Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase
文献类型：期刊论文
| 作者 | Li Wen7; Liao Liping6; Song Ning5; Liu Yanjun6; Ding Yiluan4; Zhang Yuanyuan6; Zhou Xiaoru6; Sun Zhongya6; Xiao Senhao6; Wang Hongbo3 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2022 |
| 卷号 | 43期号:2页码:470 |
| ISSN号 | 1671-4083 |
| 关键词 | glyceraldehyde 3-phosphate dehydrogenase 1 2 3 4 6-penta-O-galloyl-β-D-glucopyranose hydrogen deuterium exchange mass spectrometry reversible inhibitor glycolysis |
| 英文摘要 | 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. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304857]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.Center of Immunological Diseases,Shanghai Institute of Materia Medica,Chinese Academy of Sciences 2.塔拉理工学院 3.Biotech Drugs in Universities of Shandong,Yantai University,School of Pharmacy 4.Department of Analytical Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences 5.中国科学院大学 6.Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Drug Discovery and Design Center,the Center for Chemical Biology 7.School of Pharmacy,Biotech Drugs in Universities of Shandong,Yantai University |
| 推荐引用方式 GB/T 7714 | Li Wen,Liao Liping,Song Ning,et al. Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase[J]. ACTA PHARMACOLOGICA SINICA,2022,43(2):470. |
| APA | Li Wen.,Liao Liping.,Song Ning.,Liu Yanjun.,Ding Yiluan.,...&Luo Cheng.(2022).Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase.ACTA PHARMACOLOGICA SINICA,43(2),470. |
| MLA | Li Wen,et al."Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase".ACTA PHARMACOLOGICA SINICA 43.2(2022):470. |
入库方式： OAI收割
来源：上海药物研究所
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