细胞信号,细胞代谢,环状二核苷酸 z-bo 2020-09-16 446

　　Cyclic dinucleotide second messenger molecules (c-di-AMP, c-di-GMP, and c-GAMP) are small molecules that play an important intermediary role in the signal transduction pathway. In recent years, studies have found that they are in natural immune signaling. Play an important role in the pathway. The pathogenic bacterium Vibrio cholerae encodes a nucleotide cyclase DncV that can synthesize all three cyclic dinucleotides. Sequence alignment shows that DncV-like cyclases are widespread in intestinal pathogens.

　　Xiang Ye’s research group reported on the structure of cholera nucleotide cyclase DncV and its substrate complex. Based on the structure, the molecular mechanism by which DncV can synthesize three different cyclic dinucleotides was elucidated. In the DncV structure study, the research team also unexpectedly discovered that a small molecule similar to folic acid was bound to the back of the enzyme substrate binding pocket. This small molecule discovered through structural studies was determined to be 5-methyltetrahydrofolate (5MTHF) or 5-methyltetrahydrofolate (5MTHFGLU2) with two glutamic acids after mass spectrometry analysis, of which 5MTHFGLU2 accounted for the majority.

　　"The protein residues involved in the binding of 5MTHFGLU2 are highly conserved among DncV enzymes. Subsequent biochemical experiments confirmed that small folate molecules can inhibit the enzyme activity of DncV. At the same time, cell experiments confirmed that when the folic acid synthesis pathway in bacteria is blocked by drugs, the synthesis of cyclic dinucleotides doubles. These studies show that folic acid molecules have the biological activity of regulating pathogenic bacteria cyclic dinucleotide second messenger synthase.

　　Folic acid and its derivatives are important cell metabolism factors required by lower or higher organisms. Lack of folic acid can cause many diseases including dysentery. The pathogenic bacteria in the human body may change their folic acid synthesis due to nutritional deficiency, thereby affecting the synthesis of cyclic dinucleotide second messengers, and ultimately affecting the pathogenicity and natural immune response of the pathogen. The reviewer commented that the study is a typical representative of discovering new biological pathways through structural originality.

　　The work was completed by the cooperation of Tsinghua University, Shandong University and China CDC Infectious Disease Prevention and Control Institute. Research assistant Wang Lijun of the School of Medicine of Tsinghua University, doctoral student Liu Xue, Shandong University associate professor Zhu Deyu, doctoral students Shang Guijun and Zhu Jing are the co-first authors of this paper. The authors also include Professor Zhang Jingren from the School of Medicine of Tsinghua University, research assistant Wang Lei, researcher Kan Biao of the China CDC Institute for Infectious Disease Control and Prevention, and Lu Defen, a doctoral student at Shandong University. The corresponding author of this paper is Researcher Xiang Ye. The work received strong support from the Ministry of Science and Technology, National Natural Science Foundation of China, Tsinghua Startup Fund, Shandong Natural Science Foundation and Shanghai Synchrotron Radiation.