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MAMMAMALIAN METABOLISM

MAMMAMALIAN METABOLISM. Integration and Hormonal Regulation. Objective. Consider the major metabolic pathways in the context of the whole organism. Issues with multicellular organism. Division of labor: cell differentiation Organ/Organ system specialization :

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MAMMAMALIAN METABOLISM

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  1. MAMMAMALIAN METABOLISM Integration and Hormonal Regulation

  2. Objective • Consider the major metabolic pathways in the context of the whole organism

  3. Issues with multicellular organism • Division of labor: cell differentiation • Organ/Organ system specialization : • Characteristic fuel requirements • Characteristic metabolic patterns • Hormone Regulation • Integrate/coordinate metabolic functions of different tissue • Maximize fuel/fuel precursor allocations to each organ

  4. Approach • Recapitulate major pathways and control systems • Consider how these processes are divided among tissues and organs • Consider major hormones that control these metabolic functions

  5. Major pathways and Strategies of energy metabolism

  6. Glycolysis • Metabolic degradation of glucose • Glucose is oxidized to: • 2 molecules of pyruvate • 2 molecules of ATP • 2 molecules of NADH

  7. Anaerobic Conditions • Pyruvate converted into Lactate • Requires oxidation of NADH • Recycles NADH • In yeast: • Pyruvate converted into ethanol

  8. Aerobic Conditions • Glycolysis first step for further oxidationof glucose • NADH is processed through Oxidative Phosphorylation • Regenerates oxidized NAD • Generates ATP

  9. Regulation of glycolysis • Phosphofructokinase (PFK) • Activated by: • Increase in AMP, ADP • Fructose 2,6-bisphosphate • Inhibited by: • Increase in ATP • Citrate

  10. Regulation of glycolysis • Fructose 2,6-bisphosphate (F2,6P) • Influenced by [cAMP]: • Liver: • Increase [cAmp], decrease [F2,6P] • Muscle • Increase [cAmp], increase [F2,6P] • Mediated by: • glucogon • Epinephrine • norepinephrine

  11. Gluconeogenesis • Synthesis of glucose from simplier, noncarbohydrate precusor • Pyruvate • Lactate • Oxaloacetate • Glycerol • Gluconeogenic amino acids

  12. Gluconeogenesis • Mainly through pathways in the liver • Major intermediate: oxaloacetate • Converted to phospoenolpyruvate • Then, into glucose • Irreversible Steps • PFK bypass: Fructose 1,6-bisphosphatase • Hexokinase bypass: glucose 6-phosphatase

  13. Gluconeogenesis • Reciprical regulation of PFK and FBPase • Regulates rate and direction through glycolysis and gluconeogenesis • Both may be active simultaneously

  14. Glycogen: degradationand synthesis • Storage form of glucose in most animals • In liver and muscle • Enters glycolysis • Catalyzed by: glycogen phosphorylase • Converted into glucose 6-phosphate (G6P) • Opposed by glycogen synthase • [Enzymes] respond to • Glucagon • epinephrine

  15. Fatty Acid: Degradation and Synthesis • Degradation: beta-oxidation • In 2 carbon chunks • Form acetyl-CoA • Regulated by [FA] • Lipase in adipose cells: hormone sensitive • cAMP mediated • Stimulated by: • Glucogon • Epinephrine • Inhibited by: • insulin

  16. Fatty Acid: Degradation and Synthesis • Synthesis: from acetly CoA • Acetyl-CoA carboxylase • Activated by citrate • Inhibited by intermediate (palmitoyl-CoA) • Long term regulation: • Stimulated by insulin • Inhibited by fasting

  17. Citric Acid Cycle • Acetyl CoA oxidized to: • CO2 • H20 • Concomitant production of: • NADH • FADH2 • Glycogenic Amino Acids • Enter at a cycle intermediate

  18. Citric Acid Cycle • Regulatory enzymes • Citrate synthase • Isocitrate dehydrogenase • Alpha-ketoglutarate dehydrogenase • Controlled by: • Substrate availability • Feedback inhibition

  19. Oxidative Phosphorylation • Major products • NADH is oxidized to NAD+ • FADH2 is oxidized to FAD • Coupled to synthesis of ATP • Rate dependent upon: • [ATP] • [ADP] • [Pi]

  20. Pentose phosphate Pathway • Generates from G6P: • Ribose 5-phosphate • NADPH • Catalyzed by: • Glucose 6-phosphate dehydrogenase • Regulated by: • [NADP+] • NADPH is needed for biosynthesis

