Regulation of Glycolysis and Gluconeogenesis

Need help preparing for the Bio/Bio Chemistry section of the MCAT? MedSchoolCoach expert, Ken Tao, will teach everything you need to know about Regulation of Glycolysis and Gluconeogenesis of Metabolic Pathways which is a key component of the biochemistry section of the MCAT. Watch this video to get all the MCAT study tips you need to do well on this section of the exam!
Glycolysis and gluconeogenesis are both pathways of glucose metabolism, but produce opposite results. Glycolysis is the breakdown of a molecule of glucose into two molecules of pyruvate and free energy. Gluconeogenesis, on the other hand, is the generation of glucose from two molecules of pyruvate and other substrates. Furthermore, in the body, these two pathways are reciprocally regulated, meaning that situations that activate one pathway also inhibit the other pathway.
This reciprocal regulation is important because both pathways are operating simultaneously, resulting in what is called a futile cycle. Futile cycles are situations in which two metabolic pathways run in opposite directions at the same time, for the express purpose of generating energy in the form of heat. For example, during glycolysis, fructose-6-phosphate reacts with ATP to form fructose-1,6-bisphosphate and ADP.
During gluconeogenesis, however, the reverse reaction takes place and is catalyzed by the enzyme fructose 1,6-bisphosphatase. Both processes are co-occurring, and the net result is the hydrolysis of ATP with hardly any metabolic work involved.
Regulation occurs at specific key steps of glycolysis and gluconeogenesis. The only difference between how regulation affects the two cycles is that their respective metabolic reactions are going in opposite directions. The first key step in glycolysis involves the reaction of glucose to glucose 6-phosphate. This reaction is catalyzed by the enzyme hexokinase. Hexokinase is activated by high blood glucose concentrations, high AMP concentrations, and low cellular ATP concentrations. In other words, if blood glucose concentrations are high, the process of glycolysis, in which the cell uses glucose to produce energy, should be activated. Also, if cellular concentrations of ATP are low and concentrations of AMP are high, then the cell is at a low energy state. In this way, it will try to produce more energy using glycolysis.
Hexokinase is inhibited by fructose 6-phosphate, which is a downstream intermediate of glycolysis. This type of inhibition is an example of negative feedback. If there are high amounts of fructose 6-phosphate, glycolysis has been adequately running, and there is no need to keep driving the process forward. In this way, fructose 6-phosphate will inhibit the process of glycolysis by inhibiting the activity of hexokinase. In gluconeogenesis, the reverse reaction, glucose 6-phosphate to glucose, is catalyzed by glucose 6-phosphatase. Moreover, glucose 6-phosphatase is activated by low blood glucose concentrations, which makes sense because if blood glucose concentrations are low, the cell will want to activate glucose 6-phosphatase to make more glucose.
The next point of regulation in glycolysis is the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate using the enzyme PFK-1. Both ADP and AMP, which are indicators of a low-energy state, activate PFK-1. Again, if the cells are in a low-energy state, they want to activate glycolysis to produce ATP. Similarly, indicators of a high energy state, namely ATP and citrate, will inhibit PFK-1, and thereby glycolysis. Citrate is an intermediate of the Krebs cycle (citric acid cycle). If there are high amounts of citrate, this indicates that the citric acid cycle is running adequately, and there is no need to drive glycolysis. In gluconeogenesis, the reverse reaction, fructose 1,6-bisphosphate to fructose 6-phosphate, is catalyzed by the enzyme fructose 1,6-bisphosphatase. AMP, an indicator of a low-energy state, inhibits this enzyme. When the cell is in this state, it does not want to produce glucose but instead breaks it down to increase its energy production.
Another critical regulator for both processes is the enzyme fructose 2,6-bisphosphate. This enzyme is not the same as fructose 1,6-bisphosphatase, as the position of the phosphate group on the molecules differs. In fructose 1,6-bisphosphatase, the phosphate groups are located on carbons one and six. In fructose 2,6-bisphosphate, the phosphate groups are located on carbons two and six. Also, fructose 2,6-bisphosphate is not an intermediate of glycolysis or gluconeogenesis.
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