Gluconeogenesis | Anatomy2Medicine
glycolysis-vs-gluconeogenesis

Gluconeogenesis

    • Gluconeogenesis

 

  • synthesis of glucose from compounds that are not carbohydrates.

 

      • occurs mainly in the liver and to a small degree in the kidney
      • The major precursors for gluconeogenesis are

 

  • Lactate

 

        • amino acids (which form pyruvate or TCA cycle intermediates)
        • glycerol which forms dihydroxyacetone phos- phate [DHAP]
      • Even-chain fatty acids do not produce any net glucose.
      • glucose is not generated by a simple reversal of glycolysis.
      • The synthesis of 1 mole of glucose from 2 moles of pyruvate requires the energy equivalent of about 6 moles of ATP

 

  • Reactions of gluconeogenesis
  • Conversion of pyruvate to phosphoenolpyruvate

 

        • In the liver, pyruvate is converted to phosphoenolpyruvate (PEP) in two steps.
          • Pyruvate (produced from lactate, alanine, and other amino acids) is first converted to oxaloacetate (OAA)
            • Enzyme :  pyruvate carboxylase
            • a mitochondrial enzyme that requires biotin and ATP.
          • OAA cannot directly cross the inner mitochondrial membrane.
            • Therefore, it is converted to malate or to aspartate, which can cross the mitochondrial membrane and be reconverted to OAA in the cytosol.
        • OAA is decarboxylated by phosphoenolpyruvate carboxykinase (PEPCK) to form PEP
          • This reaction requires guanosine triphosphate (GTP).
          • PEP is converted to fructose 1,6-bisphosphate by reversal of the glycolytic reactions
      • Conversion of fructose 1,6-bisphosphate to fructose 6-phosphate
        • Fructose 1,6-bisphosphate is converted to fructose 6-phosphate in a reaction that releases inorganic phosphate
          • catalyzed by fructose-1,6-bisphosphatase (F-1,6-BP).
        • Fructose 6-phosphate is converted to glucose 6-phosphate by the same isomerase used in glycolysis.
      • Conversion of glucose 6-phosphate to glucose
        • Glucose 6-phosphate releases inorganic phosphate (Pi), which produces free glucose that enters the blood
        • enzyme is glucose 6-phosphatase.

 

  • Glucose 6 phosphatase is involved in both gluconeogenesis and glycogenolysis

 

      • Regulatory enzymes of gluconeogenesis
        • Under fasting conditions, glucagon is elevated and stimulates gluconeogenesis.

 

  • Pyruvate dehydrogenase (PDH)

 

          • Decreased insulin and increased glucagon stimulate the release of fatty acids from adipose tissue.
          • Fatty acids travel to the liver and are oxidized, producing acetyl coenzyme A (CoA), NADH, and ATP, which cause inactivation of PDH.
          • Because PDH is relatively inactive , pyruvate is converted to OAA,not to acetyl CoA.

 

  • Pyruvate carboxylase

 

          • Pyruvate carboxylase,which converts pyruvate to OAA,is activated by acetyl CoA
          • Note that pyruvate carboxylase is active in both the fed and fasting states.

 

  • PEPCK

 

          • PEPCK is an inducible enzyme.
          • Transcription of the gene encoding PEPCK is stimulated by
            • binding of proteins that are phosphorylated in response to cAMP
            • binding of glucocorticoid–protein complexes to regulatory elements in the gene.

 

  • Increased production of PEPCK messenger RNA (mRNA) leads to increased translation, resulting in higher PEPCK levels in the cell.
  • Pyruvate kinase(PK)

 

          • Glucagon
            • acts via cAMP and protein kinase A
            • causes PK to be phosphorylated and inactivated.
          • Because PK is relatively inactive, PEP formed from OAA is not reconverted to pyruvate but, in a series of steps, forms fructose 1,6-bisphosphate, which is converted to fructose 6-phosphate.
          • Phosphofructokinase-1 relatively inactive because the concentrations of
            • its activators, AMP and fructose 2,6-bisphosphate, are low
            • its inhibitor, ATP, is relatively high owing to the oxidation of fatty acids.

 

  • F-1,6-Bisphosphatase

 

          • The level of fructose 2,6-bisphosphate, an inhibitor of F-1,6-bisphosphatase, is low during fasting.
          • Therefore, F-1,6-bisphosphatase is more active.
          • F-1,6-bisphosphatase is also induced in the fasting state.
        • Glucokinase
          • Gluco kinase is relatively inactive because it has a high Km for glucose, and under conditions that favor gluconeogenesis, the glucose concentration is low. Therefore, free glucose is not reconverted to glucose 6-phosphate.
    • Precursors for gluconeogenesis
    • Lactate, amino acids, and glycerol are the major precursors for gluconeogenesis in humans.
    • Lactate
      • oxidized by NAD+ in a reaction catalyzed by lactate dehydrogenase to form pyruvate, which can be converted to glucose
      • Sources of lactate include red blood cells and exercising muscle.

