Gluconeogenesis (GNG) is ametabolic pathway that results in the biosynthesis ofglucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms.[1] In vertebrates, gluconeogenesis occurs mainly in theliver and, to a lesser extent, in thecortex of thekidneys. It is one of two primary mechanisms – the other being degradation ofglycogen (glycogenolysis) – used by humans and many other animals to maintainblood sugar levels, avoiding low levels (hypoglycemia).[2] Inruminants, because dietary carbohydrates tend to be metabolized byrumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc.[3] In many other animals, the process occurs during periods offasting,starvation,low-carbohydrate diets, or intenseexercise.
In humans, substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted topyruvate or intermediates ofglycolysis (see figure). For the breakdown ofproteins, these substrates includeglucogenic amino acids (although notketogenic amino acids); from breakdown oflipids (such astriglycerides), they includeglycerol, odd-chain fatty acids (although not even-chain fatty acids, see below); and from other parts ofmetabolism that includeslactate from theCori cycle. Under conditions of prolonged fasting, acetone derived fromketone bodies can also serve as a substrate, providing a pathway from fatty acids to glucose.[4] Although most gluconeogenesis occurs in the liver, the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting.[5]
The gluconeogenesis pathway is highlyendergonic until it is coupled to the hydrolysis ofATP orGTP, effectively making the processexergonic. For example, the pathway leading frompyruvate toglucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied fromfatty acid catabolism viabeta oxidation.[6]
In humans the main gluconeogenic precursors arelactate,glycerol (which is a part of thetriglyceride molecule),alanine andglutamine. Altogether, they account for over 90% of the overall gluconeogenesis.[8]Otherglucogenic amino acids and allcitric acid cycle intermediates (through conversion tooxaloacetate) can also function as substrates for gluconeogenesis.[9] Generally, human consumption of gluconeogenic substrates in food does not result in increased gluconeogenesis.[10]
Inruminants, propionate is the principal gluconeogenic substrate.[3][11] In nonruminants, including human beings, propionate arises from the β-oxidation of odd-chain and branched-chain fatty acids, and is a (relatively minor) substrate for gluconeogenesis.[12][13]
Lactate is transported back to the liver where it is converted intopyruvate by theCori cycle using the enzymelactate dehydrogenase. Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose.[9]Transamination ordeamination of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle. The contribution of Cori cycle lactate to overall glucose production increases withfasting duration.[14] Specifically, after 12, 20, and 40 hours of fasting by human volunteers, the contribution of Cori cycle lactate to gluconeogenesis was 41%, 71%, and 92%, respectively.[14]
Whether even-chainfatty acids can be converted into glucose in animals has been a longstanding question in biochemistry.[15]Odd-chain fatty acids can be oxidized to yieldacetyl-CoA andpropionyl-CoA, the latter serving as a precursor tosuccinyl-CoA, which can be converted to oxaloacetate and enter into gluconeogenesis. In contrast, even-chain fatty acids are oxidized to yield only acetyl-CoA, whose entry into gluconeogenesis requires the presence of aglyoxylate cycle (also known as glyoxylate shunt) to produce four-carbon dicarboxylic acid precursors.[9] The glyoxylate shunt comprises two enzymes, malate synthase and isocitrate lyase, and is present in fungi, plants, and bacteria. Despite some reports of glyoxylate shunt enzymatic activities detected in animal tissues, genes encoding both enzymatic functions have only been found innematodes, in which they exist as a single bi-functional enzyme.[16][17] Genes coding for malate synthase alone (but not isocitrate lyase) have been identified in otheranimals includingarthropods,echinoderms, and even somevertebrates. Mammals found to possess the malate synthase gene includemonotremes (platypus) andmarsupials (opossum), but notplacental mammals.[17]
The existence of the glyoxylate cycle in humans has not been established, and it is widely held that fatty acids cannot be converted to glucose in humans directly.Carbon-14 has been shown to end up in glucose when it is supplied in fatty acids,[18] but this can be expected from the incorporation of labelled atoms derived from acetyl-CoA intocitric acid cycle intermediates which are interchangeable with those derived from other physiological sources, such as glucogenic amino acids.[15] In the absence of other glucogenic sources, the 2-carbonacetyl-CoA derived from the oxidation of fatty acids cannot produce a net yield of glucose via thecitric acid cycle, since an equivalent two carbon atoms are released as carbon dioxide during the cycle. Duringketosis, however, acetyl-CoA from fatty acids yieldsketone bodies, includingacetone, and up to ~60% of acetone may be oxidized in the liver to the pyruvate precursors acetol andmethylglyoxal.[19][4] Thus ketone bodies derived from fatty acids could account for up to 11%[citation needed] of gluconeogenesis during starvation.Catabolism of fatty acids also produces energy in the form of ATP that is necessary for the gluconeogenesis pathway.
