Physiological Role
GPase’s main role is to provide phosphorylated glucose molecules (G-1-P) to metabolize in glycolysis to produce ATP for the cell. The phosphorylated glucose comes from glycogen and cellular phosphate. Glycogen is a polymer of non-phosphorylated glucose molecules. GPase catalyzes the following reversible reaction:
(Glucose)n + Pi to (Glucose)n-1 + G-1-P
The reaction starts when conditions exist to allow glycogen and Pi to react in the forward reaction. A phosphorylated glucose monomer is cleaved from the glycogen polymer through general acid catalysis by the substrate phosphate and an enzyme linked cofactor (Palm et al 1103). Since the product, G-1-P is phosphorylated during the cleavage reaction, the cell does not have to expend an ATP molecule to phosphorylate the glucose. This step saves energy because it uses no ATP, and it simplifies the energy prodction process because the glucose molecule does not have to be phosphorylated. To be used in glycolysis, G-1-P is converted to G-6-P by the enzyme phosphoglucomutase. Since this next step is a mutase reaction, the phosphate group is simply shifted from the 1 position to the 6 position by the enzyme; a phosphate does not need to be covalently added.
The above pathway is common in muscle tissue. However, the liver adds another step allowing it to maintain blood sugar levels with glucose derived from glycogen. However, the products from GPase (G-1-P) and phosphoglucomutase (G-6-P) cannot cross biological membranes to enter the bloodstream. An additional enzyme in the liver (Glucose-6-Phosphatase) removes the phosphate group to give free glucose product (essentially the reverse of the reaction catalyzed by hexokinase). Glucose can easily pass through biological membranes and enter the bloodstream where it can be utilized by other tissues.
The in vitro reaction actually favors glycogen synthesis (at pH 6.8). However, in vivo, the opposite reaction, glycogenolysis, is favored because of the ratio of Pi to G-1-P greatly exceed the equilibrium constant of 3.6 @ pH 6.8 (Newgard et al 70). This means that should cellular levels of Pi decrease, glycogenolysis will decrease. Pi levels will decrease when Pi is tied up in ATP and ADP (cellular energy levels are high). Pi levels will increase when Pi is not tied up in ATP and ADP (cellular energy levels are low).
GPase is intricately regulated because it is important to have the correct amount of fuel available to the cell under different conditions. GPase is an example of an allosteric enzyme, an enzyme whose activity is affected by the binding of other substrates. The high regulation of the enzyme allows it to be "set" to a certain optimal rate to ensure that the proper amount of glucose is available for the cell.
