Disease relevance of Phosphofructokinase activation factor

• A key regulator of glycolytic flux is fructose-2,6-bisphosphate, and its steady state concentration is regulated by the action of different isozymes product of four genes (pfkfb1-4). pfkfb3 has been found in proliferating cells and tumors, being induced by hypoxia [1].
• Pyruvate kinase from Chlamydia trachomatis is activated by fructose-2,6-bisphosphate [2].
• These strains express during growth on glucose either the native yeast FbPase, the Escherichia coli FbPase which is insensitive to inhibition by fructose-2,6-bisphosphate, or a mutated E. coli FbPase with low sensitivity to AMP [3].
• Decreases in hepatic fructose-2,6-bisphosphate level and fructose-6-phosphate,2-kinase activity in diabetic mice: a close relationship to the development of ketosis [4].
• Oral administration of 1 g glucose per kg body weight to starved rats increased glycogen levels from 4 mg/g liver to 13.5 mg/g in 2 hr but did not significantly alter fructose-2,6-bisphosphate levels [5].

High impact information on Phosphofructokinase activation factor

• TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels [6].
• By controlling the level of fructose-2,6-bisphosphate, an allosteric activator of the glycolytic enzyme 6-phosphofructo-1-kinase and an inhibitor of the gluconeogenic enzyme fructose-1,6-bisphosphatase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase regulates hepatic glucose output [7].
• Fructose-2,6-bisphosphate is responsible for mediating glucagon-stimulated gluconeogenesis in the liver [8].
• PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate [8].
• When cells were transduced with penetratin-linked AARAApSAPA, we found that this reagent bound specifically to 14-3-3s, blocked the IGF-1-induced binding of HA-PFK-2 to 14-3-3s, and completely inhibited the IGF-1-induced increase in cellular fructose-2,6-bisphosphate [9].

Biological context of Phosphofructokinase activation factor

• Fructose-2,6-bisphosphate (Fru-2,6-P(2)) regulates key reactions of the primary carbohydrate metabolism in all eukaryotes [10].
• In contrast to yeast fructose-1,6-bisphosphatase, fructose-2,6-bisphosphate had no effect on the rate of phosphorylation or dephosphorylation of the intact enzyme [11].
• Raising the cellular concentration of fructose-2,6-bisphosphate, a potent effector of the direction of carbon flux through the gluconeogenic and glycolytic pathways, also stimulated glucose-6-phosphatase gene expression in Fao cells [12].
• Lysine 356 has been implicated by protein modification studies as a fructose-2,6-bisphosphate binding site residue in the 6-phosphofructo-2-kinase domain of rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (Kitajima, S., Thomas, H., and Uyeda, K [13].
• The kinetics of phosphorylated and unphosphorylated fructose-1,6-bisphosphatase were studied with special reference to the inhibitory effects of adenine nucleotides and fructose-2,6-bisphosphate [11].

Anatomical context of Phosphofructokinase activation factor

• Here, we show that in astrocytes, after inhibition of respiration by nitric oxide, there is a rapid, cyclic GMP-independent increase in the activity of 6-phosphofructo-1-kinase (PFK1), a master regulator of glycolysis, and an increase in the concentration of its most powerful positive allosteric activator, fructose-2,6-bisphosphate (F2,6P(2)) [14].
• The cardiac isoform of 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (PFK-2), regulator of the glycolysis-stimulating fructose-2,6-bisphosphate, was among human HeLa cell proteins that were eluted from a 14-3-3 affinity column using the phosphopeptide ARAApSAPA [9].
• Regulation of fructose-2,6-bisphosphate content in rat hepatocytes, perfused hearts, and perfused hindlimbs [15].
• Regulatory role of fructose-2,6-bisphosphate in pancreatic islet glucose metabolism remains unsettled [16].
• Increase of the glycolytic rate in human resting fibroblasts following serum stimulation. The possible role of the fructose-2,6-bisphosphate [17].

Associations of Phosphofructokinase activation factor with other chemical compounds

• The active site of pig kidney fructose-1,6-bisphosphatase (EC 3.1.3.11) is shared between subunits, Arg-243 of one chain interacting with fructose-1,6-bisphosphate or fructose-2,6-bisphosphate in the active site of an adjacent chain [18].
• Pyruvate kinase was also activated, and fructose-2,6-bisphosphate concentration and lactate production were increased in glucokinase-overexpressing diabetic hepatocytes [19].
• These increases in anisotropies were used to estimate the dissociation constants of fructose-6-phosphate and fructose-2,6-bisphosphate, which were 29 +/- 3 and 2.1 +/- 0.3 microM, respectively [20].
• Acquisition of the (1)H-(15)N HSQC from a phosphate-free sample demonstrated that the existence of His-258 in the rare N1' tautomeric state is dependent upon occupation of the phosphate binding site filled by the O2 phosphate of the substrate, fructose-2,6-bisphosphate, and subsequently, the phosphohistidine intermediate [21].
• Cyclic AMP, fructose-2,6-bisphosphate and catabolite inactivation of enzymes in the hydrocarbon-assimilating yeast Candida maltosa [22].

Gene context of Phosphofructokinase activation factor

• In C. parapsilosis phosphofructokinase was poorly sensitive to ATP but fructose-2,6-bisphosphate completely relieved the light ATP inhibition [23].
• PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) is a bifunctional enzyme that regulates the steady-state concentration of fructose-2,6-bisphosphate, which is a potent activator of the key regulatory enzyme of glycolysis, phosphofructokinase [24].
• The integration of fructose-2,6-bisphosphate as very sensitively acting activator of phosphofructokinase and inhibitor of fructose-1,6-bisphosphatase gives rise either to emergence of oscillations or of their extinction [25].
• The effect of the allosteric regulator fructose-2,6-bisphosphate (F2,6bP) on the regulation of carbohydrate metabolism was investigated in vivo with Saccharomyces cerevisiae mutants containing no, very high or unregulated 6-phosphofructo-2-kinase activity [26].
• Yeast fructose-2,6-bisphosphate 6-phosphatase is encoded by PHO8, the gene for nonspecific repressible alkaline phosphatase [27].

References