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Gluconeogenesis

Gluconeogenesis. Triacylglycerol hydrolysis .  i s not a reversal of glycolysis  n oncarbohydrate precursors of Glc, carbon skeleton  t ake place in liver , minor in kidney, brain, skeletal and heart muscle, to maintain the Glc level in the blood

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Gluconeogenesis

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  1. Gluconeogenesis Triacylglycerol hydrolysis   is not a reversal of glycolysis  noncarbohydrate precursors of Glc, carbon skeleton  take place in liver, minor in kidney, brain, skeletal and heart muscle, to maintain the Glc level in the blood  Glc is the primary fuel of brain, and the only fuel of red blood cells protein breakdown  active skeletal muscle 

  2. G°´ 0.7 -0.5 - 7.5 kcal/mol

  3. Glycolysis vs. Gluconeogenesis ¤Three irreversible reactions, irrespective Glycolysis: hexokinase, phosphofructokinase, pyruvate kinase Gluconeogenesis: glucose 6-phosphatase, fructose 1,6-bisphosphatase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase

  4. The stoichiometry of Glycolysis vs. Gluconeogenesis ¤Glycolysis: Glucose + 2 ADP + 2 Pi + 2 NAD+  2 Pyr + 2 ATP + 2 NADH + 2H+ + 2 H2O G0’= - 20 kcal / mol if reverse? ¤Gluconeogenesis: 2 Pyr + 4 ATP + 2 GTP + 2 NADH + 6 H2O  Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD+ + 2H+ G0’= - 9 kcal / mol NTP hydrolysis is used to power an energetically unfavorable reaction Both reactions are exergonic

  5. Compartmental cooperation- mitochondrial Pyruvate carboxylaseMito NADH-malate dehydrogenase G0’ decarboxylation Specific transporter NAD+-malate dehydrogenase GTP PEP + CO2 PEP carboxykinase

  6. Pyruvate carboxylase(Pyr + CO2 + ATP + H2O OAA + ADP + Pi + 2 H+) (ATP-activating domain, p. 711) The onlymitochondrial enzymes among the enzymes of gluconeogenesis Carbonic anhydrase HCO3-+ ATP  HOCO2-PO32- + ADP carboxyphosphate: activated form of CO2 Biotin-Enz + HOCO2-PO32-  CO2-biotin-Enz + Pi is activated by acetyl CoA (p. 493) CO2-biotin-Enz + Pyr  biotin-Enz + OAA S -amino group of Lys (PCase)

  7. Free glucose generation (Does not take place in cytoplasm) F1,6bisP  F6P  G6P•••  Glc The endpoint of gluconeogenesis in most tissues, can keep Glc or G6P is converted into glycogen. In liver and to a lesser extent the kidney, five proteins are involved SP: a calcium-binding stabilizing protein Gluconeogenesis 

  8. p. 465 Reciprocal control:Glycolysis and gluconeogenesis are not highly active at the same time – Energy state – Intermedia: allosteric effectors – Regulators: hormones  Amounts and activities of distinctive enzymes  Starvation: glucagon rich in precursors high energy state Fed state: insulin low energy state 

  9. Biofunctional of phosphofructokinase 2phosphofructokinase / fructose bisphosphatase 2F6P  F2,6BisP Janus a single 55-kd polypeptide chain L (liver) / M (muscle) isoforms

  10. Fructose 2,6-bisphosphate: synthesis and degradation PEP carbokinase  F 1,6-bisphosphatase  Glycolytic enzymes  (pyruvate kinase) In liver:

  11. The first irreversible reaction of glycolysis:Glc  G6P ¤Hexokinase: is inhibited by G6P Km of sugars: 0.01 ~ 0.1 mM Glucokinase: not inhibited by G6P Km of glucose: ~10 mM present in liver, to monitor blood-glucose level. ¤Committed step the most important control step in the pathway G6P glycogen biosynthesis  fatty acid biosynthesis  pentose phosphate pathway

  12. Hormones ¤Affect the expression of the gene of the essential enzymes – change the rate of transcription – regulate the degradation of mRNA ¤ allosteric control (~ms); phosphorylation control (~ s); transcription control (~ h to d) The promoter of the PEP carboxykinase (OAAPEP) gene IRE: insulin response element; GRE: glucocorticoid response element TRE: thyroid response element CRE: cAMP response element

  13. Substrate cycle (futile cycle) Biological significances Simultaneously fully active (1) Amplify metabolic signals (2) Generate heat bumblebees: PFKase F1,6-bisPTase: is not inhibited by AMP honeybees:onlyPFKase (02) malignant hyperthermia If  10

  14. Cori cycle: Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize and release glucose + NADH Ala Ala transaminase + NAD+ carriers Absence of O2 Pyr Lactate Ala metabolism: maintain nitrogen balance Well-oxygenated TCA cycle

  15. Integration of glycolysis and gluconeogenesis during a sprint

  16. Lactate dehydrogenase ¤a tetramer of two kinds of 35-kd subunits encoded by similar genes ¤H type: in heart (muscle) M type: in skeletal muscle and liver ¤H4 isozyme (type 1): high affinity for lactate, lactatepyruvate, under aerobic condition H3M1 isozyme (type 2) H2M2 isozyme (type 3) H1M3 isozyme (type 4) M4 isozyme (type 5): pyruvate  lactate under anaerobic condition  a series of homologous enzymes, foster metabolic cooperation between organs.

  17. Ex. 11 Biotin: abundant in some foods and is synthesized by intestinal bacteria Avidin (Mr 70,000): rich in raw egg whites/a defense function The Biotin-Avidin System can improve sensitivity because of the potential for amplification due to multiple site binding. Purification

  18. 96T2 96T3 97T

  19. 97T 98T

  20. 98T

  21. 98T

  22. 96C 97C

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