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MUSCLE METABOLISM
Published in David M. Gibson, Robert A. Harris, Metabolic Regulation in Mammals, 2001
David M. Gibson, Robert A. Harris
Glucose and fat tv acids are both utilized as fuels by the heart antl skeletal muscle in the well-fed state (Figure 6.10). Glucose is taken up because GI.UT4 transporters arc abundantly available in the sarcolemma and T tubules for the transport of this monosaccharide (Chapter 3, Section 3.5.3). The relatively high blood insulin levels obtaining in the fed state stimulate the movement of microvesides laced with GI U'f4 transporters to the sarcolcma (figure 6.11). Insulin also promotes dcphosphorvlation of glvcogen synthase and glycogen phosphorylasc (Chapter 4, Section 4.3.1 and figure 4.3), thereby promoting glycogen synthesis. As in liver (Chapters 3 ami 8), the level of fructose 2,6-bisphosphate is critical for control of glycolysis in all types of muscle cells. Increased levels of the glycolytic intermediate fructose 6-phosphate promote fructose 2,6-bisphosphate synthesis by a mass action effect. In heart muscle, but not in skeletal muscle, stimulation of a signaling cascade by insulin brings about phosphorylation ami activation of 6-phosphofructo-2-kinase (figure 6.12). The resulting increase in fructose 2,6-bisphosphate promotes flux through 6-phosphofructo-1-kinase and inhibits backward flux through fructose 1,6-bisphosphatasc, thereby promoting glycolytic flux.
Role of Fructose 2,6-Bisphosphate in the Control of Glycolysis in Liver, Muscle, and Adipose Tissue
Published in Rivka Beitner, Regulation of Carbohydrate Metabolism, 1985
On the other hand, when rat hindlimb muscles were perfused with adrenaline or insulin, the production of lactate and the concentration of fructose-2,6-bisphosphate were increased. Fructose-2,6-bisphosphate could therefore play a role in the control of glycolysis under these conditions.75
Phosphatidate Phosphohydrolase Activity in Adipose Tissue
Published in David N. Brindley, John R. Sabine, Phosphatidate Phosphohydrolase, 2017
Transport of glucose into adipocytes is a facilitated diffusion process that is considerably increased by insulin.75 This is reflected in enhancement by the hormone of transport of nonmetabolizable analogs76-85 and increased rates of glucose utilization39,66,67,86-88 by adipose tissue preparations. This response appears to be achieved by insulin-stimulated recruitment to the plasma membrane of glucose transporters from an intracellular store69,82,84,89-91 and probably also by modification of the properties of intrinsic transporter molecules84,85,92-94 in the plasma membrane. Other physiologically relevant stimulators of glucose transport are long chain fatty acids95 and adenosine,84,96,97 a paracrine agent that affects other aspects of adipose tissue metabolism (see Section II.B). Adipose tissue phosphofructokinase is implicated as a regulatory site on the basis of the tissue contents of its reactants39,88 and because of its kinetic properties which include inhibition by glycerolphosphate, ATP and citrate, sigmoidal kinetics for its substrate fructose 6-phosphate, and stimulation by cAMP, AMP, long chain fatty acids, and fructose 2,6-bisphosphate.98,102 Increased transport of glucose in response to insulin and fatty acid supply is accompanied by an increased rate of glycolysis, 39,66,67,88,101 an increase in the fructose 6-phosphate substrate for phosphofructokinase,39,88,101,103 a persistent increase in the Vmax of phosphofructokinase,99,101 and either an increase103 or small decrease101 in the tissue content of fructose 2,6-bisphosphate. The end result is an increase in the level of glycerolphosphate,39,86-88,101 and, when fatty acid is provided as cosubstrate, insulin and glucose have interactive effects to increase triacylglycerol synthesis40,104 (see Table 1 and Figure 2).
