2. Academic Validation
  3. Natural product P57 induces hypothermia through targeting pyridoxal kinase

Natural product P57 induces hypothermia through targeting pyridoxal kinase

  • Nat Commun. 2023 Sep 26;14(1):5984. doi: 10.1038/s41467-023-41435-y.
Ruina Wang # 1,  Lei Xiao # 2,  Jianbo Pan # 3,  Guangsen Bao # 1,  Yunmei Zhu 3,  Di Zhu 1,  Jun Wang 4,  Chengfeng Pei 5,  Qinfeng Ma 3,  Xian Fu 3,  Ziruoyu Wang 1,  Mengdi Zhu 5,  Guoxiang Wang 2,  Ling Gong 2,  Qiuping Tong 2,  Min Jiang 2,  Junchi Hu 3,  Miao He 2,  Yun Wang 2,  Tiejun Li 6,  Chunmin Liang 7,  Wei Li 8,  Chunmei Xia 9,  Zengxia Li 1,  Dengke K Ma 10,  Minjia Tan 4,  Jun Yan Liu 3,  Wei Jiang 11,  Cheng Luo 12,  Biao Yu 13,  Yongjun Dang 14
Affiliations

Affiliations

  • 1 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, Shanghai, China.
  • 2 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3 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, Chongqing, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 6 Department of Pharmacology, College of Pharmacy, Naval Medical University, Shanghai, China.
  • 7 Lab of Tumor Immunology, Department of Human Anatomy, Histology and Embryology, Basic Medical School of Fudan University, Shanghai, China.
  • 8 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.
  • 9 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 10 Department of Physiology, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 11 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, Shanghai, China. [email protected].
  • 12 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 13 State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 14 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, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 37752106 DOI: 10.1038/s41467-023-41435-y
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.

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