Gluconeogenesis
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2008-06-02T21:29:25Z
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[[Image:Gluconeogenesis.png|thumb|300px|Gluconeogenesis pathway with key molecules and enzymes. Many steps are the opposite of those found in the [[glycolysis]].]]
'''Gluconeogenesis''' is a [[metabolic pathway]] that results in the generation of [[glucose]] from non-[[carbohydrate]] carbon substrates such as [[pyruvate]], [[lactic acid|lactate]], [[glycerol]], and [[glucogenic amino acid]]s.
The vast majority of gluconeogenesis takes place in the [[liver]] and, to a smaller extent, in the cortex of [[kidney]]s. This process occurs during periods of [[fasting]], [[starvation]], or intense [[exercise]] and is highly [[endergonic]]. Gluconeogenesis is often associated with [[ketosis]]. Gluconeogenesis is also a target of therapy for type II diabetes, such as [[metformin]], which inhibit glucose formation and stimulate glucose uptake by cells.<ref name = Hundal>{{cite journal | author = Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G | title = Mechanism by which metformin reduces glucose production in type 2 diabetes | journal = Diabetes | volume = 49 | issue = 12 | pages = 2063–9 | year = 2000 | pmid = 11118008 | doi = 10.2337/diabetes.49.12.2063}} {{PDFlink|[http://diabetes.diabetesjournals.org/cgi/reprint/49/12/2063 Free full text]|82 [[Kibibyte|KiB]]}}</ref>
==Entering the pathway==
Several non-carbohydrate [[carbon]] [[Substrate (biochemistry)|substrates]] can enter the gluconeogenesis [[Metabolic pathway|pathway]]. One common substrate is [[lactic acid]], formed during [[anaerobic respiration]] in skeletal muscle. 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.<ref>{{cite book |title=Principles of Biochemistry with a Human Focus |last=Garrett |first=Reginald H. |coauthors=Charles M. Grisham |year=2002 |publisher=Brooks/Cole, Thomson Learning |location=USA |isbn=0-03-097369-4 |pages=578,585 }}</ref>
All [[citric acid cycle]] intermediates, through conversion to [[oxaloacetate]], [[amino acids]] other than [[lysine]] or [[leucine]], and glycerol can also function as substrates for gluconeogenesis.<ref>{{cite book |title=Principles of Biochemistry with a Human Focus |last=Garrett |first=Reginald H. |coauthors=Charles M. Grisham |year=2002 |publisher=Brooks/Cole, Thomson Learning |location=USA |isbn=0-03-097369-4 |pages=578 }}</ref> Amino acids must have their amino group removed by [[transamination]] or [[deamination]] before entering the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle.
[[Fatty acid]]s cannot be converted into glucose in animals, the exception being odd-chain [[fatty acid]]s which yield [[propionyl CoA]], a precursor for [[succinyl CoA]]. In plants, specifically in seedlings, the [[glyoxylate cycle]] can be used to convert fatty acids ([[acetate]]) into the primary carbon source of the organism. The glyoxylate cycle produces four-carbon dicarboxylic acids that can enter gluconeogenesis.<ref>{{cite book |title=Principles of Biochemistry with a Human Focus |last=Garrett |first=Reginald H. |coauthors=Charles M. Grisham |year=2002 |publisher=Brooks/Cole, Thomson Learning |location=USA |isbn=0-03-097369-4 |pages=516-517 }}</ref> [[Glycerol]], which is a part of all [[triacylglycerol]]s, can also be used in gluconeogenesis. In organisms in which glycerol is derived from glucose (e.g., humans and other mammals), glycerol is sometimes not considered a true gluconeogenic substrate, as it cannot be used to generate ''new'' glucose.
==Pathway==
Gluconeogenesis is a pathway consisting of eleven enzyme-catalyzed reactions. The pathway can begin in the mitochondria or cytoplasm, depending on the substrate being used. Many of the reactions are reversible steps found in glycolysis.
* Gluconeogenesis begins in the mitochondria with the '''formation of oxaloacetate through carboxylation of pyruvate''' at the expense of one molecule of [[adenosine triphosphate|ATP]]. This reaction is catalyzed by [[pyruvate carboxylase]], which is stimulated by high levels of [[acetyl-CoA]] (when fatty acid oxidation is high in the liver) and inhibited by high levels of ADP.
* '''Oxaloacetate must then be [[redox|reduced]] into [[malate]]''' using [[Nicotinamide adenine dinucleotide|NADH]] in order to be transported out of the mitochondria.
* In the cytoplasm, '''malate is [[redox|oxidized]] to oxaloacetate''' using [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], where the remaining steps of gluconeogenesis occur.
* '''Oxaloacetate is then decarboxylated and phosphorylated to produce [[phosphoenolpyruvate]]''' by [[phosphoenolpyruvate carboxykinase]]. One molecule of [[guanosine triphosphate|GTP]] is hydrolyzed to [[guanosine diphosphate|GDP]] in the course of 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]]'''. The purpose of this reaction is to overcome the large negative ΔG.
* [[Glucose-6-phosphate]] is formed from [[fructose-6-phosphate]] by [[phosphoglucoisomerase]]. Glucose-6-phosphate can then be used for glucose generation or in other metabolic pathways. Free glucose is not generated automatically because glucose, unlike glucose-6-phosphate, tends to freely diffuse out of the cell.
*The final reaction of gluconeogenesis, the formation of glucose, is carried out in the [[lumen]] of the [[endoplasmic reticulum]]. '''Glucose-6-phosphate is hydrolyzed by [[glucose-6-phosphatase]] to produce glucose'''. Glucose is then shuttled into the cytosol by glucose transporters located in the membrane of the endoplasmic reticulum.
==Regulation==
While most steps in gluconeogenesis are the reverse of those found in [[glycolysis]], three regulated and strongly exergonic 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. This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevent the formation of a [[futile cycle]].
The majority of the [[enzymes]] responsible for gluconeogenesis are found in the [[cytoplasm]]; 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]].<ref>Chakravarty, K., Cassuto, H., Resef, L., & Hanson, R.W. (2005) Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C. Critical Reviews of Biochemistry and Molecular Biology, 40(3), 129-154.</ref> As there is no known mechanism to transport [[phosphoenolpyruvate]] from the [[mitochondrion]] into the cytosol, the cytosolic enzyme is believed to be the isozyme important for gluconeogenesis. The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, [[fructose-1,6-bisphosphatase]], which is also regulated through signal tranduction by [[cAMP]] and its phosphorylation.
Most factors that regulate the activity of the gluconeogenesis pathway do so by inhibiting the activity or expression of key enzymes. However, both [[acetyl CoA]] and [[citrate]] activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively). Due to the reciprocal control of the cycle, acetyl-CoA and citrate also have inhibitory roles in the activity of [[pyruvate kinase]].
== References ==
{{Reflist|}}
==External links==
* [http://themedicalbiochemistrypage.org/gluconeogenesis.html Overview at indstate.edu]
* [http://ull.chemistry.uakron.edu/Pathways/gluconeogenesis/index.html# Interactive diagram at uakron.edu]
{{Carbohydrate metabolism}}
{{Gluconeogenesis}}
{{MetabolismMap}}
[[Category:Metabolic pathways]]
[[Category:Exercise physiology]]
[[Category:Hepatology]]
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