Screening of glutaminolysis or glutamine metabolism inhibitors

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K05726
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: TAKEUCHI Toshifumi 公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (40516176)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: ペプチド / エネルギー代謝 / 全合成

Outline of Final Research Achievements

In the metabolism modulator screening program, screening was performed using a glutamine compensation assay to target glutaminolysis, which measures the cytotoxicity of cells cultured in media with glutamine or dimethyl ketoglutarate. In the glutaminolysis pathway, glutamine enters the cell and is converted into glutamic acid and α-ketoglutarate (α-KG), which enters the TCA cycle. Thus, dimethyl ketoglutarate (DMKG), a pro-drug of α-KG, can compensate for glutamine. This study identified an active n-BuOH extract from Micromonospora sp. MM609M-173N6 with glutamine dependent cytotoxicity. An acyldipeptide micromonosporamide A was isolated by bioassay-guided fractionation. The compound exhibited glutamine-dependent antiproliferative activity against the A549 and HCT116 cell lines.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

がんは様々な遺伝子変異の蓄積によって解糖系を亢進するなどエネルギー代謝経路を変化させて生存・増殖を有利にすることから，エネルギー代謝を阻害する化合物は，がん特有の代謝経路を利用した抗がん剤の候補として期待される．これまでの，エネルギー代謝阻害化合物の探索研究からアシルジペプチド マイクロモノスポラミドAを見出しその構造を決定するとともに合成経路を確立した．