Gluconeogenesis plays an important role in supplying glucose from the conversion of non carbohydrate compounds such as lactate, pyruvate, glycerol, glucogenic amino acids etc in prolonged fasting or starvation. Liver glycogen supply the glucose only for 10 to 18 hours fasting. Liver and kidney are the major organ where gluconeogenesis occurs. Approximately 90% of the gluconeogenesis occurs in liver in short term fasting (overnight fasting). While, kidney is is the main glucose supplier in prolong fasting.
Failure of gluconeogenesis in human can lead to hypoglycemic and death. Hypoglycemia causes low glucose supply to brain. It causes brain dysfunction and eventually coma.
Gluconeogenesis is not a simple reverse reactions of glycolysis because overall equilibrium of glycolysis favors the formation of pyruvate.
Substrates of Gluconeogenesis
Examples of gluconeogenic precursors are as below:
- Lactic acid
- Amino acid
Breakdown of triacylglycerol forms glycerol and fatty acids in adipose tissues. Glycerol is transported to liver where it is converted to glycerol phosphate by glycerol kinase. Glycerol phosphate is further oxidized by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate which enter glycolysis.
Lactic acid is produced from anaerobic glycolysis in skeletal muscle. Lactic acid diffuses from skeletal muscle to liver and converted to glucose. This is called Cori cycle or lactic acid cycle.
Breakdown of amino acid forms α-keto such as oxaloacetate and α-ketoglutarate can enter Krebs cycle. α-Keto can be converted to oxaloacetate and then forms phosphoenolpyruvate (PEP).
Pyruvate is gluconeogenic precursor that can be converted to glucose (Figure 1). However, the conversion of pyruvate to glucose is not a direct reverse steps of glycolysis due to three irreversible steps in glycolysis. The three irreversible steps are as below:
- Formation of oxaloacetate (intermediate) from pyruvate then PEP (In glycolysis, PEP is converted pyruvate).
- Formation of fructose-6-phosphate from fructose-1,6-bisphosphate.
- Formation of glucose from glucose-6-phosphate.
Therefore, several important enzymes play the important role.
1. Pyruvate carboxylase and PEP carboxykinase
- Pyruvate carboxylase carboxylates pyruvate to form oxaloacetate in mitochondrion. Pyruvate carboxylase needs biotin as covalently bounding to the ε-amino group of a lysine residue in the enzyme. Pyruvate carboxylase is allosterically activated by acetyl coA. Thus, elevated of oxaloacetate favors the formation of oxaloacetate in mitochondrion.
- Oxaloacetate is converted to PEP in gluconeogenesis which require cytosol and mitochondrion enzymes. However, oxaloacetate is unable to pass through the double layer membrane of mitochondrion into cytosol.Therefore, oxaloacetate is reduced to malate by malate dehydrogenase in mitochondrion. Malate then able to be transported across mitochondrion membrane into cytosol. Malate is reoxidized back into oxaloacetate.
- PEP carboxylase decarboxylases and phosphorylases the oxaloacetate to PEP with the hydrolysis of GTP. PEP is then acted in the reversible glycolysis reactions until form fructose 1,6-bisphosphate.
2. Fructose 1,6-bisphosphatase
- Fructose 1,6-bisphosphate is irreversibly changed to fructose 6-phosphate. Fructose 1.6-bisphosphatase hydrolyzes the fructose 1,6-bisphosphate and provides an energetically favorable pathway for the formation of fructose 6-phosphate.
3. Glucose 6-phosphatase
- Hydrolysis of glucose 6-phosphate to glucose by glucose 6-phosphatase. It provides an energetically favorable pathway for the formation of glucose.
Regulation of Gluconeogenesis
Hormone glucagon and the availability of gluconeogenic substances determine the regulation of gluconeogenesis. Glucagon stimulates the gluconeogenesis to increase blood glucose levels.
- Champe, PC, Harvey, RA. 2007. Biochemistry. Lippincott’s Illustrated Review. 4th Edition. Lippincott Williams & Wilkins.
- Murray, RK, Bender, DA, Botham, KM, Kennelly, PJ, Rodwell, VW, Weil, PA. 2006. Harper’s Illustrated Biochemistry, 28e. Lange, McGraw Hill.