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Title: Gluconeogenesis  
Author: World Heritage Encyclopedia
Language: English
Subject: Metabolism, Glycolysis, Fructolysis, Pyruvate carboxylase, Glucokinase
Collection: Biochemistry, Carbohydrates, Diabetes, Exercise Physiology, Glycobiology, Hepatology, Metabolic Pathways, Metabolism
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Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids.

It is one of the two main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low blood glucose level (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis).[1]

Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms.[2] In vertebrates, gluconeogenesis takes place mainly in the

  • Overview at
  • Interactive diagram at
  • The chemical logic behind gluconeogenesis
  • : Interactive representation of gluconeogenesismetpath

External links

  1. ^ Silva, Pedro. "The Chemical Logic Behind Gluconeogenesis". Retrieved September 8, 2009. 
  2. ^ David L Nelson and Michael M Cox (2000). Lehninger Principles of Biochemistry. USA: Worth Publishers. p. 724.  
  3. ^ Young JW (1977). "Gluconeogenesis in cattle: significance and methodology". J. Dairy Sci. 60 (1): 1–15.  
  4. ^ Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI (2000). "Mechanism by Which Metformin Reduces Glucose Production in Type 2 Diabetes". Diabetes 49 (12): 2063–9.   Free full text PDF (82 KiB)
  5. ^ a b Beitz, D. C. 2004. Carbohydrate metabolism. In: Reese, W. O. Dukes' physiology of domestic animals. 12th ed. Cornell Univ. Press. pp. 501-515.
  6. ^ Ferrier, Denise R; Champe, Pamela C; Harvey, Richard A (1 August 2004). "20. Amino Acid Degradation and Synthesis". Biochemistry (Lippincott's Illustrated Reviews).  
  7. ^ Gerich JE, Meyer C, Woerle HJ, Stumvoll M (2001). "Renal gluconeogenesis: Its importance in human glucose homeostasis". Diabetes Care 24 (2): 382–391.  
  8. ^ a b c Garrett, Reginald H.; Charles M. Grisham (2002). Principles of Biochemistry with a Human Focus. USA: Brooks/Cole, Thomson Learning. pp. 578, 585.  
  9. ^ Van Soest, P. J. 1994. Nutritional ecology of the ruminant. 2nd Ed. Cornell Univ. Press. 476 pp.
  10. ^ a b de Figueiredo LF, Schuster S, Kaleta C, Fell DA (2009). "Can sugars be produced from fatty acids? A test case for pathway analysis tools". Bioinformatics 25 (1): 152–158.  
  11. ^ Liu F, Thatcher JD, Barral JM, Epstein HF (1995). "Bifunctional glyoxylate cycle protein of Caenorhabditis elegans: a developmentally regulated protein of intestine and muscle". Developmental Biology 169 (2): 399–414.  
  12. ^ Kondrashov FA, Koonin EV, Morgunov IG, Finogenova TV, Kondrashova MN (2006). "Evolution of glyoxylate cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation". Biology Direct 1: 31.  
  13. ^ Weinman EO, Strisower EH, Chaikoff IL (1957). "Conversion of fatty acids to carbohydrate: application of isotopes to this problem and role of the Krebs cycle as a synthetic pathway". Physiol. Rev. 37 (2): 252–72.  
  14. ^ a b Glew RH (2010). "You can get there from here: acetone, anionic ketones and even-carbon fatty acids can provide substrates for gluconeogenesis". Niger J Physiol Sci 25 (1): 2–4.  
  15. ^ Miller ON, Bazzano G; Bazzano (1965). "Propanediol metabolism and its relation to lactic acid metabolism". Ann NY Acad Sci 119 (3): 957–973.  
  16. ^ Ruddick JA (1972). "Toxicology, metabolism, and biochemistry of 1,2-propanediol". Toxicol App Pharmacol 21: 102–111.  
  17. ^ a b Widmaier, Eric (2006). Vander's Human Physiology. McGraw Hill. p. 96.  
  18. ^ a b Mithieux G, Rajas F, Gautier-Stein A (2004). "A novel role for glucose 6-phosphatase in the small intestine in the control of glucose homeostasis.". The Journal of Biological Chemistry 279 (43): 44231–44238.  
  19. ^ Gerich JE (2010). "Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: Therapeutic implications". Diabetic Medicine 27 (2): 136–142.  
  20. ^ Overton, T. R., J. K. Drackley, C. J. Ottemann-Abbamonte, A. D. Beaulieu, L. S. Emmert and J. H. Clark. 1999. Substrate utilization for hepatic gluconeogenesis is altered by increased glucose demand in ruminants. J. Anim. Sci. 77: 1940-1951.
  21. ^ Donkin, S. S. and L. E. Armentano. 1995. Insulin and glucagon regulation of gluconeogenesis in preruminating and ruminating bovine. J. Anim. Sci. 73: 546-551.
  22. ^ Donkin SS, Armentano LE (1995). "Insulin and glucagon regulation of gluconeogenesis in preruminating and ruminating bovine". J. Anim. Sci. 73 (2): 546–51.  
  23. ^ a b c d Voet, Donald; Judith Voet; Charlotte Pratt (2008). Fundamentals of Biochemistry. John Wiley & Sons Inc. p. 556.  
  24. ^ Chakravarty K, Cassuto H, Reshef L, Hanson RW (2005). "Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C". Crit. Rev. Biochem. Mol. Biol. 40 (3): 129–54.  
  25. ^ Mutel E, Gautier-Stein A, Abdul-Wahed A, Amigó-Correig M, Zitoun C, Stefanutti A, Houberdon I, Tourette JA, Mithieux G, Rajas F (2011). "Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon". Diabetes 60 (12): 3121–3131.  


