This article will be permanently flagged as inappropriate and made unaccessible to everyone. Are you certain this article is inappropriate? Excessive Violence Sexual Content Political / Social
Email Address:
Article Id: WHEBN0000248671 Reproduction Date:
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
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 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.
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]
[5]
Citric acid cycle, Metabolism, Glucose, Hexokinase, Glyceraldehyde 3-phosphate
Protein, Glucose, Glycolysis, Citric acid cycle, Ribose
Galactose, Carbon, Glycolysis, Starch, Hydrogen
Water, Urea, Metabolism, Adenosine triphosphate, Carbon dioxide
Glycolysis, Metabolism, Citric acid cycle, Urea cycle, Fructose
Metabolism, Glycolysis, Citric acid cycle, Oxaloacetate, Pfam
Gene, Metabolism, Phosphorus, Enzyme Commission number, Mutation