Glucose transport system phosphorylation

A group of receptors exists that responds to so-called growth factors such as insulin, epidermal growth factor, platelet-derived growth factor, etc. These receptors have an extracellular domain that binds the growth factor and an intracellular domain that possesses latent kinase activity. The interaction of insulin, for example, results in autophosphorylation of the intracellular domain and subsequent internalization of the insulin-receptor complex. The internalized complex now possesses the properties of a tyrosine kinase and can phosphorylate cell substrates that produce the appropriate intracellular effect. However, these kinases differ from the usual protein kinases in that they phosphorylate proteins exclusively on tyrosine hydroxyl residues. The ensemble of proteins phosphorylated by the insulin receptor has not yet been identified, but there is supportive evidence that tyrosine kinase activity is required for the major actions of insulin. For example, it is possible that a membrane-linked glucose transport system becomes activated following insulin-stimulated phosphorylation. 

FIGURE 10.26 Glucose transport in E. coli is mediated by the PEP-dependent phosphotransferase system. Enzyme I is phosphorylated in the first step by PEP. Successive phosphoryl transfers to HPr and Enzyme III in Steps 2 and 3 are followed by transport and phosphorylation of glucose. Enzyme II is the sugar transport channel. 

In the mammal, complex polysaccharides which are susceptible to such treatment, are hydrolyzed by successive exposure to the amylase of the saliva, the acid of the stomach, and the disaccharidases (e.g., maltase, invertase, amylase, etc.) by exposure to juices of the small intestine. The last mechanism is very important. Absorption of the resulting monosaccharides occurs primarily in the upper part of the small intestine, from which the sugars are earned to the liver by the portal system. The absorption across die intestinal mucosa occurs by a combination of active transport and diffusion. For glucose, the aclive transport mechanism appears to involve phosphorylation The details are not yet fully understood. Agents which inhibit respiration (e.g., azide, fluoracetic acid, etc.) and phosphorylation (e.g., phlorizin), and those which uncouple oxidation from phosphorylation (e.g., dinitrophenol) interfere with the absorption of glucose. See also Phosphorylation (Oxidative). Once the various monosaccharides pass dirough the mucosa, interconversion of the other... 

Also, it should be pointed out in this connection that the reaction mechanism (see Fig. 4 and Section III,D,5,a) postulated on the basis of kinetic observations may be an oversimplification of the actual situation. For example, the possibility exists that separate phosphoryl-enzyme intermediates may be formed with various phosphate substrates (10). If such intermediates were interconvertible with a single phosphoryl-enzyme complex which was common to reactions involving all such substrates, and if the rates of these interconversions were very rapid relative to the other steps in the catalytic process, the system would be kinetically indistinguishable from that depicted in Fig. 4. Further work relating to the mechanism of reaction, and the experimental assessment of the possible involvement of this multifunctional catalyst in intra- and extracellular glucose transport, would appear to be in order. 

The phosphorylation flux is in practice unidirectional. The muscle does not have G6P-phosphatase [62, 74], so when the free glucose has been phosphorylated, it is trapped inside the cell. The consequence is that the control of the glucose uptake becomes crucially dependent on the removal of the produced G6P. It is therefore not sufficient just to look at glucose transport as an effector of the glucose control system. The handling of G6P is in many cases much more important than the glucose transport... 

Fig. 8.1 Glucose metabolism in coupled neuron and astrocyte system. ATP is produced via oxidative energy metabolism (glycolysis, TCA cycle and oxidative phosphorylation) in neurons and in astrocytes. Na+ entry during electrical activity initiates increased oxidative energy metabolism within neurons. The activation of neuronal Na+-K+ ATPase in the plasma membrane leads to reduced levels of ATP, which rapidly activates glycolysis. This process requires an elevated glucose level, which is transported via the neuronal glucose transporter (GT). The generated ATP can restore the Na+/K+ balance via Na+-K+ ATPase. The rapid increase of glycolysis results in increased NADH/NAD+ and increased cytoplasmic pyruvate. In astrocytes,...

When grown under aerobic conditions, the yeast produces two ATP molecules from one molecule of glucose by substrate-level phosphorylation in glycolysis. The two molecules of pyruvate produced can then be completely oxidized to CO2, and each yields a further 15 molecules of ATP. This leads to a slow decrease in the concentration of glucose, a steady production of CO2, and relatively little change in the amount of ATP. Also, the two molecules of NADH can be reoxidized to NAD+ by the electron-transport system. (This produces yet more ATP, as discussed in Chap. 14.)... 

The PEP-fructophosphotransferase system does not exist in Spirillum itersoii, Pseudomonas aeruginosa,181,182 or several other genera of aerobic, oxidative bacteria.183 The transport system for D-glucose, D-fructose, and D-mannitol is energy- and temperature-dependent, obeys saturation kinetics, and is inducible.181,182 This indicates the presence of a carrier-mediated transport-system.184 D-Fructose is transported as the free sugar, and trapped intracellularly by phosphorylation, An inducible fructokinase (EC 2.7.1.4) converts transported D-fructose into D-fructose 6-phosphate.181... 

Some effects of insulin occur within seconds or minutes, including the activation of glucose and ion transport systems, the covalent modification of enzymes (i.e., phosphorylation or dephosphorylation), and some effects on gene transcription (i.e., inhibition of the phosphoenolpyruvate carboxykinase gene). Effects on protein synthesis and gene transcription require hours, while those on cell proliferation and differentiation may take days. 

---