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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 : Characteristic fuel requirements Characteristic metabolic patterns Hormone Regulation Integrate/coordinate metabolic functions of different tissue Maximize fuel/fuel precursor allocations to each organ 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 Major pathways and Strategies of energy metabolism Glycolysis Metabolic degradation of glucose Glucose is oxidized to: 2 molecules of pyruvate 2 molecules of ATP 2 molecules of NADH Anaerobic Conditions Pyruvate converted into Lactate Requires oxidation of NADH Recycles NADH In yeast: Pyruvate converted into ethanol Aerobic Conditions Glycolysis first step for further oxidation of glucose NADH is processed through Oxidative Phosphorylation Regenerates oxidized NAD Generates ATP Regulation of glycolysis Phosphofructokinase (PFK) Activated by: Increase in AMP, ADP Fructose 2,6-bisphosphate Inhibited by: Increase in ATP Citrate Regulation of glycolysis Fructose 2,6-bisphosphate (F2,6P) Influenced by [cAMP]: Liver: Muscle Increase [cAmp], decrease [F2,6P] Increase [cAmp], increase [F2,6P] Mediated by: glucogon Epinephrine norepinephrine Gluconeogenesis Synthesis of glucose from simplier, noncarbohydrate precusor Pyruvate Lactate Oxaloacetate Glycerol Gluconeogenic amino acids 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 Gluconeogenesis Reciprical regulation of PFK and FBPase Regulates rate and direction through glycolysis and gluconeogenesis Both may be active simultaneously Glycogen: degradation and 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 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 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 Citric Acid Cycle Acetyl CoA oxidized to: Concomitant production of: CO2 H20 NADH FADH2 Glycogenic Amino Acids Enter at a cycle intermediate Citric Acid Cycle Regulatory enzymes Citrate synthase Isocitrate dehydrogenase Alpha-ketoglutarate dehydrogenase Controlled by: Substrate availability Feedback inhibition 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] Pentose phosphate Pathway Generates from G6P: Catalyzed by: Glucose 6-phosphate dehydrogenase Regulated by: Ribose 5-phosphate NADPH [NADP+] NADPH is needed for biosynthesis Amino Acid:degradation and synthesis Excess AA: Degraded to common metabolic intermediates Most paths Begin with transamination to alpha-keto acid Eventually amino group transferred to urea Amino Acid:degradation and 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 Amino Acid:degradation and synthesis Glucogenic AA Converted into glucose precursors Precursors: Pyruvate Oxaloacetate Alpha-ketoglutarate Succinyl CoA fumarate Amino Acid:degradation and synthesis Other situations: 4 AA are both ketogenic and glucogenic Essential AA: cannot be synthesized Tryptophan,Phenylalanine,Tyrosine,Isoleucine Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine, and Arginine (in young) Nonessential AA: can be synthesized Two Key Compounds Acetyl-CoA, pyruvate At metabolic crossroads Acetyl-CoA Degradation products of most fuels Oxidized to CO2 and H2O in citric acid cycle Can be used to synthesize FA Pyruvate Product of: Glycolysis Dehyddrogenation of lactate Some glucogenic AA Can yield acetyl-CoA Enter CAC Biosynthesis of FA Pyruvate Carboxylated via pyruvate carboxylase Forms oxaloacetate Replenishes intermediates Gluconeogenesis Via phosphoenolpyruvate Bypass of irreversible step in glycolysis Precursor to several AA Sites Cytosolic: Glycolysis Glycogen synthesis, degradation FA synthesis Pentose Phosphate pathway Sites Mitochondrial: FA degradation Citric Acid cycle Oxidative Phosphorylation Sites Both: Gluconeogenesis AA degradation Location controlled by specific membrane transporters Esp. inner mitochondrial membrane Controls flow of metabolites Regulation Intercellular Regulating Mechanisms Hormones Trigger cellular response Short-term: second messenger Long-term: protein synthesis Molecular Level Feedback Substrate availability Tissue Specific Metabolism 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 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 Sugars Role as Blood glucose “Buffer” Absorbs and releases glucose Response to levels of: Glucagon Epinepherine Insulin Response to [glucose] Glucose absorption Hepatocytes are permeable to glucose Convert glucose to G6P Not insulin dependent Absorption driven by [blood glucose] Catalyzed by glucokinase (not hexokinase) Blood glucose Normally lower than max phosporylation rate of glucokinase Uptake about equal to [blood glucose] Glucose absorption Other monosaccarides Can be converted to G6P Includes Fructose Galactose Mannose Release of glucose No food Blood glucose levels drop Liver keeps blood glucose at about 4mM Fate of glucose Varies with metabolic requirement G6P to glucose G6P to glycogen Requires glucose 6-phosphatase Blood transport to peripheral organs When demand for glucose is low Glycogen to G6P When demand for glucose is low Signaled by increased: Glucagon epinephrine Fate of glucose G6P to acetyl-CoA By glycolysis Need pyruvate dehydrogenase Used for synthesis of FA Phospholipids Cholesterol to bile acids 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 Fate of Fatty Acids Increased demand for metabolic fuel: FA converted into acetyl-CoA into ketone bodies KB are transportable form of acetyl Exported via blood to tissues