1 / 94

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 :

marie
Télécharger la présentation

MAMMAMALIAN METABOLISM

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related