  21. Amino Acid:degradationand synthesis • Excess AA: • Degraded to common metabolic intermediates • Most paths • Begin with transamination to alpha-keto acid • Eventually amino group transferred to urea

  22. Amino Acid:degradationand synthesis • Ketogenic AA • E.g.: leucine, lysine, tryptophane, phenylalanine, tyrosine, isoleucine • Only leucine, lysine exclusively ketogenic • Converted into • Acetyl-CoA • Acetoacetyl-CoA • Can not be glucose precursors

  23. Amino Acid:degradationand synthesis • Glucogenic AA • Converted into glucose precursors • Precursors: • Pyruvate • Oxaloacetate • Alpha-ketoglutarate • Succinyl CoA • fumarate

  24. Amino Acid:degradationand synthesis • Other situations: • 4 AA are both ketogenic and glucogenic • Tryptophan,Phenylalanine,Tyrosine,Isoleucine • Essential AA: cannot be synthesized • Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine, and Arginine (in young) • Nonessential AA: can be synthesized

  25. Two Key Compounds • Acetyl-CoA, pyruvate • At metabolic crossroads

  26. Acetyl-CoA • Degradation products of most fuels • Oxidized to CO2 and H2O in citric acid cycle • Can be used to synthesize FA

  27. Pyruvate • Product of: • Glycolysis • Dehyddrogenation of lactate • Some glucogenic AA • Can yield acetyl-CoA • Enter CAC • Biosynthesis of FA

  28. Pyruvate • Carboxylated via pyruvate carboxylase • Forms oxaloacetate • Replenishes intermediates • Gluconeogenesis • Via phosphoenolpyruvate • Bypass of irreversible step in glycolysis • Precursor to several AA

  29. Sites • Cytosolic: • Glycolysis • Glycogen synthesis, degradation • FA synthesis • Pentose Phosphate pathway

  30. Sites • Mitochondrial: • FA degradation • Citric Acid cycle • Oxidative Phosphorylation

  31. Sites • Both: • Gluconeogenesis • AA degradation • Location controlled by specific membrane transporters • Esp. inner mitochondrial membrane • Controls flow of metabolites

  32. Regulation • Intercellular Regulating Mechanisms • Hormones • Trigger cellular response • Short-term: second messenger • Long-term: protein synthesis • Molecular Level • Feedback • Substrate availability

  33. Tissue Specific Metabolism

  34. TSM: LIVER • Liver: central processing and distributing role • Furnishes other tissues/organs with appropriate mix of nutrients via the blood • Other tissues and organs are termed extrahepatic or peripheral • Handles carbohydrates, amino acids and fats

  35. TSM: LIVER • Extremely adaptable to prevailing conditions • Can shift enzymatic ally from one nutrient emphasis to another within hours • Responds to the demands of extrahepatic tissues/organs for fuels • Maintains blood levels of nutrients • Well located for the task

  36. Sugars • Role as Blood glucose “Buffer” • Absorbs and releases glucose • Response to levels of: • Glucagon • Epinepherine • Insulin • Response to [glucose]

  37. Glucose absorption • Hepatocytes are permeable to glucose • Not insulin dependent • Absorption driven by [blood glucose] • Convert glucose to G6P • Catalyzed by glucokinase (not hexokinase) • Blood glucose • Normally lower than max phosporylation rate of glucokinase • Uptake about equal to [blood glucose]

  38. Glucose absorption • Other monosaccarides • Can be converted to G6P • Includes • Fructose • Galactose • Mannose

  39. Release of glucose • No food • Blood glucose levels drop • Liver keeps blood glucose at about 4mM

  40. Fate of glucose • Varies with metabolic requirement • G6P to glucose • Requires glucose 6-phosphatase • Blood transport to peripheral organs • G6P to glycogen • When demand for glucose is low • Glycogen to G6P • When demand for glucose is low • Signaled by increased: • Glucagon • epinephrine

  41. Fate of glucose • G6P to acetyl-CoA • By glycolysis • Need pyruvate dehydrogenase • Used for synthesis of • FA • Phospholipids • Cholesterol to bile acids

  42. Fate of glucose • Substrate for the Pentose phosphate pathway • NADPH needed for biosynthesis of: Fatty acids Cholesterol D-ribose 5-phosphate precursor for nucleotide biosynthesis

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