Gluconeogenesis 1: Videos & Practice Problems

Gluconeogenesis is the metabolic pathway that generates glucose from non-carbohydrate substrates such as glycerol, lactate, and most amino acids. It is primarily the reverse of glycolysis, which breaks down glucose into pyruvate. While many of the same enzymes are used in both pathways, gluconeogenesis requires new enzymes to bypass the three irreversible steps of glycolysis. These steps are catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase in glycolysis. Additionally, gluconeogenesis is more energy-intensive, requiring 4 ATP, 2 GTP, and 2 NADH to synthesize one glucose molecule from 2 pyruvate molecules. Both pathways occur in the cytosol and are tightly regulated to prevent futile cycles.

Gluconeogenesis can utilize a variety of substrates to produce glucose. These include glycerol, which is derived from fats, and lactate, which is produced during anaerobic glycolysis. Most amino acids can also serve as substrates, except for lysine and leucine, which are exclusively ketogenic. Some amino acids contribute specific carbons to the gluconeogenic pathway, while others may end up as ketone bodies. This diversity in substrates allows the body to maintain glucose levels during periods of fasting or intense exercise.

Gluconeogenesis is considered more energy-intensive than glycolysis because it requires a higher input of energy to synthesize glucose. Specifically, to convert 2 pyruvate molecules into 1 glucose molecule, gluconeogenesis requires 4 ATP, 2 GTP, and 2 NADH. In contrast, glycolysis generates a net gain of 2 ATP and 2 NADH from the breakdown of 1 glucose molecule into 2 pyruvate molecules. This higher energy demand in gluconeogenesis is necessary to drive the endergonic reactions that reverse the irreversible steps of glycolysis.

Glycolysis and gluconeogenesis are tightly regulated to prevent futile cycles, where both pathways would run simultaneously, wasting energy without producing any net gain. This regulation is achieved through allosteric control and hormonal signals that ensure when one pathway is active, the other is inhibited. Key regulatory enzymes in glycolysis, such as hexokinase, phosphofructokinase, and pyruvate kinase, are inactivated when gluconeogenesis is active. Conversely, the enzymes specific to gluconeogenesis are inhibited when glycolysis is active. This reciprocal regulation ensures efficient energy use and metabolic balance.

Both glycolysis and gluconeogenesis occur in the cytosol of the cell. This localization makes sense because many of the enzymes involved in these pathways are shared, and the cytosol provides the necessary environment for these metabolic processes. The shared location also facilitates the tight regulation required to prevent futile cycles, ensuring that when one pathway is active, the other is inhibited.