Publication Date
8-26-2025
Journal
Cell Reports
DOI
10.1016/j.celrep.2025.116071
PMID
40742808
PMCID
PMC12648754
PubMedCentral® Posted Date
11-27-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and cell proliferation. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under pathological conditions.
Keywords
Phosphofructokinase-2, Cell Proliferation, Humans, Pyrimidines, Dihydroorotase, Aspartate Carbamoyltransferase, Glycolysis, Phosphorylation, Animals, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Mice, Warburg effect, glycolysis, de novo pyrimidine synthesis, kinase activity, PFKFB3, CAD
Published Open-Access
yes
Recommended Citation
Da, Qingen; Cai, Yongfeng; Ma, Qian; et al., "PFKFB3 Activates Cad to Enhance De Novo Pyrimidine Synthesis for Cell Growth" (2025). Faculty, Staff and Students Publications. 6455.
https://digitalcommons.library.tmc.edu/baylor_docs/6455