 

  • Amino acids for gluconeogenesis come from degradation of muscle protein.

 

      • Amino acids are released directly into the blood from muscle, or carbons from amino acids are converted to alanine and glutamine and released.

 

  • Alanine is also formed by transamination of pyruvate that is derived by oxidation of glucose.

 

      • Glutamine is converted to alanine by tissues such as gut and kidney.
      • Amino acids travel to the liver and provide carbon for gluconeogenesis.
      • Quantitatively, alanine is the major gluconeogenic amino acid.
      • Amino acid nitrogen is converted to urea.
    • Glycerol,
      • derived from adipose triacylglycerols
      • reacts with ATP to form glycerol – 3-phosphate, which is oxidized to DHAP and converted to glucose
    • Role of fatty acids in gluconeogenesis
      • Even-chain fatty acids
        • Fatty acids are oxidized to acetyl CoA,which enters the TCA cycle.
        • For every 2 carbons of acetyl CoA that enter the TCA cycle, 2 carbons are released as CO2.
        • Therefore, there is no net synthesis of glucose from acetyl CoA.
        • The PDH reaction is irreversible;thus,acetyl CoA cannot be converted to pyruvate.
        • Although even-chain fatty acids do not provide carbons for gluconeogenesis, beta-oxidation of fatty acids provides ATP that drives gluconeogenesis.
      • Odd-chain fatty acids
        • The three carbons at the omega-end of an odd-chain fatty acid are converted to propionate.
        • Propionate enters the TCA cycle as succinyl CoA, which forms malate, an intermediate in glucose formation
    • Energy requirements for gluconeogenesis
      • From pyruvate

 

  • Conversion of pyruvate to OAA by pyruvate carboxylase requires 1 mole of ATP.

 

        • Conversion of OAA to PEP by phosphoenolpyruvate carboxykinase requires 1 mole of GTP (the equivalent of 1 mole of ATP).
        • Conversion of 3-phosphoglycerate to 1,3-bisphosphoglycerate by phosphoglycerate kinase requires 1 mole of ATP.

 

  • Because 2 moles of pyruvate are required to form 1 mole of glucose, 6 moles of high-energy phosphate are required for synthesis of 1 mole of glucose.

 

      • From glycerol
        • Glycerol enters the gluconeogenic pathway at the DHAP level.
        • Conversion of glycerol to glycerol 3-phosphate, which is oxidized to DHAP, requires 1 ATP.

 

  • Because 2 moles of glycerol are required to form 1 mole of glucose, 2 moles of high-energy phosphate are required for synthesis of 1 mole of glucose.
  • Maintenance of blood glucose levels

 

      • Blood glucose levels in the fed state

 

  • Changes in insulin and glucagon levels

 

