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Natural product 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase.
Li, Wen; Liao, Li-Ping; Song, Ning; Liu, Yan-Jun; Ding, Yi-Luan; Zhang, Yuan-Yuan; Zhou, Xiao-Ru; Sun, Zhong-Ya; Xiao, Sen-Hao; Wang, Hong-Bo; Lu, Jing; Zhang, Nai-Xia; Jiang, Hua-Liang; Chen, Kai-Xian; Liu, Chuan-Peng; Zheng, Jie; Zhao, Ke-Hao; Luo, Cheng.
Afiliación
  • Li W; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • Liao LP; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Song N; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Liu YJ; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Ding YL; Center of Immunological Diseases, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhang YY; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zhou XR; Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201210, China.
  • Sun ZY; Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xiao SH; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Wang HB; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Lu J; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Zhang NX; School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China.
  • Jiang HL; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Chen KX; School of Life Science and Technology, Harbin Institute of Technology, Harbin, 200092, China.
  • Liu CP; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Zheng J; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • Zhao KH; School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China.
  • Luo C; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
Acta Pharmacol Sin ; 43(2): 470-482, 2022 Feb.
Article en En | MEDLINE | ID: mdl-33850276
Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancer cell glucose metabolism and plays a crucial role in the activation of various types of immune cells. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzes the conversion of D-glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate in the 6th critical step in glycolysis. GAPDH exerts metabolic flux control during aerobic glycolysis and therefore is an attractive therapeutic target for cancer and autoimmune diseases. Recently, GAPDH inhibitors were reported to function through common suicide inactivation by covalent binding to the cysteine catalytic residue of GAPDH. Herein, by developing a high-throughput enzymatic screening assay, we discovered that the natural product 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranose (PGG) is an inhibitor of GAPDH with Ki = 0.5 µM. PGG blocks GAPDH activity by a reversible and NAD+ and Pi competitive mechanism, suggesting that it represents a novel class of GAPDH inhibitors. In-depth hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PGG binds to a region that disrupts NAD+ and inorganic phosphate binding, resulting in a distal conformational change at the GAPDH tetramer interface. In addition, structural modeling analysis indicated that PGG probably reversibly binds to the center pocket of GAPDH. Moreover, PGG inhibits LPS-stimulated macrophage activation by specific downregulation of GAPDH-dependent glucose consumption and lactate production. In summary, PGG represents a novel class of GAPDH inhibitors that probably reversibly binds to the center pocket of GAPDH. Our study sheds new light on factors for designing a more potent and specific inhibitor of GAPDH for future therapeutic applications.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Taninos Hidrolizables / Gliceraldehído-3-Fosfato Deshidrogenasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Acta Pharmacol Sin Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Taninos Hidrolizables / Gliceraldehído-3-Fosfato Deshidrogenasas Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Acta Pharmacol Sin Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos