Gluconeogenesis- Steps, Regulation and clinical significance

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Gluconeogenesis- Thermodynamic barriers, substrates of gluconeogenesis, reciprocal regulation of glycolysis and gluconeogenesis, biological and clinical significance

Gluconeogenesis- Steps, Regulation and clinical significance

  1. 1. Gluconeogenesis- Steps, regulation and significance Biochemistry For Medics www.namrata.co
  2. 2. 2 Biochemistry for medics 01/24/14 Introduction • Gluconeogenesis is the process of converting noncarbohydrate precursors to glucose or glycogen. • Gluconeogenesis meets the needs of the body for glucose when sufficient carbohydrate is not available from the diet or glycogen reserves. • A supply of glucose is necessary especially for the nervous system and erythrocytes. • Failure of gluconeogenesis is usually fatal.
  3. 3. 3 Biochemistry for medics 01/24/14 Substrates of Gluconeogenesis • The major substrates are the glucogenic amino acids, lactate, glycerol, and propionate. • These noncarbohydrate precursors of glucose are first converted into pyruvate or enter the pathway at later intermediates such as oxaloacetate and dihydroxyacetone phosphate. • Liver and kidney are the major gluconeogenic tissues.
  4. 4. 4 Biochemistry for medics 01/24/14 Reactions of Gluconeogenesis Thermodynamic barriers • In glycolysis, glucose is converted into pyruvate; in gluconeogenesis, pyruvate is converted into glucose. • However, gluconeogenesis is not a reversal of glycolysis. • Three nonequilibrium reactions in glycolysis catalyzed by hexokinase, phosphofructokinase and pyruvate kinase are considered thermodynamic barriers which prevent simple reversal of glycolysis for glucose synthesis.
  5. 5. 5 Biochemistry for medics 01/24/14 Reactions of Gluconeogenesis In gluconeogenesis, the following new steps bypass these virtually irreversible reactions of glycolysis: 1. First bypass (Formation of Phosphoenolpyruvate from pyruvate) 2. Second bypass (Formation of Fructose 6phosphate from fructose 1,6-bisphosphate) 3. Third bypass (Formation of Glucose by hydrolysis of glucose 6-phosphate)
  6. 6. 6 First bypass (Formation of Phosphoenolpyruvate from pyruvate) Biochemistry for medics 01/24/14 • Reversal of the reaction catalyzed by pyruvate kinase in glycolysis involves two endothermic reactions. • Phosphoenolpyruvate is formed from pyruvate by way of oxaloacetate through the action of pyruvate carboxylase and phosphoenolpyruvate carboxykinase. • Pyruvate carboxylase is a mitochondrial enzyme, whereas the other enzymes of gluconeogenesis are cytoplasmic.
  7. 7. 7 Biochemistry for medics 01/24/14 Reaction catalyzed by pyruvate carboxylase • Mitochondrial pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, an ATP-requiring reaction in which the vitamin biotin is the coenzyme. • Biotin binds CO2 from bicarbonate as carboxybiotin prior to the addition of the CO 2 to pyruvate.
  8. 8. 8 Biochemistry for medics 01/24/14 Transportation of Oxaloacetate • Oxaloacetate, the product of the pyruvate carboxylase reaction, is reduced to malate inside the mitochondrion for transport to the cytosol. • The reduction is accomplished by an NADH-linked malate dehydrogenase. • When malate has been transported across the mitochondrial membrane, it is reoxidized to oxaloacetate by an NAD+-linked malate dehydrogenase in the cytosol.
  9. 9. 9 Biochemistry for medics 01/24/14 Decarboxylation of oxaloacetate A second enzyme, phosphoenolpyruvate carboxy kinase, catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP as the phosphate donor.
  10. 10. 10 Biochemistry for medics 01/24/14 Decarboxylation of oxaloacetate Biological Significance o In liver and kidney, the reaction of succinate thiokinase in the citric acid cycle produces GTP (rather than ATP as in other tissues), and this GTP is used for the reaction of phosphoenolpyruvate carboxykinase, o thus providing a link between citric acid cycle activity and gluconeogenesis, to prevent excessive removal of oxaloacetate for gluconeogenesis, which would impair citric acid cycle activity.
