日本东北大学魏范研小组宣布他们的最新研究提出了腺苷激酶和ADAL协调修饰的腺苷的解毒，以保障代谢。2025年8月20日，国际知名学术期刊《细胞》发表了这一成果。
课题组研究人员证明了三种RNA衍生的修饰腺苷，N6-甲基腺苷（m6A）， N6，N6-二甲基腺苷（m6,6A）和N6-异戊烯基腺苷（i6A），依次代谢成肌苷单磷酸（IMP），以减轻其内在的细胞毒性。经过腺苷激酶（ADK）磷酸化后，再经过腺苷脱氨酶样（ADAL）脱氨。在Adal基因敲除小鼠中，N6修饰的单磷酸腺苷（AMP）积累并变构抑制AMP活化的蛋白激酶（AMPK），导致糖代谢失调。
此外，与人类遗传性嘌呤代谢紊乱有关的ADK缺乏会提高三种修饰腺苷的水平，从而导致小鼠早期死亡。从机制上讲，过量的m6A、m6,6A和i6A通过干扰溶酶体膜蛋白而损害溶酶体功能，从而破坏脂质代谢并引起细胞毒性。通过这种核苷酸代谢途径和机制，细胞解毒修饰的腺苷，将修饰的RNA代谢与人类疾病联系起来。
据介绍，RNA包含多种转录后修饰，其分解代谢分解产生许多需要正确处理的修饰核苷，但其机制尚不清楚。
附：英文原文
Title: Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism
Author: Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei
Issue&Volume: 2025-08-20
Abstract: RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N6-methyladenosine (m6A), N6,N6-dimethyladenosine (m6,6A), and N6-isopentenyladenosine (i6A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N6-modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m6A, m6,6A, and i6A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.
DOI: 10.1016/j.cell.2025.07.041
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00863-3