出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/08/23 14:36:43」(JST)[Wiki en表示]
Gluconeogenesis (abbreviated GNG) is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, glucogenic amino acids, and odd-chain fatty acid.
It is one of the two main mechanisms humans and many other animals use to keep blood glucose levels from dropping too low (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis).
Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys. In ruminants, this tends to be a continuous process. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise. The process is highly exergonic until ATP or GTP are utilized, effectively making the process endergonic. For example, the pathway leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP. Gluconeogenesis is often associated with ketosis. Gluconeogenesis is also a target of therapy for type II diabetes, such as metformin, which inhibits glucose formation and stimulates glucose uptake by cells. In ruminants, because metabolizable dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc.
- 1 Precursors
- 2 Location
- 3 Pathway
- 4 Regulation
- 5 References
- 6 External links
Precursors[edit source | edit]
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. Other glucogenic amino acid as well as all citric acid cycle intermediates, the latter through conversion to oxaloacetate, can also function as substrates for gluconeogenesis. In ruminants, propionate is the principal gluconeogenic substrate.
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. 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.
Whether even-chain fatty acids can be converted into glucose in animals has been a longstanding question in biochemistry. It is known that odd-chain fatty acids can be oxidized to yield propionyl CoA, a precursor for succinyl CoA, which can be converted to pyruvate and enter into gluconeogenesis. In plants, specifically 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.
In 1995, researchers identified the glyoxylate cycle in nematodes. In addition, the glyoxylate enzymes malate synthase and isocitrate lyase have been found in animal tissues. Genes coding for malate synthase gene 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.
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. 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. 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.
Location[edit source | edit]
In mammals, gluconeogenesis is restricted to the liver, the kidney and the intestine. However these organs use somewhat different gluconeogenic precursors. Liver uses primarily lactate and alanine while kidney uses lactate and glutamine. 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. The capacity of liver cells to use lactate for gluconeogenesis declines from the preruminant stage to the ruminant stage in calves and lambs. In sheep kidney tissue, very high rates of gluconeogenesis from propionate have been observed. The intestine uses mostly glutamine and glycerol.
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. The location of the enzyme that links these two parts of gluconeogenesis by converting oxaloacetate to PEP, PEP carboxykinase, 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. Transport of PEP across the mitochondrial membrane is accomplished by dedicated transport proteins; however no such proteins exist for oxaloacetate. Therefore, in species that lack intra-mitochondrial PEP, oxaloacetate must be converted into malate or asparate, exported from the mitochondrion, and converted back into oxaloacetate in order to allow gluconeogenesis to continue.
Pathway[edit source | edit]
Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway may begin in the mitochondria or cytoplasm, this being dependent on the substrate being used. Many of the reactions are the reversible steps found in glycolysis.
- 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.
- 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 phosphoenolpyruvate carboxykinase. 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. This is also the rate-limiting step of gluconeogenesis.
- Glucose-6-phosphate is formed from fructose 6-phosphate by phosphoglucoisomerase. 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 lumen of the endoplasmic reticulum, where glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase to produce glucose. Glucose is shuttled into the cytoplasm by glucose transporters located in the endoplasmic reticulum's membrane.
|Metabolism of common monosaccharides, including glycolysis, gluconeogenesis, glycogenesis and glycogenolysis|
Regulation[edit source | edit]
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. 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.
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.
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.
References[edit source | edit]
- Silva, Pedro. "The Chemical Logic Behind Gluconeogenesis". Retrieved September 8, 2009.
- David L Nelson and Michael M Cox (2000). Lehninger Principles of Biochemistry. USA: Worth Publishers. p. 724. ISBN 1-57259-153-6.
- Young, J. W. 1977. Gluconeogenesis in cattle: significance and methodology. J. Dairy Sci. 60: 1-15.
- Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G (2000). "Mechanism by Which Metformin Reduces Glucose Production in Type 2 Diabetes". Diabetes 49 (12): 2063–9. doi:10.2337/diabetes.49.12.2063. PMC 2995498. PMID 11118008. PDF (82 KiB)
- Beitz, D. C. 2004. Carbohydrate metabolism. In: Reese, W. O. Dukes' physiology of domestic animals. 12th ed. Cornell Univ. Press. pp. 501-515.
- Chapter 20 (Amino Acid Degradation and Synthesis) in: Denise R., PhD. Ferrier. Lippincott's Illustrated Reviews: Biochemistry (Lippincott's Illustrated Reviews). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-2265-9.
- Gerich, J. E.; Meyer, C.; Woerle, H. J.; Stumvoll, M. (2001). "Renal gluconeogenesis: Its importance in human glucose homeostasis". Diabetes Care 24 (2): 382–391. PMID 11213896.
- Garrett, Reginald H.; Charles M. Grisham (2002). Principles of Biochemistry with a Human Focus. USA: Brooks/Cole, Thomson Learning. pp. 578, 585. ISBN 0-03-097369-4.
