TY - JOUR
T1 - Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis
AU - Sahu, Umakant
AU - Villa, Elodie
AU - Reczek, Colleen R.
AU - Zhao, Zibo
AU - O’Hara, Brendan P.
AU - Torno, Michael D.
AU - Mishra, Rohan
AU - Shannon, William D.
AU - Asara, John M.
AU - Gao, Peng
AU - Shilatifard, Ali
AU - Chandel, Navdeep S.
AU - Ben-Sahra, Issam
N1 - Publisher Copyright:
© 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024/3/29
Y1 - 2024/3/29
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85189259731
UR - https://www.scopus.com/inward/citedby.url?scp=85189259731&partnerID=8YFLogxK
U2 - 10.1126/science.adh2771
DO - 10.1126/science.adh2771
M3 - Article
C2 - 38547260
AN - SCOPUS:85189259731
SN - 0036-8075
VL - 383
SP - 1484
EP - 1492
JO - Science
JF - Science
IS - 6690
ER -