Glucose-6-phosphatase control

Both phosphorylase a and phosphorylase kinase a are dephosphorylated and inactivated by protein phos-phatase-1. Protein phosphatase-1 is inhibited by a protein, inhibitor-1, which is active only after it has been phosphorylated by cAMP-dependent protein kinase. Thus, cAMP controls both the activation and inactivation of phosphorylase (Figure 18-6). Insulin reinforces this effect by inhibiting the activation of phosphorylase b. It does this indirectly by increasing uptake of glucose, leading to increased formation of glucose 6-phosphate, which is an inhibitor of phosphorylase kinase. 

Fructose 2,6-bisphosphate is formed by phosphorylation of fructose 6-phosphate by phosphofructoki-nase-2. The same enzyme protein is also responsible for its breakdown, since it has fructose-2,6-hisphos-phatase activity. This hifrmctional enzyme is under the allosteric control of fructose 6-phosphate, which stimulates the kinase and inhibits the phosphatase. Hence, when glucose is abundant, the concentration of fructose 2,6-bisphosphate increases, stimulating glycolysis by activating phosphofructokinase-1 and inhibiting... 

Groups of 20 female Fischer 344 rats, eight weeks of age, were fed a diet containing 0 (control), 0.03, 0.10 or 1.2% di(2-ethylhexyl) phthalate [purity not specified] for two years. Neoplastic nodules or hepatocellular carcinomas were seen in 0/18 control, 1/18 low-dose, 1/19 mid-dose and 6/20 high-dose rats p < 0.01). Di(2-ethylhexyl) phthalate did not induce foci of altered hepatocytes as judged by basophilia, ATPase-deficiency or glucose-6-phosphatase-deficiency (Cattley et al., 1987). 

Figure 11-2 Roles of phosphofructose kinase and fructose 1,6-bisphosphatase in the control of the breakdown and storage (—+) of glycogen in muscle. The uptake of glucose from blood and its release from tissues is also illustrated. The allosteric effector fructose 2,6-bisphosphate (Fru-2,6-P2) regulates both phosphofructokinase and fructose 2,6-bisphosphatase. These enzymes are also regulated by AMP if it accumulates. The activity of phosphofructokinase-2 (which synthesizes Fru-2,6-P2) is controlled by a cyclic AMP-dependent kinase and by dephosphorylation by a phosphatase.

Recent studies indicate that the various phosphohydrolase and phosphotransferase activities of glucose-6-phosphatase are affected by numerous metabolites (see Table X and Sections II,C and III,D,4). The possible significance of observed activation or inhibition by a number of these compounds in vitro relative to regulation of both types of activity of the enzyme in vivo has been considered in a number of instances. Possible modes of control of net glucose release, involving the regulation by a variety of factors, of both hydrolytic and synthetic activities of the enzyme, have been discussed in considerable detail in earlier reviews by the author (9, 10). 

The following factors and experimental observations with the enzyme all are suggestive of metabolic control at the glucose-6-phosphatase phosphotransferase level ... 

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... 

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