2. Academic Validation
  3. PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth

PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth

  • Cell Rep. 2025 Aug 26;44(8):116071. doi: 10.1016/j.celrep.2025.116071.
Qingen Da 1,  Yongfeng Cai 2,  Qian Ma 3,  Qiuhua Yang 4,  Yapeng Cao 4,  Yaqi Zhou 4,  Dingwei Zhao 3,  Zhiping Liu 4,  Jiean Xu 4,  Junming Quan 5,  Liang Zhang 6,  Rui Wang 6,  Xuejun Jiang 7,  Xiao Liu 7,  Kunfu Ouyang 5,  Zhen Han 5,  Jikui Liu 5,  Tao Wang 5,  Chunxiang Zhang 8,  Neal L Weintraub 4,  David J R Fulton 4,  Jun Zhao 9,  Mei Hong 5,  Zigang Li 5,  Yuqing Huo 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Hospital, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • 2 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Hospital, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Departments of Ophthalmology, Medicine, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Departments of Ophthalmology, Medicine, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
  • 5 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Hospital, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 6 Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon 999077, Hong Kong, China.
  • 7 Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 8 Department of Cardiology, Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou 646000, China.
  • 9 Cleveland Clinic, Florida Research & Innovation Center (FRIC), Port Saint Lucie, FL 34987, USA.
  • 10 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Departments of Ophthalmology, Medicine, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: yuqing.huo@bcm.edu.
PMID: 40742808 DOI: 10.1016/j.celrep.2025.116071
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

CAD; CP: Metabolism; CP: Molecular biology; PFKFB3; Warburg effect; de novo pyrimidine synthesis; glycolysis; kinase activity.

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