          • On a normal mixed diet, glucagon will remain relatively constant after a meal, while insulin increases.
          • Blood insulin
            • levels increase as a meal is digested, following the rise in blood glucose.
            • Glucose enters the pancreatic beta cells via the insulin-independent glucose transporter, GLUT-2, which stimulates release of preformed insulin and promotes the synthesis of new insulin.
            • Additionally, amino acids (particularly arginine and leucine) cause the release of preformed insulin from beta cells of the pancreas, although to a lesser extent than that released by glucose.
          • Blood glucagon
            • levels change depending on the content of the meal.
            • A high-carbohydrate meal causes glucagon levels to decrease.
            • A high-protein meal causes glucagon to increase
        • Fate of dietary glucose in the liver
          • Glucose enters the hepatocyte via the insulin-independent GLUT-2 transporter.
            • Glucose is oxidized for energy.
            • Excess glucose is converted to glycogen and to the triacylglycerols of very-low-density lipoprotein (VLDL).
          • The enzyme glucokinase has a high Km for glucose (about 6 mM); thus, its velocity increases after a meal when glucose levels are elevated.
            • On a high-carbohydrate diet, glucokinase is induced.
          • Glycogen synthesis is promoted by insulin, which stimulates the phosphatase that dephosphorylates and activates glycogen synthase.
          • Synthesis of triacylglycerols is also stimulated.
            • The triacylglycerols are converted to VLDLs and released into the blood.
        • Fate of dietary glucose in peripheral tissues
          • All cells oxidize glucose for energy.
          • Insulin stimulates the transport of glucose into adipose and muscle cells.
          • In muscle,insulin stimulates the synthesis of glycogen.
          • Adipose cells convert glucose to the glycerol moiety for synthesis of triacylglycerols
      • Return of blood glucose to fasting levels
        • The uptake of dietary glucose by tissues (particularly liver, adipose, and muscle) causes blood glucose to decrease.
        • By 2 hours after a meal, blood glucose has returned to the fasting level of 80 to 100 mg/dL.
      • Blood glucose levels in the fasting state
        • Changes in insulin and glucagon levels
          • During fasting, insulin levels decrease, and glucagon levels increase.
          • These hormonal changes promote glycogenolysis and gluconeogenesis in the liver so that blood glucose levels are maintained.
        • Stimulation of glycogenolysis
          • Within a few hours after a meal,glucagon levels increase.
          • As a result,glycogenolysis is stimulated and begins to supply glucose to the blood.
        • Stimulation of gluconeogenesis
          • By 4 hours after a meal, the liver is supplying glucose to the blood via gluconeogenesis and glycogenolysis
        • Stimulation of lipolysis
          • During fasting, the breakdown of adipose triacylglycerols is stimulated, and fatty acids and glycerol are released into the blood.
          • Fatty acids are oxidized by certain tissues and converted to ketone bodies by the liver.
          • The ATP and NADH produced by beta-oxidation of fatty acids promote gluconeogenesis in the liver.
          • Glycerol is a source of carbon for gluconeogenesis in the liver.
        • Relative roles of glycogenolysis and gluconeogenesis in maintaining blood glucose
          • Glycogenolysis
            • stimulated as blood glucose falls to the fasting level after a meal.
            • It is the main source of blood glucose for the next 8 to 12 hours.
          • Gluconeogenesis
            • stimulated within a few hours (up to 4 hours) after a meal
            • supplies an increasingly larger share of blood glucose as the fasting state persists.
            • By 16 hours of fasting, gluconeogenesis and glycogenolysis are about equal as sources of blood glucose.
            • As liver glycogen stores become depleted, gluconeogenesis predominates.
            • By about 30 hours of fasting, liver glycogen is depleted, and thereafter, gluconeogenesis is the only source of blood glucose.
      • Blood glucose levels during prolonged fasting(starvation)

 

  • Even after 5 to 6 weeks of starvation, blood glucose levels are still in the range of 65 mg/dL.

 

        • Changes in fuel utilization by various tissues prevent blood glucose levels from decreasing abruptly during prolonged fasting.
        • The levels of ketone bodies rise in the blood, and the brain uses ketone bodies for energy, decreasing its utilization of blood glucose. (MCQ)
        • The rate of gluconeogenesis and,therefore,of urea production by the liver decreases.
        • Muscle protein is spared.
          • Less muscle protein is used to provide amino acids for gluconeogenesis.
      • Blood glucose levels during exercise

 

  • During exercise, blood glucose is maintained by essentially the same mechanisms that are used during fasting.

 

        • Use of endogenous fuels
          • As the exercising muscle contracts, ATP is used.

 

  • ATP is regenerated initially from creatine phosphate.

 

        • Muscle glycogen is oxidized to produce ATP.
          • AMP activates phosphorylase b, and
          • Ca2+-calmodulin activates phosphorylase kinase.
          • The hormone epinephrine causes the production of cAMP, which stimulates glycogen breakdown.
      • Use of fuels from the blood
        • As blood flow to the exercising muscle increases, blood glucose and fatty acids are taken up and oxidized by muscle.
        • As blood glucose levels begin to decrease, the liver, by the processes of glycogenolysis and gluconeogenesis, acts to maintain blood glucose levels.

 

Topic- Niemann pick

    • Synthesis and degradation of phosphoglycerides

 

  • Phosphoglycerides

 

        • synthesized by a process similar in its initial steps to triacylglycerol synthesis glycerol 3-phosphate combines with two fatty acyl CoA to form phosphatidic acid
        • Synthesis of phosphatidyl inositol
          • Phosphatidic acid reacts with cytidine triphosphate (CTP) to form cytidine diphosphate (CDP)-diacylglycerol, which reacts with inositol to form phosphatidylinositol.
          • Phosphatidyl inositol can be further phosphorylated to form phosphatidylinositol 4,5- bisphosphate, which is cleaved in response to various stimuli to form the compounds inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which serve as second messengers.
    • Synthesis of phosphatidyl ethanolamine,phosphatidyl choline,and phosphatidyl serine
      • Phosphatidic acid releases inorganic phosphate, and diacylglycerol is produced. DAG reacts with compounds containing cytidine nucleotides to form phosphatidyl ethanolamine and phosphatidyl choline.

 

  • Phosphatidyl ethanolamine

 

        • DAG reacts with CDP-ethanolamine to form phosphatidyl ethanolamine.

