Gluconeogenesis

Source: Wikipedia, the free encyclopedia.
Not to be confused with Glycogenesis, Glyceroneogenesis, Glycogenolysis, or Glycolysis.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose 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 the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia).[2] In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc.[3] In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

In humans, substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted to

ketone 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 highly

glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied from fatty acid catabolism via beta oxidation.[6]

Precursors

lipid synthesis
.
  • Some amino acids are catabolized into both glucogenic and ketogenic products.

    • In humans the main gluconeogenic precursors are lactate, glycerol (which is a part of the triglyceride molecule), alanine and glutamine. Altogether, they account for over 90% of the overall gluconeogenesis.[8] Other

    oxaloacetate) can also function as substrates for gluconeogenesis.[9] Generally, human consumption of gluconeogenic substrates in food does not result in increased gluconeogenesis.[10]

    In ruminants, 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 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.[9] 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. The contribution of Cori cycle lactate to overall glucose production increases with fasting 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-chain

    placental 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.

    ketone bodies, including acetone, and up to ~60% of acetone may be oxidized in the liver to the pyruvate precursors acetol and methylglyoxal.[19][4] Thus ketone bodies derived from fatty acids could account for up to 11% of gluconeogenesis during starvation. Catabolism of fatty acids
    also produces energy in the form of ATP that is necessary for the gluconeogenesis pathway.

    Location

    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 in astrocytes of the brain.[23] These organs use somewhat different gluconeogenic precursors. The liver preferentially uses lactate, glycerol, and glucogenic amino acids (especially alanine) while the kidney preferentially uses lactate, glutamine and glycerol.[24][8] Lactate from the Cori cycle is quantitatively the largest source of substrate for gluconeogenesis, especially for the kidney.[8] The liver uses both glycogenolysis and gluconeogenesis to produce glucose, whereas the kidney only uses gluconeogenesis.[8] After a meal, the liver shifts to glycogen 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 of

    oxaloacetate in order to allow gluconeogenesis to continue.[27]

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

    Pathway

    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 in glycolysis.[citation needed]

    Regulation

    While most steps in gluconeogenesis are the reverse of those found in

    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. Pyruvate kinase can be also bypassed by 86 pathways[28]
    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 the

    fructose-1,6-bisphosphatase, which is also regulated through signal transduction by cAMP
    and its phosphorylation.

    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. Insulin counteracts glucagon by inhibiting gluconeogenesis. Type 2 diabetes is marked by excess glucagon and insulin resistance from the body.[30] Insulin can no longer inhibit the gene expression of enzymes such as PEPCK which leads to increased levels of hyperglycemia in the body.[31] The anti-diabetic drug metformin reduces blood glucose primarily through inhibition of gluconeogenesis, overcoming the failure of insulin to inhibit gluconeogenesis due to insulin resistance.[32]

    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

    glucocorticoids, and acidosis.[33]

    Insulin resistance

    In the liver, the FOX protein FOXO6 normally promotes gluconeogenesis in the fasted state, but insulin blocks FOXO6 upon feeding.[34] In a condition of insulin resistance, insulin fails to block FOXO6 resulting in continued gluconeogenesis even upon feeding, resulting in high blood glucose (hyperglycemia).[34]

    Insulin resistance is a common feature of

    antidiabetic drug metformin, which inhibits gluconeogenic glucose formation, and stimulates glucose uptake by cells.[35]

    Origins

    Gluconeogenesis is considered one of the most ancient anabolic pathways and is likely to have been exhibited in the last universal common ancestor.[36] 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.[37] But the chemical mechanisms between gluconeogenesis and glycolysis, whether it is anabolic or catabolic, are similar, suggesting they both originated at the same time. Fructose 1,6-bisphosphate is shown to be nonenzymatically synthesized continuously within a freezing solution. The synthesis is accelerated in the presence of amino acids such as glycine and lysine implying that the first anabolic enzymes were amino acids. The prebiotic reactions in gluconeogenesis can also proceed nonenzymatically at dehydration-desiccation cycles. 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 from formaldehyde, glyceraldehyde, and glycolaldehyde.[38][39][40]

    See also

    References

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    2. ^ Silva P. "The Chemical Logic Behind Gluconeogenesis". Archived from the original on August 26, 2009. Retrieved September 8, 2009.
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    12. ^ Rodwell VW, Bender DA, Botham KM, Kennelly PJ, Weil PA (2018). Harper's Illustrated Biochemistry (31st ed.). McGraw-Hill Publishing Company.
    13. ^ Baynes J, Dominiczak M (2014). Medical Biochemistry (4th ed.). Elsevier.
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    28. ^ Christos Chinopoulos (2020), From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity, https://www.frontiersin.org/articles/10.3389/fphys.2020.543564/full
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    External links
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