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SCREENING AND DEVELOPMENT OF INHIBITORS AND ACTIVATORS FOR DEGRADATION OF ORNITHINE DECARBOXYLASE (ODC)

鸟氨酸脱羧酶（ODC）降解抑制剂和激活剂的筛选和开发

基本信息

批准号：
09680632
负责人：
MURAKAMI Yasuko
金额：
$ 1.54万
依托单位：
JIKEI UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09680632/
关键词：
Ornithine decarboxylase Proteasome Inhibitors Proteolysis Polyamines Actinimycetes Antizyme 放射菌プトレッシン

项目摘要

Ornithine decarboxylase (ODC) is a key enzyme in polyamine biosynthesis and the only known enzyme degraded by the 26S proteasome without ubiquitination. Reagents that could modify ODC degradation could help resolve the physiological importance of ODC degradation and analyze degradation mechanism of non-ubiquitinated substrates by the 26S proteasome. The aim of this study is screening and development of inhibitors and activators of ODC degradation. The following results were obtained by the present study. 1) Three inhibitory substances were isolated from broth of Actinimycetes. One was identified as Antimycin A (ID50 : O.1mg/ml). Chemical structures of other two substances were close to Julimycin-BII and Julichrom Ql, 4, respectively. Their activities were comparable to that of lactacystin. 2) Known antibiotics were screened, and Actinomycin D and Glioririn were found to inhibit ODC weakly. 3) A strong inhibitory activity was found in broth of a mold. It was separated to several related substances by reversed phase chromatography and IC50of some of them were lower than 1mug/ml. Their purification is under way. 4) Agmatine was found to accelerate ODC degradation by frameshift induction of antizyme. 5) Several amines or basic amino acids were found to affect the efficiency of frameshift induction of antizyme.

鸟氨酸脱羧酶(ODC)是多胺生物合成的关键酶，也是目前已知的唯一一种被26S蛋白酶体降解而没有泛素化的酶。能够修饰ODC降解的试剂有助于解决ODC降解的生理意义，并通过26S蛋白酶体分析非泛素化底物的降解机制。本研究的目的是筛选和开发ODC降解的抑制剂和激活剂。本研究取得了以下研究成果。1)从放线菌发酵液中分离得到3种抑菌物质。1例为抗霉素A(ID50：0.1 mg/ml)。另外两种物质的化学结构分别与Julimycin-BII和Julichrom QL，4相近。它们的活性与lactacystin的活性相当。2)对已知抗生素进行筛选，发现放线菌素D和格列瑞林对ODC的抑制作用较弱。3)霉菌发酵液具有较强的抑菌活性。用反相色谱分离出几种有关物质，IC50部分低于1µg/ml，目前正在进行分离纯化。4)胍丁胺通过诱导抗酶移码加速ODC的降解。5)几种氨基酸或碱性氨基酸影响抗酶移码诱导的效率。