Inhibitors of glycolysis

Class of enzymes 6-phosphofructokinase Identifiers Databases Search Phosphofructokinase Identifiers Symbol PFK Available protein structures: Phosphofructokinase-1 ( PFK-1) is one of the most important regulatory β- D- Phosphofructokinase 1 β- D- P i H 2O Structure [ ] Mammalian PFK1 is a 340kd PFK1 is an allosteric enzyme and has a structure similar to that of Each subunit of the tetramer is 319 amino acids and consists of two domains: one that binds the substrate ATP, and the other that binds fructose-6-phosphate. Each domain is a b barrel, and has cylindrical b sheet surrounded by alpha helices. On the opposite side of the each subunit from each active site is the allosteric site, at the interface between subunits in the dimer. ATP and AMP compete for this site. The N-terminal domain has a catalytic role binding the ATP, and the C-terminal has a regulatory role Mechanism [ ] PFK1 is an allosteric enzyme whose activity can be described using the PFK1 belongs to the family of E. coli PFK1 include Allosteric activators such as The hydroxyl oxygen of carbon 1 does a nucleophilic attack on the beta phosphate of ATP. These electrons are pushed to the anhydride oxygen between the beta and gamma phosphates of ATP. Regulation [ ] PFK1 is the most important control site in the mammalian glycolytic pathway. This step is subject to extensive regulation since it is not only highly PFK1 is PFK1 is also inhibited by low pH levels which augment the inhibitory effect of ATP. The pH falls...

Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and d-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied. • Lane MA, Ingram DK, Roth GS. 2-Deoxy-D-glucose feeding in rats mimics physiological effects of calorie restriction. J Anti-Aging Med. 1998;1:327–37. • Roth GS, Lane MA, Ingram DK. 2005. Caloric restriction mimetics: the next pha...

Christina P. Martins 1,2, Lee A. New 2, Erin C. O’Connor 2, Dana M. Previte 2, Kasey R. Cargill 3, Isabelle L. Tse 2, Sunder Sims- Lucas 3 and Jon D. Piganelli 2* • 1Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States • 2Department of Pediatric Surgery, Rangos Research Center, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States • 3Department of Pediatrics, Rangos Research Center, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States In Type 1 Diabetes (T1D), CD4 + T cells initiate autoimmune attack of pancreatic isletβcells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4 + T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, ...

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Endothelial cells play an obligatory role in regulating local vascular tone and maintaining homeostasis in vascular biology. Cell metabolism, converting food to energy in organisms, is the primary self-sustaining mechanism for cell proliferation and reproduction, structure maintenance, and fight-or-flight responses to stimuli. Four major metabolic processes take place in the energy-producing process, including glycolysis, oxidative phosphorylation, glutamine metabolism, and fatty acid oxidation. Among them, glycolysis is the primary energy-producing mechanism in endothelial cells. The present review focused on glycolysis in endothelial cells under both physiological and pathological conditions. Since the switches among metabolic processes precede the functional changes and disease developments, some prophylactic and/or therapeutic strategies concerning the role of glycolysis in cardiovascular disease are discussed. The endothelium lies on the innermost layer of blood vessels, regulating local vascular tone and permeability and coordinating with neighboring cells to modulate immune/inflammatory responses and blood supply. Endothelial dysfunction ...

Background Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. Methods Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. Results The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G 2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. Conclusion Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by i...

Christina P. Martins 1,2, Lee A. New 2, Erin C. O’Connor 2, Dana M. Previte 2, Kasey R. Cargill 3, Isabelle L. Tse 2, Sunder Sims- Lucas 3 and Jon D. Piganelli 2* • 1Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States • 2Department of Pediatric Surgery, Rangos Research Center, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States • 3Department of Pediatrics, Rangos Research Center, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States In Type 1 Diabetes (T1D), CD4 + T cells initiate autoimmune attack of pancreatic isletβcells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4 + T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, ...

Background Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. Methods Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. Results The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G 2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. Conclusion Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by i...

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Endothelial cells play an obligatory role in regulating local vascular tone and maintaining homeostasis in vascular biology. Cell metabolism, converting food to energy in organisms, is the primary self-sustaining mechanism for cell proliferation and reproduction, structure maintenance, and fight-or-flight responses to stimuli. Four major metabolic processes take place in the energy-producing process, including glycolysis, oxidative phosphorylation, glutamine metabolism, and fatty acid oxidation. Among them, glycolysis is the primary energy-producing mechanism in endothelial cells. The present review focused on glycolysis in endothelial cells under both physiological and pathological conditions. Since the switches among metabolic processes precede the functional changes and disease developments, some prophylactic and/or therapeutic strategies concerning the role of glycolysis in cardiovascular disease are discussed. The endothelium lies on the innermost layer of blood vessels, regulating local vascular tone and permeability and coordinating with neighboring cells to modulate immune/inflammatory responses and blood supply. Endothelial dysfunction ...

This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: Author contributions: Qian Y screened glucose transport inhibitory compounds and wrote sections for glycolysis, glycolysis inhibitors and glucose transporters of the manuscript; Wang X assisted in compound screening and wrote the section of glucose transporter inhibitors of the manuscript; Chen X supervised compound screening and wrote summary, introduction, the Warburg effect, and future direction of the manuscript and finalized the manuscript. Metabolic reprogramming and altered energetics have become an emerging hallmark of cancer and an active area of basic, translational, and clinical cancer research in the recent decade. Development of effective anticancer therapeutics may depend on improved understanding of the altered cancer metabolism compared to that of normal cells. Changes in glucose transport and glycolysis, which are drastically upregulated in most cancers and termed the Warburg effect, are one of major focuses of this new research area. By taking advantage of the new knowledge and understanding of cancer’s...

Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and d-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied. • Lane MA, Ingram DK, Roth GS. 2-Deoxy-D-glucose feeding in rats mimics physiological effects of calorie restriction. J Anti-Aging Med. 1998;1:327–37. • Roth GS, Lane MA, Ingram DK. 2005. Caloric restriction mimetics: the next pha...