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REGULATORY MECHANISMS
Published in David M. Gibson, Robert A. Harris, Metabolic Regulation in Mammals, 2001
David M. Gibson, Robert A. Harris
The levels of a few metabolic intermediates rise in concentration in response to insulin signaling. One of these, fructose 2,6-bisphosphate, stimulates glycolysis in liver at the step in which fructose 6-phosphate is converted to fructose 1,6-bisphosphate, by binding to the enzyme 6-phosphofructo-1 kinase (Figure 8.2, Chapter 8). Crucial for the opposite How toward gluconeogenesis, fructose 1,6-bisphosphatase is inhibited by the allostcric binding ol the same fructose 2,6-bisphosphate. This allostcriceffector, w hich is not on the mainline glycolytic flow, is created through insulin action in liver following feeding and diminished by glucagon signaling in starvation. The synthesis of fructose 2,6-bisphosphate is catalyzed by a kinase (acting on fructose 6-phosphate) which is active in the dcphosphorylated state and thus fits into the pattern of the insulin-cued "dephosphorylation set". In the same circumstance dephosphorylation (by insulin) of the opposing fructose 2,6-bisphosphatase blocks its activity. Interestingly these competing activities, catalyzed by distinct active sites, are domains of a single polypeptide, a "(»¡functional enzvme" (Figure 8.S, Chapter 8). Insulin-signaled dephosphorylation of the enzyme affects both the (increased) kinase and (decreased) phosphatase directions. Glucagon, through PKA protein phosphorylation of the bifunctional enzyme, switches the whole operation around, thereby promoting gluconeogenesis. A similar but distinctive system operates in skeletal and cardiac muscles (Chapter 6).
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
The enzymes responsible for the synthesis and breakdown of fructose-2,6-bisphosphate have only been studied in the liver. Fructose-2,6-bisphosphate is synthesized from fructose 6-phosphate and ATP by 6-phosphofructo-2-kinase, also called phosphofructokinase-2.32–35 In the presence of 5 mM Pi, the Km for fructose 6-phosphate is 50 μM; i.e., in the physiological range. The activity of the enzyme is inhibited by physiological concentrations of citrate, phosphoenolpyruvate, and sn-glycerol 3-phosphate. Fructose-2,6-bisphosphate is hydrolyzed to fructose 6-phosphate and Pi by a phosphatase called fructose-2,6-bisphosphatase.36–38 The Km for fructose-2,6-bisphosphate is very low (below micromolar;37 however much higher values have been reported36,38) and much smaller than the usual concentrations of fructose-2,6-bisphosphate in the livers of fed animals. The enzyme is strongly inhibited by fructose 6-phosphate (Ki: 10 to 40 μM)37,38 and is stimulated by physiological concentrations of Pi,37,38 sn-glycerol 3-phosphate,37 and nucleotide triphosphates.37 The Vmax of each enzyme is relatively low (less than 20 mU/g of liver) and changes in fructose-2,6-bisphosphate concentration require several minutes to become complete. In addition, both liver enzymes are substrates for cyclic AMP-dependent protein kinase.35–42 Phosphorylation of the protein (1 mol of Pi per mole of subunit) results in an inactivation of phosphofructokinase-2 and an activaton of fructose-2,6-bisphosphatase.
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.
BCG-induced trained immunity in macrophage: reprograming of glucose metabolism
Published in International Reviews of Immunology, 2020
Yuntong Liu, Shu Liang, Ru Ding, Yuyang Hou, Feier Deng, Xiaohui Ma, Tiantian Song, Dongmei Yan
Conversion between fructose-6-phosphate(F-6-P) and fructose-2,6-diphosphate (F-2,6-BP) is catalyzed by 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) family. F-2,6-BP is the strongest allosteric activator of PFK1, which mediates the key rate-limiting step of glycolysis. In the PFKFB family, PFKFB3 mainly mediates the synthesis of F-2,6-BP to enhance glycolysis, and the synergistic induction of PFKFB3 is mediated by the transcription factor Sp1 instead of HIF-1α. It has been found that PFKFB3 can affect the phagocytosis and autophagy pathway of macrophages, promoting their defense against virus.54,55 Recent studies have shown that activation of NLRP3 inflammasome can increase the expression of PFKFB3,67 further demonstrating the interaction between glycolysis and NLRP3 inflammasome. Recently, it has been found that the up-regulation of PFKFB3 in human hepatocellular carcinoma infiltrating monocytes increases the expression of programed death ligand 1 (PD-L1) through nuclear factor-kappa B (NF-κB) signaling pathway, and the infiltration level of PFKFB3+ CD68+ cell is negatively correlated with the overall survival rate of patients.56
The potential utility of PFKFB3 as a therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2018
Ramon Bartrons, Ana Rodríguez-García, Helga Simon-Molas, Esther Castaño, Anna Manzano, Àurea Navarro-Sabaté
Fru-2,6-P2 synthesis and degradation are catalyzed by a homodimeric bifunctional enzyme, 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). The monomer structure of this enzyme consists of two functional domains within the same polypeptide chain [16–19]. The discovery of mutations affecting the kinase activity of the enzyme [17,19] and the occurrence of ATPγS in the structure lead to the identification of the N-terminal domain as the kinase domain (PFK-2), which catalyzes Fru-2,6-P2 synthesis using fructose-6-P and ATP as substrates (Figure 1). The structural and sequence homology with yeast phosphoglycerate mutase and rat acid phosphatase, together with the identification of mutations affecting phosphatase activity, indicated the C-terminal domain to contain the bisphosphatase (FBPase-2) activity of the enzyme [17,19,20]. This domain is responsible for the hydrolytic degradation of Fru-2,6-P2 into fructose-6-P and inorganic phosphate (Pi). Analysis of the crystal structure of the testis isoenzyme confirmed that the PFK-2 domain is structurally related to the adenylate kinase, Ras, and EF-Tu family of nucleotide-binding proteins; whereas, the FBPase-2 domain shares homology with the phosphoglycerate mutases and acid phosphatases [21,22]. These two mutually opposing catalytic activities are modulated by different mechanisms in such a way that either activity predominates in a given physiological condition (Figure 1).