- Van Soest, P. J. 1994. Nutritional ecology of the ruminant. 2nd Ed. Cornell Univ. Press. 476 pp.
- Figueiredo, Luis F., Stefan Schuster, Christoph Kaleta, David A. Fell (2009). "Can sugars be produced from fatty acids? A test case for pathway analysis tools". Bioinformatics 25 (1): 152–158. doi:10.1093/bioinformatics/btn621. PMID 19117076.
- Liu, F., et al. (1995). "Bifunctional glyoxylate cycle protein of Caenorhabditis elegans: a developmentally regulated protein of intestine and muscle". Developmental Biology 169 (2): 399–414. doi:10.1006/dbio.1995.1156. PMID 7781887.
- Fyodor A Kondrashov, Eugene V Koonin, Igor G Morgunov, Tatiana V Finogenova, Marie N Kondrashova (2006). "Evolution of glyoxylate cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation". Biology Direct 1: 31. doi:10.1186/1745-6150-1-31. PMC 1630690. PMID 17059607.
- Weinman, E.O., et al. (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. PMID 13441426.
- Widmaier, Eric (2006). Vander's Human Physiology. McGraw Hill. p. 96. ISBN 0-07-282741-6.
- 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. doi:10.1074/jbc.R400011200. PMID 15302872.
- Gerich, J. E. (2010). "Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: Therapeutic implications". Diabetic Medicine 27 (2): 136–142. doi:10.1111/j.1464-5491.2009.02894.x. PMID 20546255.
- 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.
- 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.
- Sasaki, S., K. Ambo, M. Muramatsu and T. Tsuda. 1975. Gluconeogenesis in the kidney-cortex slices of normal fed and starved sheep. Tohoku J. Agr. Res. 26: 20-29.
- Voet, Donald; Judith Voet, Charlotte Pratt (2008). Fundamentals of Biochemistry. John Wiley & Sons Inc. p. 556. ISBN 978-0-470-12930-2.
- 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.
- Mutel, E., Gautier-Stein, A., Abdul-Wahed, A., Amigó-Correig, M., Zitoun, C., Stefanutti, A., Houberdon, I., Tourette, J.A., 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. doi:10.2337/db11-0571. PMC 3219939. PMID 22013018.
[edit source | edit]
- Overview at indstate.edu
- Interactive diagram at uakron.edu
- The chemical logic behind gluconeogenesis
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
- 1. 健常被験者および糖尿病患者における低血糖に対する生理的応答 physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus
- 2. 乳児および小児における低血糖症の原因 causes of hypoglycemia in infants and children
- 3. 成人における低血糖：臨床症状、定義、および原因 hypoglycemia in adults clinical manifestations definition and causes
- 4. 乳児および小児における低血糖に対するアプローチ approach to hypoglycemia in infants and children
- 5. 糖尿病でない成人における低血糖症：診断的アプローチ hypoglycemia in adults without diabetes mellitus diagnostic approach
- 松崎 公信,白石 渉,岩永 育貴,山本 明史
- 産業医科大学雑誌 37(1), 43-47, 2015-03-01
- 症例は55歳,アルコール多飲歴のある男性で,来院の数日前からほとんど食事を摂取していなかった.自宅で突然意識障害を呈し当院に救急搬送された.来院時は意識障害を呈しており,検査所見で著明な低血糖とβ-ヒドロキシ酪酸優位のケトアシドーシスを認めた.生活状況も勘案してアルコール性ケトアシドーシス(AKA)と診断した.ブドウ糖投与と補液で症状は速やかに改善した.AKAは腹痛,悪心,嘔吐などの症状を呈するが …
- NAID 110009924217
- 齋藤 昇
- 岡山大学農学部学術報告 104, 55-59, 2015-02-01
- … In mammals, AQP7 and AQP9 which are aquaglyceroporin have a role in the transportation of glycerol related to the gluconeogenesis in the liver. … But, a roll in gluconeogenesis of liver is not clear in the chicks. … Therefore, further study is necessary to understand the gluconeogenesis in the chicks. …
- NAID 120005537573
- Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice
- Zhang Lijing,Yang Bin,Yu Baoping
- Biological and Pharmaceutical Bulletin 38(7), 1005-1011, 2015
- Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Paeoniflorin, a natural product and active ingredient of Paeonia lactiflora, has been demonstrated to have …
- NAID 130005086279
- Hexokinase or Glucokinase (Glycolysis) catalyzes: glucose + ATP à glucose-6-phosphate + ADP Glucose-6-phosphatase (Gluconeogenesis) catalyzes: glucose-6-phosphate + H 2 O à glucose + P i Glucose-6-phosphatase enzyme is embedded in the endoplasmic reticulum (ER) membrane in liver cells.
- gluconeogenesis [gloo″ko-ne″o-jen´ĕ-sis] the synthesis of glucose from noncarbohydrate sources, such as amino acids and glycerol. It occurs primarily in the liver and kidneys whenever the supply of carbohydrates is insufficient to ...