 

  • Phosphatidyl ethanolamine can also be formed by decarboxylation of phosphatidyl serine
  • Phosphatidyl choline

 

        • DAG reacts with CDP-choline to form phosphatidyl choline(lecithin).
        • Phosphatidylcholine can also be formed by methylation of phosphatidylethanolamine.
        • S-Adenosylmethionine (SAM) provides the methyl groups.

 

  • Phosphatidylcholine : important functions (MCQ)
  • important component of cell membranes and the blood lipoproteins

 

          • provides the fatty acid for the synthesis of cholesterol esters in high-density lipoprotein (HDL) by the lecithin:cholesterol acyltransferase (LCAT) reaction

 

  • as the dipalmitoyl derivative, serves as a component of lung surfactant.
  • If choline is deficient in the diet, phosphatidylcholine can be synthesized de novo from glucose

 

        • Respiratory distress syndrome (RDS) of the newborn
          • occurs in premature infants
          • due to a deficiency of surfactant in the lungs, which leads to a decrease in lung compliance.
          • Dipalmitoyl phosphatidylcholine (DPPC, also called lecithin), is the primary phospholipid in surfactant, which lowers surface tension at the alveolar air–fluid interface.

 

  • Surfactant is normally produced at gestational week 30
  • Phosphatidyl serine

 

        • Phosphatidyl serine is formed when phosphatidyl ethanolamine reacts with serine Serine replaces the ethanolamine moiety
    • Degradation of phosphoglycerides
      • Phospho glycerides are hydrolyzed by phospholipases.
        • Phospholipase A1 releases the fatty acid at position 1 of the glycerol moiety
        • Phospholipase A2 releases the fatty acid at position 2
        • Phospholipase C releases the phosphorylated head group (e.g., choline) at position 3
        • Phospholipase D releases the free head group.
    • Synthesis and degradation of sphingo lipids
      • Sphingolipids are derived from serine rather than glycerol.
      • Serine condenses with palmitoyl CoA in a reaction in which the serine is decarboxylated by a pyridoxal phosphate–requiring enzyme.
      • The product of the condensation reaction is a derivative of sphingosine. Subsequent reactions convert this product to sphingosine.
      • A fatty acyl CoA forms an amide with the nitrogen of sphingosine, and the resulting compound is ceramide.
    • The hydroxymethyl moiety of ceramide combines with various compounds to form sphingolipids and sphingoglycolipids.
      • Phosphatidylcholine reacts with ceramide to form sphingomyelin.

 

  • Uridine diphosphate (UDP)-sugars react with ceramide to form galactocerebrosides or glucocerebrosides.
  • What are gangliosides

 

    • A series of sugars can add to ceramide, with UDP sugars serving as precursors.
    • CMP-NANA (N-acetylneuraminic acid, a sialic acid) can form branches from the carbohydrate chain. These ceramide-oligosaccharide compounds are gangliosides.

Sphingolipidoses

    • Sphingolipids are degraded by lysosomal enzymes.

 

  • Fabry disease

 

      • -Galactosidase A deficiency
      • Glycolipids in brain, heart, and kidney, resulting in ischemia of affected organs
      • Severe pain in the extremities (acroparesthesia), skin lesions (angiokeratomas), hypohidrosis, and ischemic infarction of the kidney, heart, and brain

 

  • Gaucher disease

 

      • Glucocerebrosidase deficiency
      • Glucocerebrosides in blood cells, liver, and spleen
      • Hepatosplenomegaly  anemia, thrombocytopenia, bone pain, and Erlenmeyer flask deformity of the distal femur.
      • autosomal recessive deficiency

 

  • Metachromatic leukodystrophy
  • Arylsulfatase A deficiency

 

      • Sulfated glycolipid (sulfatide) compounds accumulate in neural tissue
      • cause demyelination of central nervous system and peripheral nerves.
      • Clinical consequences of demyelination include loss of cognitive and motor functions, intellectual decline in school performance, ataxia, hyporeflexia, and seizures.

 

  • Niemann-Pick disease

 

      • Sphingomyelinase deficiency
      • Sphingomyelin in the brain and blood cells
      • Mental retardation, spasticity, seizures, and ataxia
      • Death usually results by age 2-3 years
      • Inheritance is autosomal recessive.

 

  • Krabbe disease

 

      • -Galactosidase deficiency

 

  • Glycolipids causing destruction of myelin-producing oligodendrocytes

 

      • Clinical consequences of demyelination include spasticity and rapid neurodegeneration leading to death.
      • Clinical signs include hypertonia and hyperreflexia, leading to decerebrate posturing, blind- ness, and deafness.
      • Inheritance is autosomal recessive.

 

  • Tay-Sachs disease

 

    • Hexosaminidase A deficiency
    • GM2 gangliosides in neurons
    • Progressive neurodegeneration, developmental delay, and early death.
    • autosomal recessive deficiency