  11. 11. 11 Second bypass (Formation of Fructose 6-phosphate from fructose 1,6bisphosphate) bisphosphate Biochemistry for medics 01/24/14 • On formation, phosphoenolpyruvate is metabolized by the enzymes of glycolysis but in the reverse direction. • These reactions are near equilibrium under intracellular conditions; so, when conditions favor gluconeogenesis, the reverse reactions will take place until the next irreversible step is reached. • This step is the hydrolysis of fructose 1,6bisphosphate to fructose 6-phosphate and Pi.
  12. 12. 12 Second bypass (Formation of Fructose 6-phosphate from fructose 1,6-bisphosphate) Biochemistry for medics 01/24/14 • Fructose 1,6-bisphosphatase catalyzes this exergonic hydrolysis. • Its presence determines whether a tissue is capable of synthesizing glucose (or glycogen) not only from pyruvate, but also from triose phosphates. • It is present in liver, kidney, and skeletal muscle, but is probably absent from heart and smooth muscle. • Like its glycolytic counterpart, it is an allosteric enzyme that participates in the regulation of gluconeogenesis.
  13. 13. 13 Biochemistry for medics 01/24/14 Third bypass (Formation of Glucose by hydrolysis of glucose 6-phosphate) • The fructose 6-phosphate generated by fructose 1,6-bisphosphatase is readily converted into glucose 6-phosphate. • In most tissues, gluconeogenesis ends here. Free glucose is not generated; rather, the glucose 6phosphate is processed in some other fashion, notably to form glycogen. • One advantage to ending gluconeogenesis at glucose 6-phosphate is that, unlike free glucose, the molecule cannot diffuse out of the cell.
  14. 14. 14 Biochemistry for medics 01/24/14 Third bypass (Formation of Glucose by hydrolysis of glucose 6-phosphate) • To keep glucose inside the cell, the generation of free glucose is controlled in two ways. First, the enzyme responsible for the conversion of glucose 6-phosphate into glucose, glucose 6-phosphatase, is regulated. • Second, the enzyme is present only in tissues whose metabolic duty is to maintain blood-glucose homeostasistissues that release glucose into the blood. • These tissues are the liver and to a lesser extent the kidney the enzyme is absent in muscle and adipose tissue, which therefore, cannot export glucose into the blood stream.
  15. 15. 15 Formation of Glucose by hydrolysis of glucose 6phosphate Biochemistry for medics 01/24/14 o This final step in the generation of glucose does not take place in the cytosol. o Rather, glucose 6-phosphate is transported into the lumen of the endoplasmic reticulum, where it is hydrolyzed to glucose by glucose 6-phosphatase, which is bound to the membrane. o An associated Ca2+binding stabilizing protein is essential for phosphatase activity. o Glucose and Pi are then shuttled back to the cytosol by a pair of transporters.
  16. 16. 16 Biochemistry for medics 01/24/14 Formation of Glucose by hydrolysis of glucose 6-phosphate The glucose transporter in the endoplasmic reticulum membrane is like those found in the plasma membrane.
  17. 17. 17 Reactions of Gluconeogenesis Biochemistry for medics 01/24/14 oIn the kidney, muscle and especially the liver, G6P be shunted toward glycogen if blood glucose levels are adequate. oThe reactions necessary for glycogen synthesis are an alternate bypass series of reactions o The G6P produced from gluconeogenesis can be converted to glucose-1-phosphate (G1P) by phosphoglucose mutase (PGM). o G1P is then converted to UDPglucose (the substrate for glycogen synthase) by UDP-glucose pyro phosphorylase, a reaction requiring hydrolysis of UTP.
  18. 18. 18 Biochemistry for medics 01/24/14 Energetics of gluconeogenesis • Six nucleotide triphosphate molecules are hydrolyzed to synthesize glucose from pyruvate in gluconeogenesis, whereas only two molecules of ATP are generated in glycolysis in the conversion of glucose into pyruvate. • Thus it is not a simple reversal of glycolysis but it is energetically an expensive affair. • The overall reaction of gluconeogenesis is- The overall reaction of glycolysis is-
  19. 19. 19 Biochemistry for medics 01/24/14 Substrates of Gluconeogenesis The major substrates are the glucogenic amino acids, lactate, glycerol, and propionate. A)Glucogenic amino acids- Amino acids are derived from the dietary proteins, tissue proteins or from the breakdown of skeletal muscle proteins during starvation. After transamination or deamination, glucogenic amino acids yield either pyruvate or intermediates of the citric acid cycle.
  20. 20. 20 Biochemistry for medics 01/24/14 Glucogenic amino acids • Amino acids that are degraded to pyruvate, αketoglutarate, succinyl CoA, fumarate, or oxaloacetate are termed glucogenic amino acids. The net synthesis of glucose from these amino acids is feasible because these citric acid cycle intermediates and pyruvate can be converted into phosphoenolpyruvate. • Amino acids that are degraded to acetyl CoA or Acetoacetyl CoA are termed ketogenic amino acids because they can give rise to ketone bodies or fatty acids.
  21. 21. 21 Biochemistry for medics 01/24/14 Entry of glucogenic amino acids 1) Pyruvate is the point of entry for alanine, serine, cysteine, glycine, Threonine, and tryptophan 2) Oxalo acetate- Aspartate and Asparagine are converted into oxaloacetate, a citric acid cycle intermediate. Aspartate, a four-carbon amino acid, is directly transaminated to oxaloacetate. 3) α-Ketoglutarate is the point of entry of several five-carbon amino acids that are first converted into glutamate.
  22. 22. 22 Biochemistry for medics 01/24/14 The entry of glucogenic amino acids 4) Succinyl CoA is a point of entry for some of the carbon atoms of methionine, isoleucine, and valine. Propionyl CoA and then Methylmalonyl CoA are intermediates in the breakdown of these three nonpolar amino acids. 5) Fumarate is the point of entry for Aspartate, Phenyl alanine and Tyrosine.
  23. 23. 23 Entry of lactate in to the pathway of gluconeogenesis Biochemistry for medics 01/24/14 B) Lactate- Lactate is formed by active skeletal muscle when the rate of glycolysis exceeds the rate of oxidative metabolism. Lactate is readily converted into pyruvate by the action of lactate dehydrogenase.
  24. 24. 24 Biochemistry for medics 01/24/14 Entry of lactate in to the pathway of gluconeogenesis Biological Significance During anaerobic glycolysis in skeletal muscle, pyruvate is reduced to lactate by lactate dehydrogenase (LDH). This reaction serves two critical functions during anaerobic glycolysis.
  25. 25. 25 Biochemistry for medics 01/24/14 Entry of lactate in to the pathway of gluconeogenesis Biological Significance (contd.) o First, in the direction of lactate formation the LDH reaction requires NADH and yields NAD+ which is then available for use by the glyceraldehyde-3-phosphate dehydrogenase reaction of glycolysis. o These two reactions are, therefore, intimately coupled during anaerobic glycolysis.
  26. 26. 26 Biochemistry for medics 01/24/14 Entry of lactate in to the pathway of gluconeogenesis Biological Significance (contd.) Secondly, the lactate produced by the LDH reaction is released to the blood stream and transported to the liver where it is converted to glucose. The glucose is then returned to the blood for use by muscle as an energy source and to replenish glycogen stores. This cycle is termed the Cori cycle.
  27. 27. 27 Cori’s cycle Biochemistry for medics 01/24/14 • The liver furnishes glucose to contracting skeletal muscle, which derives ATP from the glycolytic conversion of glucose into lactate. • Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize glucose. • These reactions constitute the Cori cycle
  28. 28. 28 Biochemistry for medics 01/24/14 Entry of propionate in to the pathway of gluconeogenesis C) Propionate- Propionate is a major precursor of glucose in ruminants; it enters gluconeogenesis via the citric acid cycle. o After esterification with CoA, Propionyl-CoA is carboxylated to D-Methylmalonyl-CoA, catalyzed by Propionyl-CoA carboxylase, a biotin-dependent enzyme o Methylmalonyl-CoA Racemase catalyzes the conversion of D-Methylmalonyl-CoA to L-Methylmalonyl-CoA, which then undergoes isomerization to succinyl-CoA catalyzed by Methylmalonyl-CoA mutase. o Methylmalonyl CoA Isomerase/ mutase is a vitamin B12 dependent enzyme, and in deficiency methylmalonic acid is excreted in the urine (methylmalonic aciduria).
  29. 29. 29 Fate of Propionyl co A Biochemistry for medics 01/24/14 In non-ruminants, including humans, propionate arises from the Beta -oxidation of odd-chain fatty acids that occur in ruminant lipids, as well as the oxidation of isoleucine and the side-chain of cholesterol, and is a (relatively minor) substrate for gluconeogenesis.