In mammals, gluconeogenesis has been believed to be restricted to the liver,[20] the kidney,[20] the intestine,[21] and muscle,[22] but recent evidence indicates gluconeogenesis occurring inastrocytes of the brain.[23] These organs use somewhat different gluconeogenic precursors. The liver preferentially uses lactate, glycerol, and glucogenic amino acids (especiallyalanine) while the kidney preferentially uses lactate,glutamine and glycerol.[24][8] Lactate from theCori cycle is quantitatively the largest source of substrate for gluconeogenesis, especially for the kidney.[8] The liver uses bothglycogenolysis and gluconeogenesis to produce glucose, whereas the kidney only uses gluconeogenesis.[8] After a meal, the liver shifts toglycogen synthesis, whereas the kidney increases gluconeogenesis.[10] The intestine uses mostly glutamine and glycerol.[21]
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.[25] The capacity of liver cells to use lactate for gluconeogenesis declines from the preruminant stage to the ruminant stage in calves and lambs.[26] In sheep kidney tissue, very high rates of gluconeogenesis from propionate have been observed.[26]
In all species, the formation ofoxaloacetate frompyruvate and TCA cycle intermediates is restricted to the mitochondrion, and the enzymes that convertPhosphoenolpyruvic acid (PEP) to glucose-6-phosphate are found in the cytosol.[27] The location of the enzyme that links these two parts of gluconeogenesis by convertingoxaloacetate to PEP –PEP carboxykinase (PEPCK) – is variable by species: it can be found entirely within themitochondria, entirely within thecytosol, or dispersed evenly between the two, as it is in humans.[27] Transport of PEP across themitochondrial membrane is accomplished by dedicated transport proteins; however no such proteins exist foroxaloacetate.[27] Therefore, in species that lack intra-mitochondrial PEPCK,oxaloacetate must be converted intomalate oraspartate, exported from themitochondrion, and converted back intooxaloacetate in order to allow gluconeogenesis to continue.[27]
Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway will begin in either the liver or kidney, in the mitochondria or cytoplasm of those cells, this being dependent on the substrate being used. Many of the reactions are the reverse of steps found inglycolysis.[28]
| Metabolism of commonmonosaccharides, includingglycolysis, gluconeogenesis,glycogenesis andglycogenolysis |
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While most steps in gluconeogenesis are the reverse of those found inglycolysis, three regulated and strongly endergonic reactions are replaced with more kinetically favorable reactions.Hexokinase/glucokinase,phosphofructokinase, andpyruvate kinase enzymes of glycolysis are replaced withglucose-6-phosphatase,fructose-1,6-bisphosphatase, andPEP carboxykinase/pyruvate carboxylase. These enzymes are typically regulated by similar molecules, but with opposite results. For example,acetyl CoA andcitrate activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively), while at the same time inhibiting the glycolytic enzymepyruvate kinase. This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevents afutile cycle of synthesizing glucose to only break it down. Pyruvate kinase can be also bypassed by 86 pathways[29] not related to gluconeogenesis, for the purpose of forming pyruvate and subsequently lactate; some of these pathways use carbon atoms originated from glucose.