Global control of gluconeogenesis is mediated by glucagon (released when blood glucose is low); it triggers phosphorylation of enzymes and regulatory proteins by Protein Kinase A (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis. Recent studies have shown that the absence of hepatic glucose production has no major effect on the control of fasting plasma glucose concentration. Compensatory induction of gluconeogenesis occurs in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis.[25]

The majority of the enzymes responsible for gluconeogenesis are found in the cytosol; the exceptions are mitochondrial pyruvate carboxylase and, in animals, phosphoenolpyruvate carboxykinase. The latter exists as an isozyme located in both the mitochondrion and the cytosol.[24] The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, fructose-1,6-bisphosphatase, which is also regulated through signal transduction by cAMP and its phosphorylation.

While most steps in gluconeogenesis are the reverse of those found in glycolysis, three regulated and strongly endergonic reactions are replaced with more kinetically favorable reactions. Hexokinase/glucokinase, phosphofructokinase, and pyruvate kinase enzymes of glycolysis are replaced with glucose-6-phosphatase, fructose-1,6-bisphosphatase, and PEP carboxykinase/pyruvate carboxylase. These enzymes are typically regulated by similar molecules, but with opposite results. For example, acetyl CoA and citrate activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively), while at the same time inhibiting the glycolytic enzyme pyruvate kinase. This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevents a futile cycle of synthesizing glucose to only break it down.


  • Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. This enzyme is stimulated by high levels of acetyl-CoA (produced in β-oxidation in the liver) and inhibited by high levels of ADP and glucose.
  • Oxaloacetate is reduced to malate using NADH, a step required for its transportation out of the mitochondria.
  • Malate is oxidized to oxaloacetate using NAD+ in the cytosol, where the remaining steps of gluconeogenesis take place.
  • Oxaloacetate is decarboxylated and then phosphorylated to form phosphoenolpyruvate using the enzyme PEPCK. A molecule of GTP is hydrolyzed to GDP during this reaction.
  • The next steps in the reaction are the same as reversed glycolysis. However, fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate to fructose 6-phosphate, using one water molecule and releasing one phosphate (in glycolysis phosphofructokinase 1 converts F6P to F1,6BP). This is also the rate-limiting step of gluconeogenesis.
  • Glucose-6-phosphate is formed from fructose 6-phosphate by phosphoglucoisomerase (the reverse of step 2 in glycolysis). Glucose-6-phosphate can be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which intracellular glucose levels are controlled by cells.
  • The final reaction of gluconeogenesis, the formation of glucose, occurs in the hexokinase catalyzes the conversion of glucose and ATP into G6P and ADP. Glucose is shuttled into the cytoplasm by glucose transporters located in the endoplasmic reticulum's membrane.

Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway may begin in the mitochondria or cytoplasm (of the liver/kidney), this being dependent on the substrate being used. Many of the reactions are the reversible steps found in glycolysis.


Gluconeogenesis pathway with key molecules and enzymes. Many steps are the opposite of those found in the glycolysis.

In all species, the formation of oxaloacetate from pyruvate and TCA cycle intermediates is restricted to the mitochondrion, and the enzymes that convert Phosphoenolpyruvic acid (PEP) to glucose are found in the cytosol.[23] The location of the enzyme that links these two parts of gluconeogenesis by converting oxaloacetate to PEP—PEP carboxykinase (PEPCK)—is variable by species: it can be found entirely within the mitochondria, entirely within the cytosol, or dispersed evenly between the two, as it is in humans.[23] Transport of PEP across the mitochondrial membrane is accomplished by dedicated transport proteins; however no such proteins exist for oxaloacetate.[23] Therefore, in species that lack intra-mitochondrial PEPCK, oxaloacetate must be converted into malate or aspartate, exported from the mitochondrion, and converted back into oxaloacetate in order to allow gluconeogenesis to continue.[23]

In mammals, gluconeogenesis is restricted to the liver,[17] the kidney[17] and possibly the intestine.[18] However these organs use somewhat different gluconeogenic precursors. The liver uses primarily lactate, alanine and glycerol while the kidney uses lactate, glutamine and glycerol.[19] Propionate is the principal substrate for gluconeogenesis in the ruminant liver, and the ruminant liver may make increased use of gluconeogenic amino acids, e.g. alanine, when glucose demand is increased.[20] The capacity of liver cells to use lactate for gluconeogenesis declines from the preruminant stage to the ruminant stage in calves and lambs.[21] In sheep kidney tissue, very high rates of gluconeogenesis from propionate have been observed.[22] The intestine uses mostly glutamine and glycerol.[18]


The existence of glyoxylate cycles in humans has not been established, and it is widely held that fatty acids cannot be converted to glucose in humans directly. However, carbon-14 has been shown to end up in glucose when it is supplied in fatty acids.[13] Despite these findings, it is considered unlikely that the 2-carbon acetyl-CoA derived from the oxidation of fatty acids would produce a net yield of glucose via the citric acid cycle - however, acetyl-CoA can be converted into pyruvate and lactate through the ketogenic pathway.[10][14] Put simply, acetic acid (in the form of acetyl-CoA) is used to partially produce glucose; acetyl groups can only form part of the glucose molecules (not the 5th carbon atom) and require extra substrates (such as pyruvate) in order to form the rest of the glucose molecule. But a roundabout pathway does lead from acetyl-coA to pyruvate, via acetoacetate, acetone, hydroxyacetone (acetol) and then either propylene glycol or methylglyoxal.[14][15][16]

In 1995, researchers identified the glyoxylate cycle in nematodes.[11] In addition, the glyoxylate enzymes malate synthase and isocitrate lyase have been found in animal tissues.[12] Genes coding for malate synthase have been identified in other metazoans including arthropods, echinoderms, and even some vertebrates. Mammals found to possess these genes include monotremes (platypus) and marsupials (opossum) but not placental mammals. Genes for isocitrate lyase are found only in nematodes, in which, it is apparent, they originated in horizontal gene transfer from bacteria.

[8] Whether even-chain

Lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase. Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose.[8] Transamination or deamination of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle.

In humans the main gluconeogenic precursors are lactate, glycerol (which is a part of the triacylglycerol molecule), alanine and glutamine. Altogether, they account for over 90% of the overall gluconeogenesis.[7] Other glucogenic amino acids as well as all citric acid cycle intermediates, the latter through conversion to oxaloacetate, can also function as substrates for gluconeogenesis.[8] In ruminants, propionate is the principal gluconeogenic substrate.[5][9]

Catabolism of proteinogenic amino acids. Amino acids are classified according the abilities of their products to enter gluconeogenesis:[6]



  • Precursors 1
  • Location 2
  • Pathway 3
  • Regulation 4
  • References 5
  • External links 6


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