Metabolic significance of lysosomal beta-alanine

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K08528
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Juntendo University
• Principal Investigator: Ueno Takashi 順天堂大学, 大学院医学研究科, 客員教授 (10053373)
• Co-Investigator(Kenkyū-buntansha): 數野 彩子 順天堂大学, 大学院医学研究科, 助教 (00338344)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: ピリミジン分解 / ウラシル / ウレイドプロピオン酸 / β－アラニン / リソソーム / ジヒドロウラシルデヒドロゲナーゼ / ウレイドプロピオナ－ゼ

Outline of Final Research Achievements

During the course of my research on liver autophagy I found that β-alanine, a non-proteinaceous amino acid, is abundantly present in autolysosomes and lysosomes isolated from rat and mouse livers. In view of this novel finding, I aimed at clarifying the mechanism by which endogenous β-alanine produced from uracil in the pyrimidine catabolic pathway is stored in lysosomes of many hepatocyte-derived cell lines, including HepG2, BRL, and Huh7. However, when the cells were cultured in the presence of β-alanine precursors, such as uracil and ureidopropionic acid, the amount of β-alanine synthesis was very low, and the possibility that this endogenous synthetic pathway contributes to β-alanine accumulation in the lysosome is very small. Since 14C-labeled β-alanine is rapidly taken up into the cells from the media, it is necessary to investigate the possibility that exogenous β-alanine taken up into the cells are further sequestered in the lysosome.

Free Research Field

タンパク分解

Academic Significance and Societal Importance of the Research Achievements

肝臓のピリミジン分解で生じるβ－アラニンがタンパク分解の拠点であるリソソームになぜ多いのかという疑問は、アミノ酸代謝の未知の問題として興味深く、β－アラニンが筋収縮を活性化するイミダゾールジペプチドのカルノシンやアンセリンの材料として機能することに鑑みれば、肝リソソームでのβ－アラニン貯留機構を明らかにする意義は、臓器間のクロストークという意味合いからも大きい。本研究で肝細胞での内在性β－アラニン合成そのものを確実に捉えられずに終わった点は、生化学的アプローチで扱える酵素反応の時間軸を遥かに超えた緩慢な反応と理解できる点で予想を裏切られたという感慨である。