Up to one third of energy in heart 60-70% in brain during prolonged fast Major oxidative fuel of the liver FA converted into acetyl-CoA to CAC Fate of Fatty Acids Decreased demand for metabolic fuel FA converted into liver lipids Some acetyl from FA (and glucose) converted into cholesterol Specialized mechanisms for transport of lipids in blood Converted into lipoproteins, then to adipose for storage Bound to albumin as free FA, transported in blood to skeletal and cardiac muscle FA: degradation and synthesis Compartmentalized Prevent futile cycling FA oxidation: in mitochondria FA synthesis: in cytosol FA: degradation and synthesis Interactions Carnitine Palmitoly Transferase I (CPTI) CPTI inhibited by Malonyl-CoA MCoA) Transport FA into mitochondria MCoA is key intermediate in FA synthesis When FA are synthesized, can not transport FA into mitochondria FA: degradation and synthesis Interactions When metabolic demand for fuel is low: acetyl-CoA comes from glucose When metabolic demand for fuel is high: Inhibits FA synthesis FA into Mitochondria into ketone bodies Fatty Acids Liver can not use Ketone Bodies Lacks 3-ketoacyl-CoA-transferase When metabolic demand is increased: Fatty Acids are the liver's main source of acetyl-CoA Fate of Amino Acids AA degraded to variety of intermediates Glucogenic AA Pyruvate Citric acid intermediates Ketogenic AA Ketone bodies (sometimes) Fate of Amino Acids After about 6 hour fast Glycogen stores are depleted Gluconeogenesis from AA Mostly muscle protein Degrated to alanine and glutamine Animals can not convert Fat to Glucose Proteins are an important fuel reserve Fate of Amino Acids AA degraded to variety of intermediates Glucogenic AA Pyruvate Citric acid intermediates Ketogenic AA Ketone bodies (sometimes) TSM: Brain High Respiratory Rate About 2% of body weight; 20% of resting O2 consumption Independent of activity level Most: power (Na+-K+)-ATPase TSM: Brain Most conditions Only fuel: glucose Extended fasting: ketone body Needs steady suppy TSM: Brain With blood glucose below half normal Brain dysfunction Drop more Coma Irreversible damage death TSM: Muscle Major Fuels Glucose from Glycogen FA Ketone Bodies Storage: Glycogen Can Not Export Glucose: No gluconeogenesis No G-6-phosphatase No receptors for Glucagon TSM: Muscle Energy Reservoir Proteins into Amino Acids Amino Acids into Pyruvate Pyruvate into Alanine into the liver into pyruvate into glucose Epinephrine Receptors Regulates glycogen breakdown and synthesis Increase cAMP in muscle Activates glycogen breakdown Activates glycolysis Increase glucose consumption Epinephine acts independently of glycogen With insulin Regulates general blood glucose levels Muscle Contraction Skeletal Muscle at rest: Can increase 25% in exercise Shifts to glycolysis of G6P from glycogen about 30% of O2 consumption Much of G6P into Lactate Cori Cycle Respiratory burden shifted to liver Delay of O2 dept Muscle Fatigue Definition Inability of muscle to maintain a given power output About 20% drop in contraction strength Aerobic ( Red Fiber: slow twitch) Difficult to fatigue Oxidative Phosphorylation Good vascular supply myoglobin Muscle Fatigue Anaerobic With in about 20 sec in max exertion I.E.: Tetanic Exertion Results from sustained contraction of white fibers (fast twitch) Depends on glycolysis Creatine phosphate (CP) Glygogen storage Cause of Fatigue Drop in intramuscular pH From 7.0 to as low a 6.4 From glycolytic proton generation How does increased acidity cause muscle fatigue? Maybe decresed enzyme activity? Esp PFK TSM: Cardiac Muscle Continuous activity Aerobic Many mitochondria Fuel FA: fuel of choice Ketone bodies Stored glycogen to glucose (with heavy workload) Pyruvate lacctate TSM: Adipose Tissue/Adipocytes General Metabolism Location Under skin Abdominal cavity In skeletal muscle Around blood vessels In mammary glands TSM: Adipose Tissue/Adipocytes General Metabolism Quanity Normal male: about 21% Normal female: about 25% Functions: Energy storage Maintenance of metabolic homeostasis (second only to the liver) TSM: Adipose Tissue/Adipocytes General Metabolism Source of Fatty Acids Liver Diet To form stored triglycerides Fatty acyl-CoA esterified with PGA Glycerol-3-Phosphate Formed from reduction of DAP Glycolytically generated from glucose Adipose cells lack enzyme to phosphorylate endogenoous glycerol TSM: Adipose Tissue/Adipocytes General Metabolism Hydrolyze triglycerides to Fatty Acids and Glycerol In response to levels of: Glucogon Epinephrine Insulin Catalyzed by “hormone-sensitive” lipase Increased [PGA]: reform triglycerides Decreased [PGA}: release FA to blood TSM: Adipose Tissue/Adipocytes Rate of Glucose uptake by adipocytes Regulated by: Insulin Glucose availability Controlling factor in Formation of triglycerides Mobilization of triglycerides TSM: Blood Mediates metabolism between organs Transports: Nutrients Waste products Tissues to kidneys Respiratory gases Small intestine to liver Liver to adipose tissue, other organs O2: lungs to tissues CO2: tissues to lungs Regulatory molecules (hormones) TSM: Blood Composition About 5-6L in average adult Cells/formed elements Erythrocytes Leukocytes Platelets TSM: Blood Composition Plasma 90% water 10% solutes Plasma proteins Inorganic components Organic components Major effort of homeostasis to keep values within normal ranges Blood glucose levels are regulated by: Epinephrine, glucagon and insulin