Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis

Science. 2024 Mar 29;383(6690):1484-1492. doi: 10.1126/science.adh2771. Epub 2024 Mar 28.


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.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Citric Acid Cycle*
  • HeLa Cells
  • Humans
  • Lipogenesis*
  • Oxidation-Reduction
  • Protein Kinases / metabolism
  • Pyrimidines* / metabolism
  • Pyruvate Dehydrogenase Complex* / metabolism
  • Pyruvates* / metabolism
  • Thiamine / metabolism
  • Thiamine Pyrophosphate / metabolism
  • Uridine Triphosphate / metabolism


  • Adenosine Triphosphate
  • Pyrimidines
  • Pyruvates
  • Thiamine
  • Thiamine Pyrophosphate
  • Uridine Triphosphate
  • Protein Kinases
  • Pyruvate Dehydrogenase Complex