  30. 30. 30 Biochemistry for medics 01/24/14 Entry of glycerol in to the pathway of gluconeogenesis • The hydrolysis of triacylglycerols in fat cells yields glycerol and fatty acids. Glycerol may enter either the gluconeogenic or the glycolytic pathway at Dihydroxyacetone phosphate • In the fasting state glycerol released from lipolysis of adipose tissue triacylglycerol is used solely as a substrate for gluconeogenesis in the liver and kidneys. • This requires phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to Dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate dehydrogenase (G3PDH).
  31. 31. 31 Biochemistry for medics 01/24/14 Entry of glycerol in to the pathway of gluconeogenesis • Glycerol kinase is absent in adipose tissue, so glycerol released by hydrolysis of triglycerides can not be utilized for re -esterification, it is a waste product. • • It is carried through circulation to the liver and is used for gluconeogenesis or glycolysis as the need may be. In fact adipocytes require a basal level of glycolysis in order to provide them with DHAP as an intermediate in the synthesis of triacylglycerols.
  32. 32. 32 Biochemistry for medics 01/24/14 “It is incorrect to say that fats can not be converted to glucose” • Triglycerides (fats) on hydrolysis yield fatty acids and glycerol. • Even chain fatty acids are not the glucogenic precursors, • Oxidation of these fatty acids yields enormous amounts of energy on a molar basis, however, the carbons of the fatty acids cannot be utilized for net synthesis of glucose. • The two carbon unit of acetyl-CoA derived from β-oxidation of fatty acids can be incorporated into the TCA cycle, however, during the TCA cycle two carbons are lost as CO2. • Moreover the formation of acetyl CoA from pyruvate is an irreversible step, thus acetyl CoA can not be converted back into glucose.
  33. 33. 33 Biochemistry for medics 01/24/14 “It is incorrect to say that fats can not be converted to glucose” • Odd chain fatty acids on oxidation produce Propionyl co A which is a substrate for gluconeogenesis through formation of succinyl co A. • Glycerol component of fats can also be utilized for the formation of glucose through formation of Dihydroxy acetone phosphate. • Hence therefore except for even chain fatty acids, the other fat components are glucogenic, so the above given statement that “It is incorrect to say that fats can not be converted to glucose”, is a justified statement.
  34. 34. 34 Biochemistry for medics 01/24/14 Regulation of Gluconeogenesis • Gluconeogenesis and glycolysis are coordinated so that within a cell one pathway is relatively inactive while the other is highly active. • The amounts and activities of the distinctive enzymes of each pathway are controlled so that both pathways are not highly active at the same time.
  35. 35. 35 Regulation of Gluconeogenesis Biochemistry for medics 01/24/14 • Changes in the availability of substrates are responsible for most changes in metabolism either directly or indirectly acting via changes in hormone secretion. • Three mechanisms are responsible for regulating the activity of enzymes – (1)changes in the rate of enzyme synthesis, (Induction/Repression) (2)covalent modification by reversible phosphorylation, and (3) allosteric effects.
  36. 36. 36 Biochemistry for medics 01/24/14 Induction & Repression of Key Enzymes • The amounts and the activities of essential enzymes are regulated by hormones. • The enzymes involved catalyze nonequilibrium (physiologically irreversible) reactions. • Hormones affect gene expression primarily by changing the rate of transcription, as well as by regulating the degradation of mRNA.
  37. 37. 37 Biochemistry for medics 01/24/14 Induction & Repression of Key Enzymes • Insulin, which rises subsequent to eating, stimulates the expression of phosphofructokinase, pyruvate kinase, and the bifunctional enzyme that makes and degrades F-2,6-BP. • Glucagon, which rises during starvation, inhibits the expression of these enzymes and stimulates instead the production of two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and fructose 1,6bisphosphatase. • Transcriptional control in eukaryotes is much slower than allosteric control; it takes hours or days in contrast with seconds to minutes.
  38. 38. 38 Biochemistry for medics 01/24/14 2) Covalent Modification by Reversible Phosphorylation • It is a rapid process. • Glucagon and epinephrine, hormones that are responsive to a decrease in blood glucose, inhibit glycolysis and stimulate gluconeogenesis in the liver by increasing the concentration of cAMP. • This in turn activates cAMP-dependent protein kinase, leading to the phosphorylation and inactivation of pyruvate kinase. • They also affect the concentration of fructose 2,6bisphosphate and therefore glycolysis and gluconeogenesis are appropriately regulated .
  39. 39. 39 Biochemistry for medics 01/24/14 3) Allosteric Modification It is an instantaneous process. a) Role of Acetyl co A • As an allosteric activator of pyruvate carboxylase • This means that as acetyl-CoA is formed from pyruvate, it automatically ensures the provision of oxaloacetate and, therefore, its further oxidation in the citric acid cycle, by activating pyruvate carboxylase • The activation of pyruvate carboxylase and the reciprocal inhibition of pyruvate dehydrogenase by acetyl-CoA derived from the oxidation of fatty acids explain the action of fatty acid oxidation in sparing the oxidation of pyruvate and in stimulating gluconeogenesis.
  40. 40. 40 Biochemistry for medics 01/24/14 3) Allosteric Modification(contd.) B) Role of ATP and AMP o The interconversion of fructose 6-phosphate and fructose 1,6bisphosphate is stringently controlled o Phosphofructokinase (phosphofructokinase-1) occupies a key position in regulating glycolysis and is also subject to feedback control. o AMP stimulates phosphofructokinase, whereas ATP and citrate inhibit it. o Fructose 1,6- bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. o A high level of AMP indicates that the energy charge is low and signals the need for ATP generation. o Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are abundant. Under these conditions, glycolysis is nearly switched off and gluconeogenesis is promoted.
  41. 41. 41 Biochemistry for medics 01/24/14 3) Allosteric Modification(contd.) Role of ATP and AMP o The interconversion of phosphoenolpyruvate and pyruvate also is precisely regulated. o Pyruvate kinase is controlled by allosteric effectors and by phosphorylation. o High levels of ATP and alanine, which signal that the energy charge is high and that building blocks are abundant, inhibit the enzyme in liver. o Likewise, ADP inhibits phosphoenolpyruvate carboxy kinase. o Hence, gluconeogenesis is favored when the cell is rich in biosynthetic precursors and ATP.
  42. 42. 42 Biochemistry for medics 01/24/14 3) Allosteric Modification(contd.) c) Role of Fructose 2,6-Bisphosphate o The most potent positive allosteric activator of phosphofructokinase-1 and inhibitor of fructose 1,6bisphosphatase in liver is fructose 2,6-bisphosphate. o It relieves inhibition of phosphofructokinase-1 by ATP and increases the affinity for fructose 6-phosphate. o It inhibits fructose 1,6-bisphosphatase by increasing the Km for fructose 1,6-bisphosphate o Its concentration is under both substrate (allosteric) and hormonal control (covalent modification)
  43. 43. 43 Biochemistry for medics 01/24/14 3) Allosteric Modification(contd.) c) Role of Fructose 2,6-Bisphosphate (contd.) o Fructose 2,6-bisphosphate is formed by phosphorylation of fructose 6-phosphate by phosphofructokinase-2. o The same enzyme protein is also responsible for its breakdown, since it has fructose 2,6-bisphosphatase activity. o This bifunctional enzyme is under the allosteric control of fructose 6-phosphate, which stimulates the kinase and inhibits the phosphatase.
  44. 44. 44 Biochemistry for medics 01/24/14 3) Allosteric Modification(contd.) c) Role of Fructose 2,6-Bisphosphate (contd.) • When there is an abundant supply of glucose, the concentration of fructose 2,6-bisphosphate increases, stimulating glycolysis by activating phosphofructokinase-1 and inhibiting fructose 1,6-bisphosphatase. • In the fasting state, glucagon stimulates the production of cAMP, activating cAMP-dependent protein kinase, which in turn inactivates phosphofructokinase-2 and activates fructose 2,6-bisphosphatase by phosphorylation. • Hence, gluconeogenesis is stimulated by a decrease in the concentration of fructose 2,6-bisphosphate, which inactivates phosphofructokinase-1 and relieves the inhibition of fructose 1,6-bisphosphatase.
  45. 45. 45 Reciprocal Regulation of Gluconeogenesis and Glycolysis in the Liver Biochemistry for medics 01/24/14 oGlycolysis and Gluconeogenesis are reciprocally regulated . oWhen glycolysis is on Gluconeogenesis is turned off especially in the fed state, whereas under conditions of starvation, gluconeogenesis is fully on and glycolysis is turned off. o Both the cycles are never active at the same pace at the same time.
