Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase
Autor: | Yuanyuan Zhang, Yiluan Ding, Wen Li, C.Q. Liu, Hong-Bo Wang, Kaixian Chen, Jie Zheng, X. H. Zhou, Cheng Luo, Naixia Zhang, Hualiang Jiang, Liping Liao, Zhong-Ya Sun, Yanjun Liu, Jing Lu, Kehao Zhao, Ning Song, Senhao Xiao |
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Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Magnetic Resonance Spectroscopy Drug Evaluation Preclinical Hydrogen Deuterium Exchange-Mass Spectrometry Dehydrogenase Real-Time Polymerase Chain Reaction Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine stomatognathic system Glyceraldehyde Organometallic Compounds Animals Humans Pharmacology (medical) Glycolysis Lactic Acid Glyceraldehyde 3-phosphate dehydrogenase Pharmacology chemistry.chemical_classification biology Glyceraldehyde-3-Phosphate Dehydrogenases General Medicine Hydrolyzable Tannins Mice Inbred C57BL Glucose 030104 developmental biology Enzyme Biochemistry chemistry Anaerobic glycolysis 030220 oncology & carcinogenesis biology.protein NAD+ kinase Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) Cysteine |
Zdroj: | Acta Pharmacol Sin |
ISSN: | 1745-7254 1671-4083 |
Popis: | 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-β-D-glucopyranose (PGG) is an inhibitor of GAPDH with K(i) = 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. |
Databáze: | OpenAIRE |
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