Gluconeogenesis: Conversion Reactions

Gluconeogenesis

• Gluconeogenesis is the reverse of glycolysis, and the reaction from F6P to G-6-P is catalyzed by the same enzyme, phosphoglucose isomerase.
• The reaction from G6P to glucose and Pi is the reverse of the reaction catalyzed by glucokinase and hexokinase during glycolysis, but in gluconeogenesis, it is catalyzed by glucose-6-phosphatase, which is present only in gluconeogenic tissues.
• Gluconeogenesis and glycolysis are reciprocally regulated.

Regulation of Gluconeogenesis and Glycolysis

• Insulin stimulates glycolysis, while glucagon stimulates gluconeogenesis.
• A high AMP concentration indicates a low energy charge, signaling the need for ATP, whereas high ATP and citrate concentrations indicate a high energy charge and abundant intermediates.

Gluconeogenesis Stoichiometry

• The stoichiometry of gluconeogenesis is: 2pyruvate + 4ATP + 2GTP + 2NADH + 6H2O → glucose + 4ADP + 2GDP + 6Pi + 2NAD+ + 2H+.
• The Gibbs free energy (ΔG°’) is -9kcal mol-1, which is the reverse of glycolysis with a ΔG°’ of 20kcal mol-1.

Pentose Phosphate Pathway

• The pentose phosphate pathway provides a source of reduced NADPH for reductive biosynthesis, a source of ribose-5-phosphate for nucleic acid biosynthesis, and a route for the conversion of pentoses to fructose-6-phosphate.
• The pathway is most active in erythrocytes, liver, mammary gland, adipose tissue, and adrenal cortex.
• The enzymes of this pathway are located in the cytoplasm.

Oxidative Phase of the Pentose Phosphate Pathway

• The oxidative phase is irreversible and regulated by glucose-6-phosphate dehydrogenase (G6PD), which is inhibited by NADPH and activated by glucose-6-phosphate and GSSG.
• A high CHO diet triggers the synthesis of G6PD and phosphogluconate dehydrogenase.

Anabolism

• Anabolism is the process of building complex molecules from simpler ones, requiring energy from ATP.
• Some cells have specific nutrient requirements, and certain compounds like vitamins, amino acids, and microorganisms cannot be synthesized and must be supplied in the diet or media.

Carbohydrate Metabolism

• Carbohydrate digestion involves the breakdown of carbohydrates into glucose, which is the major metabolic fuel of mammals, except ruminants.
• Glucose is converted to pyruvate through glycolysis, which can occur aerobically or anaerobically.
• Aerobic glycolysis produces pyruvate, which is oxidized to Acetyl Co-A, entering the Kreb's cycle, while anaerobic glycolysis produces lactate.
• Glycolysis is central in generating both energy and metabolic intermediates.

Glycolysis

• Glycolysis is the breakdown of glucose into 2 molecules of pyruvic acid, producing 2 ATP molecules.
• The pathway occurs in the cytoplasm and can function either aerobically or anaerobically.
• All carbohydrates to be catabolized must enter the glycolytic pathway.
• Glycolysis is regulated by three irreversible kinase reactions: hexokinase or glucokinase, phosphofructokinase, and pyruvate kinase.

Fate of Pyruvate

• Under anaerobic conditions, pyruvate is converted to lactate, which is important in red blood cells, parts of the retina, and skeletal muscle cells during strenuous exercise.
• Lactate fermentation is reversible, allowing pyruvate to be regenerated in alternative metabolism.
• Lactate dehydrogenase (LDH) has multiple forms, including the M and H forms, which are present in different tissues and have different functions.