Insulin Signaling Modulates Neuronal Metabolism
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
As discussed earlier, neurons express all essential genes involved in glucose uptake and glycolysis. The glycolytic capacity of neurons, however, is relatively low compared with glial cells in the brain. This is due to the rapid neuronal degradation of 6-phosphofructo-2-kinase /fructose-2,6-bisphosphatase-3 (PFKFB3) (40, 41), which produces fructose-2,6-bisphosphate (F2,6P2), an allosteric activator of phosphofructokinase 1 (PFK1) to potently enhance the glycolytic capacity (40, 42, 43). Therefore, neurons are unable to produce F2,6P2, resulting in a low basal glycolytic rate and the inability to stimulate glycolysis according to substrate abundance (Figure 3.1). From this perspective, as the “execution unit” in the brain controlling neural functions, neurons lack metabolic flexibility.
Role of Fructose 2,6-Bisphosphate in the Control of Glycolysis in Liver, Muscle, and Adipose Tissue
Rivka Beitner in Regulation of Carbohydrate Metabolism, 1985
The fall in fructose-2,6-bisphosphate brought about by glucagon increases fructose-1,6-bisphosphatase activity, decreases phosphofructokinase activity and eventually stops the flux through this enzyme. Since glucagon also causes the inactivation of pyruvate kinase,48 the whole glycolytic flux is blocked by this dual lock. The extent of the inhibition of glycolysis by glucagon, however, depends on the presence of glycogen. In the fed state, glucagon promotes glycogen breakdown and causes an increase in the concentration of hexose 6-phosphates which stimulates phosphofructokinase-1 and -2, thus counteracting the effect of glucagon on phosphofructokinase-2/fructose-2,6-bisphosphatase. Indeed, the experimental evidence shows that in the livers of fed rats treated with glucagon, glycolytic flux is not entirely blocked and that recycling occurs between glucose and triose phosphates.6,26 In livers of starved rats such a situation does not exist, phosphofructokinase-1 and -2 are inactive and recycling between fructose 6-phosphate and fructose-1,6-bisphosphate cannot be measured.6,26
Glucose metabolism inhibitor PFK-015 combined with immune checkpoint inhibitor is an effective treatment regimen in cancer
Published in OncoImmunology, 2022
Jia Bo Zheng, Chau Wei Wong, Jia Liu, Xiao-Jing Luo, Wei-Yi Zhou, Yan-Xing Chen, Hui-Yan Luo, Zhao-Lei Zeng, Chao Ren, Xiao-Ming Xie, De-Shen Wang
Glycolysis intensity is regulated by the activity of three physiologically reversible enzymes: hexokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase. PFK-1 is the main rate-limiting enzyme of glycolysis and the activity of PFK-1 is regulated by metabolic products such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and fructose 2–6 biphosphate.4 Of these compounds, F-2-6-BP is a reaction product catalyzed by 6-phosphofructose 2-kinase/fructose-2,6-biphosphatase (PFK-2/FBPase-2/PFKFB), which is also the most potent positive allosteric effector of PFK-1.4,5 PFKFB is a bifunctional enzyme responsible for the catalyzation of both the synthesis and degradation of F-2,6-BP mediated through its N-terminal domain (2-kase) and C-terminal domain (2-pase) respectively. Of note, the active site of the 2-kase domain has 2 distinct key areas (the F-6-P binding loop and the ATP-binding loop) which are essential for PFKFB to function.6
Discover potential inhibitors for PFKFB3 using 3D-QSAR, virtual screening, molecular docking and molecular dynamics simulation
Published in Journal of Receptors and Signal Transduction, 2018
Yinfeng Bao, Lu Zhou, Duoqian Dai, Xiaohong Zhu, Yanqiu Hu, Yaping Qiu
In the process of glycolysis, the conversion of fructose-6-phosphate (F-6-P) into F-2,6-BP was catalyzed by PFKFB3, and F-2,6-BP binds to the phosphofructokinase-1 (PFK-1) promoter, which improved the activity of PFK-1, increasing the flow of glycolysis, and providing the necessary energy and material basis for the growth and reproduction of cancer cells. PFK-1 is a key irreversible enzyme in glycolysis, and its activity is regulated by F-2,6-BP, which is a potent allosteric activator of PFK-1 [14–16]. Simultaneously, the catalytic synthesis and hydrolysis of F-2,6-BP are regulated by PFKFB3. The PFKFB3 is a bifunctional enzyme, N-terminal region in the activity center of the PFKFB3 catalyzed F-6-P convert to F-2,6-BP, while the F-2,6-BP is converted to F-6-P in the activity center of PFKFB3 C-terminal region [17,18]. In the hypoxic conditions, PFKFB3 is induced by hypoxia-inducible factor 1 (HIF-1), which can promote the production of F-2,6-BP in cancer cells. Thereby the uptake of glucose and glycolysis flow increased in cancer cells. These studies indicate that PFKFB3 enzyme plays an important role in regulating glucose metabolism during cell proliferation [19]. Therefore, it is possible to block the glycolytic pathway by inhibiting the action of PFKFB3; meanwhile, it can inhibit the growth and reproduction of cancer cells.
Targeting endothelial cell metabolism in cancerous microenvironment: a new approach for anti-angiogenic therapy
Published in Drug Metabolism Reviews, 2022
Parisa Mohammadi, Reza Yarani, Azam Rahimpour, Fatemeh Ranjbarnejad, Joana Mendes Lopes de Melo, Kamran Mansouri
As previously mentioned, ECs are extremely dependent on glycolysis even more than multiple cancer cell types; and this pathway is upregulated in proliferating ECs (angiogenic cells). TECs have even higher levels of glycolysis than proliferating ECs in normal tissue (NECs). Also, TECs have a higher rate of glycolytic side pathways such as PPP and serine biosynthesis pathways to generate more building blocks for proliferation (Li et al. 2019). The upregulation of glycolytic and side pathways key enzymes is observed in these cells. Hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinase M2 (PKM2) are three rate-controlling enzymes in the glycolysis pathway; whereas glucose 6 phosphate dehydrogenase (G6PD) and transketolase are rate-controlling enzymes in the oxidative branch (oxPPP) and the non-oxidative branch of PPP (non-oxPPP), respectively (Figure 2). Other agents affecting these pathways include PFKFB3, lactate dehydrogenases (LDHs), and monocarboxylate transporters (MCTs). MCTs contribute to the entry/exit of lactate in/from the cell, with MCT1 being responsible for the entry of lactate into the cell and MCT4 removing it. LDHs catalyze the conversion of lactate to pyruvate and back (Li et al. 2019), glycolysis-derived pyruvate and NADH are converted to lactate and NAD + by LDHA catalytic activity whereas LDHB catalyzes the reverse reaction.
Related Knowledge Centers
- Adenosine Diphosphate
- Enzyme
- Enzyme Inhibitor
- Muscle
- Platelet
- Liver
- Glycolysis
- Allosteric Enzyme
- Fructose 6-Phosphate
- Adenosine Triphosphate