Nature Communications (Sep 2023)
Natural product P57 induces hypothermia through targeting pyridoxal kinase
- Ruina Wang,
- Lei Xiao,
- Jianbo Pan,
- Guangsen Bao,
- Yunmei Zhu,
- Di Zhu,
- Jun Wang,
- Chengfeng Pei,
- Qinfeng Ma,
- Xian Fu,
- Ziruoyu Wang,
- Mengdi Zhu,
- Guoxiang Wang,
- Ling Gong,
- Qiuping Tong,
- Min Jiang,
- Junchi Hu,
- Miao He,
- Yun Wang,
- Tiejun Li,
- Chunmin Liang,
- Wei Li,
- Chunmei Xia,
- Zengxia Li,
- Dengke K. Ma,
- Minjia Tan,
- Jun Yan Liu,
- Wei Jiang,
- Cheng Luo,
- Biao Yu,
- Yongjun Dang
Affiliations
- Ruina Wang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Lei Xiao
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Jianbo Pan
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- Guangsen Bao
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Yunmei Zhu
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- Di Zhu
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Jun Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Chengfeng Pei
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Qinfeng Ma
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- Xian Fu
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- Ziruoyu Wang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Mengdi Zhu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Guoxiang Wang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Ling Gong
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Qiuping Tong
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Min Jiang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Junchi Hu
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- Miao He
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Yun Wang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University
- Tiejun Li
- Department of Pharmacology, College of Pharmacy, Naval Medical University
- Chunmin Liang
- Lab of Tumor Immunology, Department of Human Anatomy, Histology and Embryology, Basic Medical School of Fudan University
- Wei Li
- Department of Medicinal Chemistry, China Pharmaceutical University
- Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Zengxia Li
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Dengke K. Ma
- Department of Physiology, Cardiovascular Research Institute, University of California San Francisco
- Minjia Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Jun Yan Liu
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- Wei Jiang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University
- Cheng Luo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Biao Yu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Yongjun Dang
- Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Institute of Life Sciences, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
- DOI
- https://doi.org/10.1038/s41467-023-41435-y
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 15
Abstract
Abstract Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.