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 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.
Growth factor signaling pathways in vascular development and disease
Published in Growth Factors, 2019
VEGFA also promotes sprouting angiogenesis through modulation of EC metabolism. ECs in growing vascular networks increase their rates of glycolysis to meet the energy needs required for migration and proliferation (De Bock, Georgiadou, and Carmeliet 2013). VEGFA induces the expression of glycolytic pathway genes including the glucose transporter GLUT1 and the glycolytic enzymes phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) and lactate dehydrogenase A (LDHA) (De Bock et al. 2013; Parra-Bonilla et al. 2010; Yeh, Lin, and Fu 2008). FGF2 signaling via FGFR1 and FGFR3 also promotes glycolysis during angiogenesis. FGF2 signaling increases the expression of Myc, a driver of cell growth and proliferation, which in turn upregulates another glycolytic pathway enzyme, hexokinase 2 (HK2) (Yu et al. 2017). Mice lacking endothelial PFKFB3 or HK2 have reduced angiogenic vessel growth due to defects in EC proliferation and motility (De Bock et al. 2013; Yu et al. 2017). Lowering both glycolysis and mitochondrial respiration is necessary to reestablish EC quiescence (Wilhelm et al. 2016) demonstrating that metabolic control is, therefore, a key mechanism by which growth factors regulate sprouting angiogenesis.
Redox-sensitive transcription factors play a significant role in the development of rheumatoid arthritis
Published in International Reviews of Immunology, 2018
Scott Le Rossignol, Natkunam Ketheesan, Nagaraja Haleagrahara
RA synovial fluid is hypoxic, acidic, lower in glucose concentration, higher in lactate, acetate, and carbon dioxide concentrations compared to non-rheumatoid synovial fluid [25,48]. Suggestive of utilization of anaerobic metabolism in the synovial environment. Indeed, hypoxia alters RA FLS from a resting state to a metabolically active state, which is achieved by downregulating mitochondrial respiration and promoting glycolysis. This active state is required to drive acilitates proliferation and maturation in the synovium [39]. T cells in RA have a uncoordinated glycolytic pathway, referred to as the Warburg effect, with a shift to the pentose phosphate pathway (PPP) promoting reductive stress on the cell due to increases in NADPH [49]. This lack of co-ordination has been attributed to insufficient induction of 6-phosphofructokinase-2-kinase/fructose-2,6-bisphophatase 3 [49]. The presence of immune complexes in the synovium facilitates migration and proliferation of leukocytes. Leukocytes rely on aerobic metabolism and an increased number in the synovium results in local hypoxia [50]. Synovial hyperproliferation and high metabolic demand of inflamed synovial tissue compounds this hypoxia and only the cells closest to the blood vessel have adequate oxygen 47. Hypoxia and pro-inflammatory cytokines drive production of ROS and RNS from macrophages and neutrophils [11]. In RA, the endothelium is dysfunctional with inadequate tissue oxygen homeostasis and results in hypoxic-reperfusion injury [47]. The degree of hypoxia in synovium correlates with an increased frequency of mitochondrial DNA mutations occurring in response to increased levels of ROS [51]. Mitochondrial mutagenesis resulting in decreased expression of cytochrome C, an oxygen sensor, leading to dysregulated production of ROS [32,51]. TLR2 has been demonstrated to induce mutations in mitochondrial DNA, production of ROS and lipid peroxidation [52]. Moreover, the NLRP3 inflammasome senses mitochondrial dysfunction via accumulation of ROS and reduced levels of autophagy potentiating chronic inflammation in RA [53]. In early and established phases of RA endothelial dysfunction is apparent [47]. Chondrocytes adapt to hypoxic conditions, producing ROS via oxygen fluctuation resulting in ischemia-reperfusion injury [33].
Related Knowledge Centers
- Enzyme
- Fructose
- Mannose
- Phosphofructokinase 1
- Metabolism
- Gluconeogenesis
- Glycolysis
- Fructose 2,6-Bisphosphate
- Fructose 6-Phosphate
- Fructose 1,6-Bisphosphatase