Gluconeogenesis: Glucose Synthesis

Gluconeogenesis

• Gluconeogenesis refers to the synthesis of glucose from pyruvate.
• It is an anabolic pathway
• Gluconeogenesis occurs mainly in the liver, to a lesser extent in the kidney, and very little in other tissues.
• Gluconeogenesis is particularly vital during fasting or starvation, as glucose serves as the main fuel for the brain and the exclusive fuel for red blood cells.

Glucose Synthesis from Noncarbohydrate Precursors

• Pyruvate can arise from muscle-derived lactate in the liver through the action of lactate dehydrogenase.
• Carbon skeletons of certain amino acids can be transformed into gluconeogenic intermediates.
• Glycerol, derived from triacylglycerol hydrolysis, can be converted into dihydroxyacetone phosphate, which can then be processed through gluconeogenesis or glycolysis.

Gluconeogenesis and Glycolysis

• Gluconeogenesis is not a complete reversal of glycolysis and the three irreversible steps in glycolysis must be bypassed in gluconeogenesis
• The formation of phosphoenolpyruvate from pyruvate necessitates two enzymes: pyruvate carboxylase and phosphoenolpyruvate carboxykinase.
• These two reactions effectively reverse the activity of pyruvate kinase.
• Pyruvate carboxylase requires the vitamin biotin (B7) as a cofactor.
• The formation of oxaloacetate through pyruvate carboxylase occurs in the mitochondria.
• Oxaloacetate is then reduced to malate, transported into the cytoplasm, and subsequently oxidized back to oxaloacetate, generating cytoplasmic NADH.
• PEP is synthesized from oxaloacetate via phosphoenolpyruvate carboxykinase (PEPCK).
• Phosphoenolpyruvate is metabolized by glycolytic enzymes in reverse until the hydrolysis of fructose 1,6-bisphosphate.
• Conversion of fructose 1,6-bisphosphate to fructose 6-phosphate, is catalyzed by fructose 1,6-bisphosphatase (allosteric enzyme)
• Reversing PFK activity.
• Generation of free glucose occurs mainly in the liver
• Glucose 6-phosphatase, which is an integral membrane protein on the inner surface of the endoplasmic reticulum, catalyzes glucose creation from glucose 6-phosphate.
• Synthesizing glucose from pyruvate requires six high-transfer-potential phosphoryl groups
• 2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2H+ + 6 H₂O → glucose + 4 ADP + 2 GDP + 6 P₁ + 2 NAD+
• AG°' = -38 kJ mol¯¹ (-9 kcal mol¯¹)

Regulation of Gluconeogenesis and Glycolysis

• Gluconeogenesis and glycolysis are regulated to ensure that within a cell, only one pathway is highly active at any given time.
• Reciprocal regulation ensures that glycolysis predominates when glucose is abundant, and gluconeogenesis is highly active when glucose is scarce.
• Fructose 1,6-bisphosphate and fructose 6-phosphate is a key regulatory site of interconversion of fructose.
• Additionally, glycolysis and gluconeogenesis are reciprocally regulated at the interconversion of phosphoenolpyruvate and pyruvate.
• If ATP is needed, glycolysis predominates. If glucose is needed and energy charge is high, gluconeogenesis is favored.
• The key regulator of glucose metabolism in the liver is fructose 2,6-bisphosphate (F-2,6-BP).
• F-2,6 BP stimulates phosphofructokinase, while inhibiting fructose 1,6-bisphosphatase activity.
• F-2,6-BP is made and broken down by the enzyme PFK-2, whose activity is modulated by glucagon, and is made when glucose is abundant and broken down when blood glucose levels are low.

Metabolism Context

• Muscle and liver work together in a series of reactions called the Cori cycle:
• Lactate produced by muscled during contraction is released into the blood
• Liver removes lactate from blood and converts it into glucose which is then released back into the blood.