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Sibc511- Integration of Metabolism

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Sibc511- Integration of Metabolism SIBC511SIBC511-- INTEGRATIONINTEGRATION OFOF METABOLISMMETABOLISM Assistant Professor Dr. Chatchawan Srisawat INTEGRATION OF METABOLISM INTEGRATION OF METABOLISM Dietary intake FedFed statestate FastingFasting statestate • The metabolism of carbohydrate, lipid, and protein are coordinated and well regulated to meet the bodily requirements, especially the energy need, under various conditions. INTEGRATION OF METABOLISM Major metabolic fuels: • GLUCOSE • FAT (TRIACYLGLYCEROL) (glycerol + fatty acids) INTEGRATION OF METABOLISM GLUCOSEGLUCOSE • An important fuel for most Normal range tissues (e.g. muscle, red blood cells, and particularly neurons*). Hunger, sweating, trembling • During the fasting state, the glucose level is prevented from Convulsion, coma dropping too low. Permanent brain damage (if prolonged) Death VariousVarious cellularcellular andand hormonalhormonal regulationsregulations ofof thethe metabolicmetabolic pathwayspathways workwork togthertogther toto preservepreserve glucoseglucose asas aa fuelfuel forfor thethe importantimportant organsorgans (e.g.,(e.g., brain,brain, RBC)RBC) andand shiftshift thethe sourcesource ofof fuelfuel inin otherother tissuestissues toto fattyfatty acidsacids andand ketones.ketones. INTEGRATION OF METABOLISM GLUCOSEGLUCOSE Diabetes mellitus • An important fuel for most Normal range tissues (e.g. muscle, red blood cells, and particularly neurons*). Hunger, sweating, trembling • During the fed state, the glucose level is also kept from Convulsion, coma rising too high (as it can be harmful to the body). Permanent brain damage (if prolonged) Death VariousVarious cellularcellular andand hormonalhormonal regulationsregulations ofof thethe metabolicmetabolic pathwayspathways workwork togthertogther toto accelerateaccelerate glucoseglucose utilizationutilization asas aa fuelfuel andand storestore thethe excessexcess asas glycogenglycogen andand triacylglycerol.triacylglycerol. INTEGRATION OF METABOLISM Dietary intake FedFed statestate FastingFasting statestate • utilize & restore foodstuff • release foodstuff (e.g. glycogen, fat, protein) (e.g. glucose, fatty acid, amino acid) Glycolysis Gluconeogenesis Glycogenesis Glycogenolysis Lipogenesis Lipolysis Protein synthesis Ketogenesis, ketolysis Protein breakdown INSULIN glucagon, epinephrine growth hormone, cortisol FEDFED STATESTATE • Insulin – secreted from β cells in the islet of Langerhan in pancreas • Its secretion can be stimulated by various compounds (e.g. neuro- transmitters, neuropeptides, amino acids) but the most important one is glucose CARBOHYDRATE METABOLISM DURING FED STATE - GLUCOSE TRANSPORT • Insulin can reduce blood glucose by: Glucose uptake of glucose in adipose tissue, muscle * insulin-independent glucose transport in brain, liver, kidney, RBC CARBOHYDRATE METABOLISM DURING FED STATE - GLUCOSE TRANSPORT Note GLUT 1, GLUT 3 : basal glucose Glucose uptake in many tissues, e.g., brain, nerve, RBC GLUT 2 : liver and the islet β cells GLUT 4 : insulin-stimulated glucose uptake in adipose tissue and muscle * In muscle, more GLUT4 can be recruited to the cell membrane during exercise independent of insulin actions to promote glucose uptake and utilization. CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS Glycolysis converts 1 molecule of glucose (C6) into 2 molecules of pyruvate (C3) Glucose location: cytosol Glucose-6-phosphate functions: Fructose-6-phosphate - yields 2 ATP, 2 NADH, and 2 Fructose-1,6-bisphosphate pyruvate per one glucose molecule Glyceraldehyde-3-phosphate +NADH 1,3-bisphosphoglycerate - Major energy-producing pathway +ATP in RBC, brain 3-phosphoglycerate 2-phosphoglycerate - Glycolytic intermediates are important for the biosynthesis of Phosphoenolpyruvate +ATP various compounds (e.g. glycerol, Pyruvate acetyl-CoA, 2,3-BPG) CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS important enzymes: Glucose phosphofructokinase 1 (rate-limiting step)* ** Glucose-6-phosphate phosphofructokinase 2 (activated by insulin, inhibited by glucagon) Fructose-6-phosphate F-2,6-P PFK1* Fructose-1,6-bisphosphate Glyceraldehyde-3-phosphate +NADH 1,3-bisphosphoglycerate +ATP 3-phosphoglycerate 2-phosphoglycerate Phosphoenolpyruvate *** +ATP Pyruvate CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS Mechanisms of enzyme regulation Allosteric regulation – fructose-2,6-bisphosphate, AMP, ADP, ATP etc. Covalent modification – phosphorylation (e.g. through actions of hormones) CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS important enzymes: Glucose Three irreversible reactions in ** glycolytic pathway Glucose-6-phosphate Fructose-6-phosphate