美国西北大学Issam Ben-Sahra团队近期取得重要工作进展，他们研究提出，嘧啶维持线粒体丙酮酸氧化以支持从头脂肪生成。相关研究成果
据介绍，细胞嘌呤，特别是5′-三磷酸腺苷（ATP），为许多代谢反应提供燃料，但人们对于嘧啶直接影响细胞代谢的细节知之甚少。
研究人员发现嘧啶（而不是嘌呤）通过调节丙酮酸脱氢酶（PDH）活性来维持丙酮酸氧化和三羧酸-柠檬酸（TCA）循环。PDH活性需要足够的底物和辅因子，包括焦磷酸硫胺素（TPP）。细胞中嘧啶的消耗会减少TPP的合成，TPP激酶1(TPK1)负责进行这一反应，据报道，TPK1利用ATP使硫胺素（维生素B1）磷酸化。研究人员发现尿苷5′-三磷酸（UTP）是TPK1的首选底物，能够促进细胞TPP合成、PDH活性、TCA循环活性、脂肪生成和脂肪细胞分化。
因此，UTP是维生素B1利用以维持丙酮酸氧化和脂肪生成所必需的。
附：英文原文
Title: Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis
Author: Umakant Sahu, Elodie Villa, Colleen R. Reczek, Zibo Zhao, Brendan P. O’Hara, Michael D. Torno, Rohan Mishra, William D. Shannon, John M. Asara, Peng Gao, Ali Shilatifard, Navdeep S. Chandel, Issam Ben-Sahra
Issue&Volume: 2024-03-29
Abstract: Cellular purines, particularly adenosine 5′-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5′-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.
DOI: adh2771
Source: https://www.science.org/doi/10.1126/science.adh2771