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 () and Yongjun Dang ()
Additional contact information
Ruina Wang: Shanghai Medical College, Fudan University
Lei Xiao: Shanghai Medical College, Fudan University
Jianbo Pan: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
Guangsen Bao: Shanghai Medical College, Fudan University
Yunmei Zhu: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
Di Zhu: Shanghai Medical College, Fudan University
Jun Wang: Chinese Academy of Sciences
Chengfeng Pei: Chinese Academy of Sciences
Qinfeng Ma: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
Xian Fu: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
Ziruoyu Wang: Shanghai Medical College, Fudan University
Mengdi Zhu: Chinese Academy of Sciences
Guoxiang Wang: Shanghai Medical College, Fudan University
Ling Gong: Shanghai Medical College, Fudan University
Qiuping Tong: Shanghai Medical College, Fudan University
Min Jiang: Shanghai Medical College, Fudan University
Junchi Hu: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
Miao He: Shanghai Medical College, Fudan University
Yun Wang: Shanghai Medical College, Fudan University
Tiejun Li: Naval Medical University
Chunmin Liang: Basic Medical School of Fudan University
Wei Li: China Pharmaceutical University
Chunmei Xia: Shanghai Medical College, Fudan University
Zengxia Li: Shanghai Medical College, Fudan University
Dengke K. Ma: University of California San Francisco
Minjia Tan: Chinese Academy of Sciences
Jun Yan Liu: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University
Wei Jiang: Shanghai Medical College, Fudan University
Cheng Luo: Chinese Academy of Sciences
Biao Yu: Chinese Academy of Sciences
Yongjun Dang: the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-41435-y

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