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

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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.