Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase

Wen, Lijun; Liao, Liping; Song, Ning; Liu, Yanjun; Ding, Yiluan; Zhang, Yuanyuan; Zhou, Xiao-Ru; Sun, Zhongya; Xiao, Shu-Hua; Wang, Hongbo; Lü, Jing; Zhang, Nai-Xia; Jiang, Hualiang; Chen, Kaixian; Liu, Chuanpeng; Zheng, Jie; Zhao, Kehao; Luo, Cheng

doi:10.1038/s41401-021-00653-0

Cited by 10 publications

(8 citation statements)

References 53 publications

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“…Thus, the catalytic Cys residue of GAPDH differs from the regular thiol groups, therefore, even low IA concentrations can inhibit GAPDH activity. Interestingly, natural products are also screened the inhibitory activities, as 1,2,3,4,6-penta-O-galloyl-β-D-Glc (PGG) has been isolated as the inhibitory agent, which reversibly inhibits GAPDH activity by a NAD+ and Pi competitive mode [ 93 ]. PGG interacts with a NAD+-disrupting and phosphate-binding site, inducing a conformational shift of the tetrameric GAPDH structure.…”

Section: Gapdh Inhibition In Cancer Cellsmentioning

confidence: 99%

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Abekura

Kim

Chang

et al. 2022

IJMS

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Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a “metabolically abnormal system”. Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the “Warburg effect”. Energy–metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the “Warburg effect”, tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.

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Section: Gapdh Inhibition In Cancer Cellsmentioning

confidence: 99%

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Abekura

Kim

Chang

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…GAPDH exerts metabolic flux control during aerobic glycolysis and therefore is an attractive therapeutic target for cancer. 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG) downregulated the GAPDH-dependent glycolysis pathway in LPS-stimulated macrophages, which represents a novel class of GAPDH inhibitors ( Li et al, 2022a ). Parthenolide was identified as a moderate activator of PKM2, a vital kinase in the glycolysis system, and showed significant anti-Glioblastoma multiforme activity and significantly suppressed tumor growth in the HT29 xenograft model ( Ding et al, 2020 ; Liu X. et al, 2021 ).…”

Section: Natural Products Targeting Glycolysis In Cancermentioning

confidence: 99%

“…Co-delivery of PD-L1 siRNA and resveratrol, natural polyphenol detected in more than 70 plant species, especially in grapes’ skin and seeds, showed boost of anti-tumor immune response by modulation of TME via balancing glucose metabolic pathways of glycolysis and mitochondrial OXPHOS ( Jia et al, 2021 ). 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose, a major component of the root of P. suffruiticosa inhibits LPS-stimulated macrophage activation through specific downregulation of GAPDH-dependent glucose consumption and lactate production ( Li et al, 2022a ).…”

Section: Natural Products Targeting Glycolysis In Cancermentioning

confidence: 99%

Natural products targeting glycolysis in cancer

et al. 2022

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Many energy metabolism pathways exist in cancer, including glycolysis, amino acid metabolism, fatty acid oxidation, and mitochondrial respiration. Tumor cells mainly generate energy through glycolysis to maintain growth and biosynthesis of tumor cells under aerobic conditions. Natural products regulate many steps in glycolysis and targeting glycolysis using natural products is a promising approach to cancer treatment. In this review, we exemplify the relationship between glycolysis and tumors, demonstrate the natural products that have been discovered to target glycolysis for cancer treatment and clarify the mechanisms involved in their actions. Natural products, such as resveratrol mostly found in red grape skin, licochalcone A derived from root of Glycyrrhiza inflate, and brusatol found in Brucea javanica and Brucea mollis, largely derived from plant or animal material, can affect glycolysis pathways in cancer by targeting glycolytic enzymes and related proteins, oncogenes, and numerous glycolytic signal proteins. Knowledge of how natural products regulate aerobic glycolysis will help illuminate the mechanisms by which these products can be used as therapeutics to inhibit cancer cell growth and regulate cellular metabolism.Systematic Review Registration: https://pubmed.ncbi.nlm.nih.gov/, https://clinicaltrials.gov/, http://lib.zzu.edu.cn/

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“…[21] Hydrogen-deuterium exchange mass spectrometry (HDX-MS) has often been applied to probe changes in protein dynamics induced by ligand interaction. [22,23] The different deuterium uptake (hydrogen/deuterium exchange) rates of peptides lead to the changes of the molecular mass of the targeted peptides, which can be detected by mass spectrometry. Hydrogen/deuterium exchange occurring upon ligand binding reveals the specific regions that interact with ligand as well as conformational changes induced by ligand binding.…”

Section: Small Molecule Dcdbs84 Specifically Binds To the Rt Loop Of ...mentioning

confidence: 99%

Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis

et al. 2022

Self Cite

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Conventional antiplatelet agents indiscriminately inhibit both thrombosis and hemostasis, and the increased bleeding risk thus hampers their use at more aggressive dosages to achieve adequate effect. Blocking integrin 𝜶IIb𝜷3 outside-in signaling by separating the 𝜷3/Src interaction, yet to be proven in vivo, may nonetheless resolve this dilemma. Identification of a specific druggable target for this strategy remains a fundamental challenge as Src SH3 is known to be responsible for binding to not only integrin 𝜷3 but also the proteins containing the PXXP motif. In vitro and in vivo mutational analyses show that the residues, especially E97, in the RT loop of Src SH3 are critical for interacting with 𝜷3. DCDBS84, a small molecule resulting from structure-based virtual screening, is structurally validated to be directed toward the projected target. It specifically disrupts 𝜷3/Src interaction without affecting canonical PXXP binding and thus inhibits the outside-in signaling-regulated platelet functions. Treatment of mice with DCDBS84 causes a profound inhibition of thrombosis, equivalent to that induced by extremely high doses of 𝜶IIb𝜷3 antagonist, but does not compromise primary hemostasis. Specific targets are revealed for a preferential inhibition of thrombosis that may lead to new classes of potent antithrombotics without hemorrhagic side effects.

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Natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a reversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase

Cited by 10 publications

References 53 publications

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Natural products targeting glycolysis in cancer

Targeting the RT loop of Src SH3 in Platelets Prevents Thrombosis without Compromising Hemostasis

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