Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis

• 成果类型: Article
• 署名作者: Sahu, Umakant; Villa, Elodie; Reczek, Colleen R.; Zhao, Zibo; O'Hara, Brendan P.; Torno, Michael D.; Mishra, Rohan; Shannon, William D.; Asara, John M.; Gao, Peng; Shilatifard, Ali; Chandel, Navdeep S.; Ben-Sahra, Issam
• 署名单位: Northwestern University; Feinberg School of Medicine; Northwestern University; Robert H. Lurie Comprehensive Cancer Center; Ann & Robert H. Lurie Children's Hospital of Chicago; Northwestern University; Feinberg School of Medicine; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Northwestern University; Robert H. Lurie Comprehensive Cancer Center; Ann & Robert H. Lurie Children's Hospital of Chicago
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8170
• DOI: 10.1126/science.adh2771
• 发表日期: 2024-03-29
• 页码: 1484-1492
• 关键词: mass-spectrometry; metabolism; dehydrogenase; biosynthesis; atp; pyrophosphokinase; enzymes; binding; protein; flux

摘要

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.