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Gluconeogenesis and Beta-oxiation

Gluconeogenesis and Beta-oxiation. Lecture 22. Glucogneogenesis. Essentially a reversal of glycolysis Pyruvate  Glucose Requires three irreversible steps of glycolysis to be bypassed Glucose ‘trapping’ The first step in glycolysis Phosphofructokinase The rate limiting step in glycolysis

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Gluconeogenesis and Beta-oxiation

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  1. Gluconeogenesis and Beta-oxiation Lecture 22

  2. Glucogneogenesis • Essentially a reversal of glycolysis • Pyruvate  Glucose • Requires three irreversible steps of glycolysis to be bypassed • Glucose ‘trapping’ • The first step in glycolysis • Phosphofructokinase • The rate limiting step in glycolysis • Pyruvate kinase • The final step in glycolysis • Gluconeogenesis can only occur in the liver • Mainly cytoplasmic

  3. Glucose 6-phosphatase • Reversal of glucose trapping • Catalysed by hexokinase/glucokinase • Required for release of glucose into the bloodstream • Begins with transport of G6P into vesicles of endoplasmic reticulum • Special transporter required • Hydrolysis of G6P • By glucose 6-phosphatase (G6Pase) • Glucose goes back into cytoplasm through GLUT-9 • Glucose released into blood via GLUT-2 • Remember these are very active and [glucose]blood = [glucose]liver • G6Pase is increased in activity on starvation • Regulated by increased transcription/translation of gene

  4. Fructose 1,6 bisphosphatase • Reversal of F6P  F16BP • Above reaction stimulated by allosteric effector F26BP • F26BP made by PFK-2 • F26BP inhibits F16BPase and stimulates PFK • So when F26BP is high, glycolysis is favoured • Phosphorylation of PFK-2 converts it into F26BPase • Thus the amount of F26BP decreases • PFK is inhibited and F16BPase increases • So when F26BP is low, gluconeogensis is favoured • Phosphoryation is catalysed by cAMP-dependant protein kinase • Protein kinase A • PKA will be active when cAMP is high • When glucagon has bound to its receptors on the liver cell membrane • F16BPase is activated when glucagon levels are high • As in starvation!

  5. Gluconeogenesis & Glycolysis • When starving • glucagon    [cAMP] • [F2,6BP]  • No stimulus for PFK  no glycolysis • No inhibition for F1,6BPase  favours gluconeogenesis

  6. Reverse PEPpyruvate • Glycolytic step catalysed by pyruvate kinase • Step at which ATP is made • Requires two bypass steps • Carboxylation to oxaloacteate • Mitochondrial, pyruvate carboxylase • Decarboxylation to PEP • Cytosolic, phosphoenolpyruvate carboxykinase (PEPCK) • Both steps require ATP (or GTP) • Pyruvate carboxylase • Stimulated by acetyl-CoA • So will be stimulated by fatty acid oxidation • PEPCK • Stimulated by increased transcription/translation of the gene

  7. Gluconeognesis • Requires ATP • Stimulated in starvation • Only happens in liver • Control steps illustrative of • Reversible phosphorylation • Allosteric activation • Gene expression • Substrates include • Lactate • Enters as pyruvate at the bottom • Glycerol • Enters at aldolase stage (just as F16BP has split) • Amino acid carbon-skeletons • Can enter in a variety of places • Eg, oxaloacetate from aspartate, pyruvate from alanine

  8. Fatty acid oxidation • Also called beta-oxidation • Because most action occurs on the beta-carbon atom • Old fashioned nomenclature  • Requires tissues to have mitocondria • Reciprocally regulated with glucose oxidation • Fatty acid oxidation inhibits glucose oxidation • Insulin inhibits fatty acid oxidaiton • Consumes a lot of FAD, NAD, CoA • Availability of cofactors is important

  9. Different Naming Systems

  10. Transport of FA

  11. Transport of FA • FA needs to be transported from blood into tissues • FA is carried in blood on albumin, which has several binding sites for FA • There are specific transporters for FA: CD36/FATP • CD36 moves to the cell surface whenever there is a need to take up FA at a rapid rate • FA is carried on FABP (fatty acid binding protein) in cytoplasm

  12. Trapping of FA • FA is trapped by CoA • CoA - not only traps FA, but also “activates” it (primes it) • Requires quite a lot of energy,  ATP is not converted into ADP, but AMP

  13. Transport of FA: Mitochondria

  14. Transport of FA: Mitochondria • FA-CoA cannot cross the inner-mitochondrial membrane • FA needs to be transferred to carnitine in order to get into the mitochondria (carnitine forms ester with FA) • CAT = carnitine acyl transferase • Converts FA into a form that can be taken into the mitochondria (by specific carrier) • Regenerates CoA – • CoA is needed for trapping more FA • CoA: pool in cytoplasm and pool in mitochondria never mix  compartmentalization,  CoA can be at different concentration in the cytoplasm & in the mitochondria

  15. Transport of FA: Mitochondria • Malonyl CoA is a very strong inhibitor of CAT-I • CAT-I is the key regulator of fat oxidation - once FA gets into the mitochondria, it will be oxidized (i.e. the only fate of mitochondrial FA-CoA is oxidation) • Alternative fate of FA-CoA in the cytoplasm is esterification with glycerol-3-phosphate to form lipid • Insulin inhibits CAT-I via  malonyl CoA • Which is produced by acetyl CoA carboxylase • Normally associated with lipogenesis but occurs in muscle tissue too in a regulatory role

  16. b-oxidation

  17. Summary of b-oxidation • Example: 16C FA-CoA • 7 NADH & 7FADH2 are produced, 7 CoA are required • 16C FA-CoA  8 acetyl CoA

  18. Unsaturated FAs • Examples: • C18:1 (9) - oleic • 18 carbons, 1 double bond at the 9th position • C18:2 (9, 12) - linoleic

  19. Oxidation of Unsaturated FAs • After 3 rounds of b-oxidation, intermediates would normally have double bonds between a and b carbon, but in unsaturated FAs, the double bonds will be between b and g carbon  need to move the double bond

  20. Oxidation of Unsaturated FAs • The process of b-oxidation will halt if the double bonds cannot be moved to the appropriate position • Our body has enzymes that can shift the double bond position  but only if the double bonds are in cis configuration

  21. The double bonds in natural occurring unsaturated FAs are in cis The double bonds in unsaturated FAs result from hydrogenation are in both cis and trans Oxidation of Unsaturated FAs • Polyunsaturated FAs are liquid. To make them more solid – so as to be spreadable like butter, Hs are added to the FAs • Hydrogenation is a chemical process – using strange temperatures, pressures and catalysts • Creates some strangly positioned and configured double bonds

  22. Ketogenesis • Only occurs in the liver • Need lots of NAD, FAD & CoA to keep beta-oxidation going, • so need to regenerate co-factors • NAD & FAD are regenerated in the electron transport chain which is dependent on ATP production/demand • CoA is regenerated by sending acetyl CoA into Krebs cycle • there is limit to how much acetyl CoA can enters the Krebs cycle • only when energy is needed • So normally CoA regeneration is dependent on ATP demand • Ketogenesis represents an extra way of regenerating CoA • Thus allowing beta-oxidation to happen very fast in the liver

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