Question

Regulation of GNG and glycolysis

1. Describe how high energy charge favors gluconeogenesis over glycolysis based on the ratio of [ATP]/[AMP] of high energy charge and allosteric regulation (McKee page 298).
2. Describe how low energy charge measured by low ratio of [ATP]/[AMP] inhibits the rate of GNG based on allosteric regulation of fructose 1,6 bisphosphatase by AMP.
3. Compare the rates of GNG and glycolysis in a liver cell with low energy charge based on allosteric regulation.
4. Differentiate between the blood concentrations of insulin and glucagon hormones based on the period after a carbohydrate meal
5. Differentiate between the blood concentrations of insulin and glucagon hormones based on fasting period
6. Differentiate between regulation by hormone and energy charge based on the time frame of the response
7. Differentiate between regulation by hormone and energy charge based on the locations in which hormones and allosteric effectors bind with respect to the cell
8. Describe how hormones regulate enzyme activity by phosphorylation based on a series of reactions that start with hormone binding (see video lecture).
9. Differentiate between stimulation of glycolysis and GNG based on a cell stimulated by insulin
10. Differentiate between stimulation of glycolysis and GNG based on a cell stimulated by glucagon.
11. Describe how increase in oxaloacetic acid (OAA) concentration stimulates glycolysis based on Le Chatelier’s principle.

Answer 1

Ans 1: Gluconeogenesis is the process of formation of glucose from non-carbohydrate precursors and Glycolysis is the breaking down of glucose in order to produce energy and we know that ATP is the energy currency of the cell. So high ATP/AMP ratio suggest that currently the cell has enough concentration of ATP and it does not required any more ATP right now so this will inhibit the process of glycolysis and favors gluconeogenesis. Also one of the main regulatory enzyme phosphofructokinase which catalyzes the conversion of fructose-6-phosphate into fructose-1,6-bisphosphate in glycolysis is inhibited by ATP and activated by AMP so in the case of high ATP/AMP ratio this enzyme will be inhibited and in case of gluconeogenesis the enzyme fructose bisphosphatase which catalyzes the conversion of Fructose-1,6-bisphosphate into Fructose-6-phosphate is inhibited by AMP and in case of low AMP concentration this enzyme is not being inhibited which will favor the gluconeogenesis.

2: As i described in the first part that Fructose-1,6-bisphosphatase one of the regulatory enzyme in the gluconeogenesis is inhibited by AMP so in case of low ATP/AMP ratio the AMP concentration will be rises and this will inhibit the enzyme.

3: As i described in the first part that Fructose-1,6-bisphosphatase one of the regulatory enzyme in the gluconeogenesis is inhibited by AMP so in case of low ATP/AMP ratio which is the low energy charge, the AMP concentration will be rises and this will inhibit the enzyme. Similarly Phosophofructokinase one of the regulatory enzyme in glycolysis is inhibited by ATP and activated by AMP so in case of low ATP/AMP ratio the enzyme will be favored and so will the glycolysis. So low energy point in liver cells inhibits the gluconeogenesis and activated glycolysis because low energy point indicates that the cell requires energy and this energy will be produced by glycolysis process.

4: Insulin is released in the blood by the pancreas to regulate the blood glucose concentration which means that if the blood glucose level rises from the optimum level insulin will favor the storage of glucose by promoting either glycogenesis or glycolysis. So just after the carbohydrate meal the blood sugar level will be elevated and this will favor the pancreas to release the insulin in the blood in order to regulate the elevated blood glucose level. Glucagon is released by pancreas in order to couterbalance the effect of insulin which means that if at some point the blood glucose level decrease below the optimum level the glucagon favor glycogenolysis which is the breaking of glycogen to produce more glucose in the blood. So after a carbohydrate meal cell does not required to break the glycogen molecules and hence the concentration of glucagon will be low.

5: During the fasting period the blood glucose level decreases because cell is not getting carbohydrate from the energy source and hence it is using the blood glucose to generate energy. So in this case the level of blood glucose will be decrease below the optimum level. So i described above that this will increase the concentration of glucagon in the blood in order to promote glycogenolysis and the insulin concentration will be decreased in the blood because of the absence of elevated blood sugar level.

6: When we are taking carbohydrate meal the blood sugar level increases and this will releases the insulin in blood which will regulate the blood sugar level by favoring glycogenosis or glycolysis but the high energy point will inhibit the glycolysis process because of the high ATP/AMP ratio.

Similarly when the blood sugar level is decreased below the optimum level this will release the glucagon in the blood which will favor the glycogenolysis in order to break the glycogen molecule into glucose molecules and also gluconeogenesis but low energy point activates the glycolysis process and inhibits gluconeogenesis.

7: Binding of insulin to receptors on cells leads rapidly to fusion of cytoplasmic vesicles carrying GLUT4 which is a transpoter for glucose, with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.

After this insulin activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase and this finally favors the glycogenesis process which is the process of glycogen fromation from glucose molecules.

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase. Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers.

8: From the previous answers listed above we can say that insulin activates glycolysis and inactivates gluconeogenesis because blood sugar level is already elevated and making more glucose molecule does not make sense.

9: Similarly glucagon inactivates glycolysis and activated gluconeogensis because the blood sugar level is decreased and it require more glucose molecule.

10 : Oxaloacetic acid is produced from the pyruvate molecule by using pyruvate carboxylase. Now according to Le Chatelier's principle, increasing the concentration of products will drive the reaction to the left which means more production of pyruvate molecules. And as we know that pyruvate molecules are produced by glucose through glycolysis hence increase in oxaloacetic acid will favor the glycolysis process.