A temperature-regulated bioorthogonal reaction to target lysine: Hemiacetal pharmacophore in genipin irreversibly binds with UCP2, inhibiting mitochondrial thermogenesis |
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| Institution: | 1. Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai 201203, China;2. The Institutes of Integrative Medicine of Fudan University, Shanghai 200040, China;3. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;1. Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People''s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China;2. College of Food and Bioengineering, Xihua University, Chengdu 610039, China;3. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;4. Emergency Intensive Care Unit, Sichuan Academy of Medical Science & Sichuan Provincial People''s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China |
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| Abstract: | Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species (ROS) production have been associated with aging, cancer, neurodegenerative diseases, and other disorders. Uncoupling protein 2 (UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin (GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ɛ-amine of lysine on the UCP2 proton leakage channel through ring-opening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ɛ-amine of lysine on proteins. |
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