PFKFB3 downregulation aggravates Angiotensin II-induced podocyte detachment
Published in Renal Failure, 2023
Xiaoxiao Huang, Zhaowei Chen, Zilv Luo, Yiqun Hao, Jun Feng, Zijing Zhu, Xueyan Yang, Zongwei Zhang, Jijia Hu, Wei Liang, Guohua Ding
The homodimeric and bifunctional enzyme family of phosphofructokinase-2/Fructose-2,6-bisphosphatase (PFK-2/PFKFB) promotes glycolysis by increasing levels of fructose-2,6-bisphosphate (F2,6P2), which in turn activates the key rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1) and enhances the conversion of fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6P2) in the glycolytic pathway. This causes increased glycolytic flux and increased ATP and NADH production [16]. Among the PFKFB family of four enzymes (PFKFB1-4), PFKFB3 has the highest ratio of kinase to phosphatase activity, which ensures a high glycolytic rate [17]. Recent findings have indicated that PFKFB3 exerts protective effects on the kidneys [18] and promotes the activation of cyclin-dependent kinase-1(cdk1) [19], which promotes talin1 phosphorylation [20]. Excessive talin1 phosphorylation promotes integrin beta1 subunit (ITGB1) activity on the cell surface [21]. Active ITGB1 is an important adhesion molecule on the surface of podocytes, and its activation enhances podocyte adhesion capacity [22–25]. Inhibiting PFKFB3 significantly reduces the expression of cell adhesion molecules, resulting in diminished cell adhesion [26–29]. Therefore, we speculated that Ang II could inhibit talin1 phosphorylation and ITGB1 activation through downregulating PFKFB3 expression. Therefore, we investigated the role of PFKFB3 in Ang II-induced podocyte injury and identified a novel target for CKD treatment.
Role of PFKFB3-driven glycolysis in sepsis
Published in Annals of Medicine, 2023
Min Xiao, Dadong Liu, Yao Xu, Wenjian Mao, Weiqin Li
Recently, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a bifunctional enzyme regulating glycolysis, has been brought to the forefront of immune metabolism research. It can accelerate glycolysis by modulating and maintaining the intracellular concentrations of fructose-2,6-bisphosphate (F-2,6-BP) to allosterically activate 6-phosphofructokinase-1 (PFK-1), the key rate-limiting enzyme of glycolysis (Figure 1) [18]. Recent studies have revealed that PFKFB3 is widely expressed in tissues and plays a vital role in the occurrence and metastasis of tumors, organ damage in diabetes mellitus, and angiogenesis [19–21]. Alterations in the levels of PFKFB3 have been reported in different sepsis-associated cells, such as macrophages [22], neutrophils [22], endothelial cells (ECs) [23] and lung fibroblasts [24]. Furthermore, increased PFKFB3 is associated with an excessive inflammatory response in sepsis. Thus, PFKFB3 has become a novel therapeutic target for inhibiting excessive inflammation in sepsis.
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 developed and underdeveloped countries, cancer is the leading cause of death [1], which seriously threatened human health due to the constant proliferation of cells. According to the investigation, more and more people have suffered from cancer in recent years and millions of people die from cancer each year [2]. Normal cells complete energy metabolism is mainly by glucose oxidative phosphorylation in mitochondria, but the energy metabolism of cancer cells is mostly by a large intake of glucose and aerobic glycolysis [3], which can maintain an abnormally high rate of aerobic glycolysis. This phenomenon was known as the Warburg effect [4]. The 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a master regulator of glycolysis in cancer cells [5]. It is a member of PFKFB family, which is encoded by four different genes that are PFKFB1, PFKFB2, PFKFB3 and PFKFB4 [6]. Each isoform was different in tissue distribution, phosphatase and kinase activity, and its regulatory response to protein kinases [7]. PFKFB1 mainly expressed in liver and skeletal muscle, PFKFB2 expressed in heart tissue, PFKFB3 expressed ubiquitously in several tissues, and PFKFB4 originally found in testis [8,9]. Among all PFKFB isoenzymes, PFKFB3 has the highest kinase/phosphatase activity ratio and is beneficial to synthesize fructose-2,6-bisphosphate (F-2,6-BP) [10], which is consistent with its role as a potent glycolytic activator [11]. Besides, PFKFB3 induced by hypoxia [12] has been found in proliferating cells and tumors, and it is overexpressed in a wide variety of cancers, including breast, prostate, colon, astrocytoma, and ovarian cancers [13]. Considering the wide distribution of PFKFB3 in human and its ability to express in a variety of cancer cells, thus, it is identified as a promising target for cancer therapy.