESIS OF NOVEL ADRENOCORTICAL STEROIDS

新型肾上腺皮质类固醇的生物合成

• 批准号: 6138074
• 负责人: JOHN M HAMLYN
• 金额: $ 20.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138074
• 关键词: adrenal glands; aldosterone; animal tissue; chemical structure function; gas chromatography; immunologic assay /test; mass spectrometry; nuclear magnetic resonance spectroscopy; ouabain; radioimmunoassay; radiotracer; sodium potassium exchanging ATPase; steroid biosynthesis; tissue /cell culture

DESCRIPTION (Adapted from applicant's abstract): Cardiac glycosides are steroidal compounds of plant origin that enjoy widespread use in medicine and the basic sciences. They bind with high affinity and specificity to a highly conserved site on the sodium-potassium pump. Overwhelming structural and functional evidence shows the presence of an isomer of ouabain in the circulation, and tissues of mammals including man and cattle. Much evidence suggests that the adrenal cortex may be the primary source of the circulating isomer (i.e., an "adrenal derived endogenous ouabain, AEO). However, the biosynthesis of AEO by mammals has not been described. The successful outcome of this investigation may constitute a major advance in steroid biochemistry and lend further credence to the evidence that AEO and related steroids are of physiological and medical significance. The proposal describes experiments using established procedures that investigate the synthesis of AEO by bovine adrenocortical tissue and cells in culture. The aims are: 1) to determine whether common steroidogenic precursors support synthesis and adrenal secretion of AEO and aldosterone; 2) to use radiolabeled precursors to determine whether they can be transformed by an ordered sequential process to AEO, and the point at which the pathway diverges from that for aldosterone; 3) to determine the functional activity of the secreted materials by analysis of the binding and inhibitory mechanism of action on the sodium pump, and 4) to investigate the structure of the secreted AEO and stable biologically active precursors using mass spectral and nuclear magnetic resonance techniques. Detailed knowledge of the structure of the adrenal materials can provide new insights into the design of improved cardiotonics as well as novel agents that interfere with receptor binding and adrenal biosynthesis.

描述（改编自申请人的摘要）：强心苷是 在医学上广泛使用的植物来源的甾体化合物 和基础科学。 它们以高亲和力和特异性结合 钠钾泵上高度保守的位点。 压倒性的结构 功能证据表明，哇巴因异构体的存在 包括人和牛在内的哺乳动物的循环和组织。 很多证据 表明肾上腺皮质可能是 循环异构体（即“肾上腺衍生的内源性哇巴因，AEO）”。 然而，哺乳动物AEO的生物合成尚未被描述。 此次调查的成功结果可能构成重大进展 类固醇生物化学并进一步证明 AEO 的证据 及相关类固醇具有生理和医学意义。 这 提案描述了使用既定程序进行的实验 牛肾上腺皮质组织和培养细胞合成 AEO。 目的是： 1) 确定是否存在常见的类固醇生成前体 支持AEO和醛固酮的合成和肾上腺分泌； 2）使用 放射性标记的前体以确定它们是否可以被 AEO 的有序顺序过程，以及路径的点 与醛固酮不同； 3）确定功能活性 通过分析结合和抑制来分析分泌物质 对钠泵的作用机制，以及4）研究结构 使用质量分析分泌的 AEO 和稳定的生物活性前体 光谱和核磁共振技术。 详细知识 肾上腺材料的结构可以提供新的见解 改进的强心剂以及干扰的新型药物的设计 受体结合和肾上腺生物合成。

项目成果

Plasma ouabain-like factor during acute and chronic changes in sodium balance in essential hypertension.

原发性高血压钠平衡急性和慢性变化期间的血浆哇巴因样因子。

• 发表时间: 2001-08
• 作者: Manunta, P;Messaggio, E;Ballabeni, C;Sciarrone, M T;Lanzani, C;Ferrandi, M;Hamlyn, J M;Cusi, D;Galletti, F;Bianchi, G;Salt Sensitivity Study Group of the Italian Society of Hypertension
• 通讯作者: Salt Sensitivity Study Group of the Italian Society of Hypertension