PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth
Summary: 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...
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725008423 |
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| author | Qingen Da Yongfeng Cai Qian Ma Qiuhua Yang Yapeng Cao Yaqi Zhou Dingwei Zhao Zhiping Liu Jiean Xu Junming Quan Liang Zhang Rui Wang Xuejun Jiang Xiao Liu Kunfu Ouyang Zhen Han Jikui Liu Tao Wang Chunxiang Zhang Neal L. Weintraub David J.R. Fulton Jun Zhao Mei Hong Zigang Li Yuqing Huo |
| author_facet | Qingen Da Yongfeng Cai Qian Ma Qiuhua Yang Yapeng Cao Yaqi Zhou Dingwei Zhao Zhiping Liu Jiean Xu Junming Quan Liang Zhang Rui Wang Xuejun Jiang Xiao Liu Kunfu Ouyang Zhen Han Jikui Liu Tao Wang Chunxiang Zhang Neal L. Weintraub David J.R. Fulton Jun Zhao Mei Hong Zigang Li Yuqing Huo |
| author_sort | Qingen Da |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-7d5c3faedd7048ffaf32a8c73a3a3686 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-7d5c3faedd7048ffaf32a8c73a3a36862025-08-20T02:46:40ZengElsevierCell Reports2211-12472025-08-0144811607110.1016/j.celrep.2025.116071PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growthQingen Da0Yongfeng Cai1Qian Ma2Qiuhua Yang3Yapeng Cao4Yaqi Zhou5Dingwei Zhao6Zhiping Liu7Jiean Xu8Junming Quan9Liang Zhang10Rui Wang11Xuejun Jiang12Xiao Liu13Kunfu Ouyang14Zhen Han15Jikui Liu16Tao Wang17Chunxiang Zhang18Neal L. Weintraub19David J.R. Fulton20Jun Zhao21Mei Hong22Zigang Li23Yuqing Huo24State 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, USAState 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, USAVascular 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, USAVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAVascular 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, USAVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAState 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, ChinaDepartment of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon 999077, Hong Kong, ChinaDepartment of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon 999077, Hong Kong, ChinaInstitute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ChinaInstitute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ChinaState 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, ChinaState 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, ChinaState 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, ChinaState 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, ChinaDepartment 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, ChinaVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USAVascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USACleveland Clinic, Florida Research & Innovation Center (FRIC), Port Saint Lucie, FL 34987, USAState 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, ChinaState 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, ChinaVascular 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725008423CP: MetabolismCP: Molecular biology |
| spellingShingle | Qingen Da Yongfeng Cai Qian Ma Qiuhua Yang Yapeng Cao Yaqi Zhou Dingwei Zhao Zhiping Liu Jiean Xu Junming Quan Liang Zhang Rui Wang Xuejun Jiang Xiao Liu Kunfu Ouyang Zhen Han Jikui Liu Tao Wang Chunxiang Zhang Neal L. Weintraub David J.R. Fulton Jun Zhao Mei Hong Zigang Li Yuqing Huo PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth Cell Reports CP: Metabolism CP: Molecular biology |
| title | PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth |
| title_full | PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth |
| title_fullStr | PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth |
| title_full_unstemmed | PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth |
| title_short | PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth |
| title_sort | pfkfb3 activates cad to enhance de novo pyrimidine synthesis for cell growth |
| topic | CP: Metabolism CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725008423 |
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