  46. 46. 46 Biochemistry for medics 01/24/14 Clinical significance Alcohol-related hypoglycemia o It is due to hepatic glycogen depletion combined with alcoholmediated inhibition of gluconeogenesis. o It is most common in malnourished alcohol abusers o The implications of alcohol abuse are due to altered NAD+/NADH ratio o Excessive NADH • inhibits fatty acid oxidation that provides ATP • Pyruvate to lactate reaction is favored depleting supply of pyruvate for gluconeogenesis.
  47. 47. 47 Hypoglycemia in premature and Low birth weight infants Biochemistry for medics 01/24/14 o Premature and low-birth-weight babies are more susceptible to hypoglycemia, since they have little adipose tissue to provide alternative fuels such as free fatty acids or ketone bodies during the transition from fetal dependency to the free-living state o The enzymes of gluconeogenesis may not be completely functional at this time, o Little glycerol, which would normally be released from adipose tissue, is available for gluconeogenesis, but that is not sufficient to fulfill the energy needs. o Small for date babies have inadequate glycogen stores as well, so at the time of need there is diminished outpouring of glucose. o The situation worsens further due to prematurity since the glycogen stores are laid in the last months of pregnancy. o Hence a premature baby has diminished stores and frequently undergoes hypoglycemia.
  48. 48. 48 Biochemistry for medics 01/24/14 Hypoglycemia in babies of diabetic mothers • The growing fetus of a diabetic mother is exposed to maternal hyperglycemia which leads to hyperplasia of pancreatic islet cells. • After delivery the baby fails to suppress the excessive insulin secretions and develops hypoglycemia.
  49. 49. 49 Biochemistry for medics 01/24/14 Maternal or fetal hypoglycemia • Maternal and fetal hypoglycemia may also be observed during pregnancy, • fetal glucose consumption increases and there is a risk of maternal and possibly fetal hypoglycemia, • particularly if there are long intervals between meals or at night. • Basic reason is imbalance between demand and supply of glucose
  50. 50. 50 Biochemistry for medics 01/24/14 Role played by kidney in gluconeogenesis • During periods of severe hypoglycemia that occur under conditions of hepatic failure, the kidney can provide glucose to the blood via renal gluconeogenesis. • In the renal cortex, glutamine is the preferred substance for gluconeogenesis. • Glutamine is produced in high amounts by skeletal muscle during periods of fasting as a means to export the waste nitrogen resulting from amino acid catabolism.
  51. 51. 51 Biochemistry for medics 01/24/14 Role played by kidney in gluconeogenesis(contd.) • Through the actions of transaminases, a mole of waste ammonia is transferred to α-ketoglutarate via the glutamate dehydrogenase catalyzed reaction yielding glutamate. • Glutamate is then a substrate for glutamine synthetase which incorporates another mole of waste ammonia generating glutamine. • The glutamine is then transported to the kidneys where the reverse reactions occur liberating the ammonia and producing α-ketoglutarate which can enter the TCA cycle and the carbon atoms diverted to gluconeogenesis via oxaloacetate.
  52. 52. 52 Biochemistry for medics 01/24/14 Role played by kidney in gluconeogenesis(contd.) • This process serves two important functions. • The ammonia (NH3) that is liberated spontaneously ionizes to ammonium ion (NH 4+) and is excreted in the urine effectively buffering the acids in the urine. • In addition, the glucose that is produced via gluconeogenesis can provide the brain with critically needed energy.
  53. 53. 53 Summary Chart- Regulation of Gluconeogenesis Biochemistry for medics 01/24/14 Induction/ Repression Clinical Significance Enzyme Effect of substrate concentration Allosteric modification/ Feed back Inhibition Pyruvate carboxylase Inhibited by high carbohydrate diet Activator-Acetyl Induced by CoA Glucocorticoids, glucagon, Inhibitor epinephrine ADP Repressed by Insulin Activity increases in Diabetes Mellitus Activator-Citrate Induced by Glucocorticoids, Inhibitor glucagon, AMP, Fr 2,6 epinephrine bisphosphate Repressed by Insulin Activity increases in Diabetes Mellitus Stimulated during fasting Fructose 1,6 Inhibited by high bisphosphata carbohydrate diet se Stimulated during fasting
  54. 54. 54 Biochemistry for medics 01/24/14 For further reading Follow the linkshttp://www.namrata.co/substrates-of-gluconeogenesishttp://www.namrata.co/substrates-of-gluconeogenesis/

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