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Study on the Regulatory Mechanism of Isocitrate Dehydrogenase1 Activity through Acetylation Modification

• 1、Cryus Tang Medical Institute,Soochou University,Suzhou,Jiangsu,215123

Abstract：Isocitrate Dehydrogenase1 (IDH1) is a key metabolic enzyme located in the cytoplasm that is involved in the oxidative decarboxylation of isocitrate to produce a-ketoglutarate (a-KG) in the tricarboxylic acid cycle and catalyzes the reduction of NADP+ to NADPH. Although studies in recent years have revealed the existence of multiple acetylation modification sites in IDH1 and initially revealed the regulatory roles of these modifications in tumor metabolism, oxidative stress, etc., the molecular mechanisms of acetylation at different sites and their potential value in tumor therapy still need to be further elucidated. In this paper, the acetylation modification of IDH1 in glioma cells was detected by treatment with deacetylase inhibitors, and the enzyme kinetic assay comparing in vitro purified wild-type and mutant protease activities revealed that K374 deacetylation significantly inhibited IDH1 enzyme activity, while the acetylation modification had a promotional effect on IDH1 activity, and the in vitro NADP+ binding assay showed that the IDH1 K374R mutated protein (mimicking deacetylated mutant) was not able to regulate tumor metabolism and oxidative stress. In vitro NADP+ binding assay showed that IDH1 K374R mutated protein (mimicking deacetylation mutation) was blocked from binding to NADP+, and significantly inhibited tumor cell proliferation. The present study elucidates a new mechanism by which IDH1 K374 acetylation affects tumor metabolism and progression through the regulation of enzyme activity, expanding the understanding of IDH1 function in tumors and suggesting that acetylation modification of the IDH1 K374 site may be a potential therapeutic target for IDH1 wild-type tumors.

Keywords： IDH1 acetylation modification tumor cell proliferation