The majority of theenzymes responsible for gluconeogenesis are found in thecytosol; the exceptions are mitochondrialpyruvate carboxylase and, in animals,phosphoenolpyruvate carboxykinase. The latter exists as an isozyme located in both themitochondrion and thecytosol.[30] 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 bycAMP and its phosphorylation.
Global control of gluconeogenesis is mediated byglucagon (released when blood glucose is low); it triggers phosphorylation of enzymes and regulatory proteins byProtein Kinase A (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis.Insulin counteracts glucagon by inhibiting gluconeogenesis. Type 2 diabetes is marked by excess glucagon andinsulin resistance from the body.[31] Insulin can no longer inhibit the gene expression of enzymes such as PEPCK which leads to increased levels of hyperglycemia in the body.[32] The anti-diabetic drugmetformin reduces blood glucose primarily through inhibition of gluconeogenesis, overcoming the failure of insulin to inhibit gluconeogenesis due to insulin resistance.[33]
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 byglucagon,glucocorticoids, and acidosis.[34]
In the liver, theFOX proteinFOXO6 normally promotes gluconeogenesis in the fasted state, butinsulin blocks FOXO6 upon feeding.[35] In a condition ofinsulin resistance, insulin fails to block FOXO6 resulting in continued gluconeogenesis even upon feeding, resulting in high blood glucose (hyperglycemia).[35]
Insulin resistance is a common feature ofmetabolic syndrome andtype 2 diabetes. For this reason, gluconeogenesis is a target of therapy for type 2 diabetes, such as theantidiabetic drugmetformin, which inhibits gluconeogenic glucose formation, and stimulates glucose uptake by cells.[36]
Gluconeogenesis is considered one of the most ancient anabolic pathways and is likely to have been exhibited in thelast universal common ancestor.[37] Rafael F. Say and Georg Fuchs stated in 2010 that "all archaeal groups as well as the deeply branching bacterial lineages contain a bifunctional fructose 1,6-bisphosphate (FBP) aldolase/phosphatase with both FBP aldolase and FBP phosphatase activity. This enzyme is missing in most other Bacteria and in Eukaryota, and is heat-stabile even in mesophilic marine Crenarchaeota". It is proposed that fructose 1,6-bisphosphate aldolase/phosphatase was an ancestral gluconeogenic enzyme and had preceded glycolysis.[38] However, a prebiotic glycolysis would follow the same chemical mechanisms as gluconeogenesis, due to microscopic reversibility, and in this view would have occurred at the same time.Fructose 1,6-bisphosphate is shown to be nonenzymatically synthesized within a freezing solution.[39] The synthesis is accelerated in the presence of amino acids such as glycine and lysine. Some of the other reactions of gluconeogenesis can also proceed nonenzymatically.[40] Such chemistry could have occurred in hydrothermal environments, including temperature gradients and cycling of freezing and thawing. Mineral surfaces might have played a role in the phosphorylation of metabolic intermediates from gluconeogenesis and have to been shown to produce tetrose, hexose phosphates, and pentose fromformaldehyde, glyceraldehyde, and glycolaldehyde.[41]
Metabolism map | ||
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 Majormetabolic pathways inmetro-style map. Click any text (name of pathway or metabolites) to link to the corresponding article. Single lines: pathways common to most lifeforms. Double lines: pathways not in humans (occurs in e.g. plants, fungi, prokaryotes).  Orange nodes:carbohydrate metabolism. Violet nodes:photosynthesis. Red nodes:cellular respiration. Pink nodes:cell signaling. Blue nodes:amino acid metabolism. Grey nodes:vitamin andcofactor metabolism. Brown nodes:nucleotide andprotein metabolism. Green nodes:lipid metabolism. | ||
