德国马克斯·普朗克衰老生物学研究所Constantinos Demetriades、瑞士弗里堡大学Claudio De Virgilio和Stefano Vanni以及德国癌症研究中心Aurelio A. Teleman合作发现，丙二酰辅酶A是一种保守的内源性ATP竞争性雷帕霉素复合物1 (mTORC1)抑制剂。相关论文于2023年8月10日发表在《自然-细胞生物学》杂志上。

他们表明mTORC1通过检测丙二酰辅酶A的水平来感知细胞合成脂肪酸的能力，丙二酰辅酶A是这种生物合成途径的中间产物。他们发现，在酵母和哺乳动物细胞中，这种调节是直接的，丙二酰辅酶A结合到mTOR催化口袋并作为特定的ATP竞争抑制剂。当脂肪酸合成酶(FASN)下调/抑制时，升高的丙二酰辅酶A水平被引导到近端mTOR分子，与乙酰辅酶A羧化酶1 (ACC1)和FASN形成直接的蛋白-蛋白相互作用。

他们的研究结果代表了一种保守而独特的稳态机制，即受损的脂肪酸生物生成导致mTORC1活性降低，从而协调将这种代谢途径与整个细胞生物合成输出联系起来。此外，他们揭示了一种生理代谢物的存在，通过与ATP竞争结合，直接抑制哺乳动物细胞中信号激酶的活性。

据介绍，细胞生长受哺乳动物/机制靶mTORC1的调节，它既是营养传感器，也是几乎所有生物合成途径的主控制器。这确保了细胞只有在生长条件最佳时才具有代谢活性。值得注意的是，尽管已知mTORC1调节脂肪酸的生物合成，但细胞脂质生物合成能力如何以及是否能发出信号，以微调mTORC1活性，仍然知之甚少。

附：英文原文

Title: Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor

Author: Nicastro, Raffaele, Brohe, Laura, Alba, Josephine, Nchel, Julian, Figlia, Gianluca, Kipschull, Stefanie, Gollwitzer, Peter, Romero-Pozuelo, Jesus, Fernandes, Stephanie A., Lamprakis, Andreas, Vanni, Stefano, Teleman, Aurelio A., De Virgilio, Claudio, Demetriades, Constantinos

Issue&Volume: 2023-08-10

Abstract: Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here we show that mTORC1 senses the capacity of a cell to synthesise fatty acids by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When fatty acid synthase (FASN) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein–protein interactions with acetyl-CoA carboxylase 1 (ACC1) and FASN. Our findings represent a conserved and unique homeostatic mechanism whereby impaired fatty acid biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.

DOI: 10.1038/s41556-023-01198-6

Source: https://www.nature.com/articles/s41556-023-01198-6