glucokinase/hexokinase ** PFK1* phosphofructokinase * Fructose-1,6-bisphosphate pyruvate kinase *** Glyceraldehyde-3-phosphate +NADH 1,3-bisphosphoglycerate +ATP 3-phosphoglycerate Need new sets of enzymes to operate in the opposite direction, 2-phosphoglycerate i.e., the gluconeogenetic pathway. Phosphoenolpyruvate *** +ATP Pyruvate CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS Anaerobic glycolysis In cells deprived of oxygen supply or pyruvate lactate in RBC (lacking mitochondria), + NADH + H+ NAD pyruvate can be converted to lactate by lactate dehydrogenase (LDH) to regenerate NAD+ from NADH to be reused in glycolysis. Lactate is released into the bloodstream and taken up by the liver to convert it to pyruvate and glucose. CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS Aerobic glycolysis When oxygen supply is adequate, pyruvate pyruvate enters mitochondria and is converted into acetyl CoA by pyruvate dehydrogenase (PDH). pyruvate NAD+ * NADH + H+ Note acetyl CoA • PDH contains thaimine (vit B1), lipoic acid, CoA, FAD (vit B2), NAD oxaloacetate (niacin or vit B3) as coenzymes. citrate Krebs • Disease association cycle Wernicke-korsakoff B1 deficiency (beri-beri) CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOLYSIS aerobic glycolysis pyruvate Pyruvate dehydrogenase pyruvate - acetyl CoA Pyruvate + carboxylase oxaloacetate NADH TCA citrate FADH2 cycle GTP Important feedback controls of acetyl CoA: - activates Pyruvate carboxylase - inhibits Pyruvate dehydrogenase KREBS CYCLE kinky = marked by unconventional Cindy Is Kinky So She sexual preferences or behavior, as Fornicates More Often fetishism, sadomasochism, or the like Krebs or Citric acid or tricarboxylic acid cycle location: mitochondria functions: - Complete oxidation of acetyl CoA acetyl CoA Æ 2CO2 + 3NADH + FADH2 + GTP KREBS CYCLE *** Krebs or Citric acid or tricarboxylic acid cycle important enzymes: isocitrate dehydrogenase (rate-limiting step – inhibited by NADH) KREBS CYCLE * Krebs cycle intermediates are linked with the metabolic pathways of many important compounds (e.g. amino acids, fatty acids, nucleic acids, etc). KREBS CYCLE aerobic glycolysis NADH Electron transport system FADH2 H O O2 2 FADH2 NADH + H+ NAD+ ADP + Pi ATP CARBOHYDRATE METABOLISM DURING FED STATE - GLYCOGENESIS • Excess glucose during the fed state is glucose also stored as glycogen in liver and muscle (Glycogenesis). glucose-6-phosphate location: cytosol glycogen synthase important enzymes: branching enzyme glycogen synthase (rate-limiting step) activated by insulin Glycogen CARBOHYDRATE METABOLISM DURING FED STATE – PENTOSE PHOSPHATE PATHWAY • In addition, excess glucose also enters the pentose phosphate pathway (Hexose monophosphate shunt) glucose location: cytosol functions: generate glucose-6-phosphate •NADPH - synthesis of fatty acid, Glucose-6- cholesterol, nucleotides phosphate dehydrogenase * - coenzymes of antioxidant enzymes Pentose phosphate pathway •Ribose - DNA & RNA synthesis important enzymes: glucose-6-phosphate dehydrogenase G6PD (rate-limiting step) FATTY ACID SYNTHESIS AND LIPOGENESIS adipocyte glucose liver DHAP glycolysis acetyl CoA •Stored as acetyl CoA carboxylase triacylglycerol pyruvate malonyl CoA NADPH acetyl CoA fatty acid glycerol oxaloacetate citrate triacylglycerol Krebs cycle lipoprotein (VLDL) • During the fed state, the increased glucose and insulin levels stimulate the syntheses of fatty acid and triacylglycerol (Lipogenesis). - Excessive intake of high carbohydrate diet can lead to obesity. - On average, a 70-kg man stores ~ 12 kg of fat, which can provide enough energy for 2 months during starvation (fat gives 9 kcal/g). FATTY ACID SYNTHESIS AND LIPOGENESIS adipocyte glucose liver DHAP glycolysis acetyl CoA •Stored as acetyl CoA carboxylase triacylglycerol pyruvate malonyl CoA NADPH acetyl CoA fatty acid glycerol oxaloacetate citrate triacylglycerol Krebs cycle lipoprotein (VLDL) Fatty acid synthesis location: cytosol Therfore, acetyl CoA has to be transported into the cytosol as citrate, which is then converted back to acetyl CoA in the cytosol by citrate lyase. FATTY ACID SYNTHESIS AND LIPOGENESIS adipocyte glucose liver DHAP glycolysis acetyl CoA •Stored as acetyl CoA carboxylase triacylglycerol pyruvate malonyl CoA NADPH acetyl CoA fatty acid glycerol oxaloacetate citrate triacylglycerol Krebs cycle lipoprotein (VLDL) Fatty acid synthesis important enzymes: acetyl CoA carboxylase (rate-limiting step) activated by insulin and citrate fatty acid synthase (use NADPH derived from the pentose phosphate pathway) FATTY ACID SYNTHESIS AND LIPOGENESIS adipocyte glucose liver DHAP glycolysis acetyl CoA •Stored as acetyl CoA carboxylase triacylglycerol pyruvate malonyl CoA NADPH acetyl CoA fatty acid glycerol oxaloacetate citrate triacylglycerol Krebs cycle lipoprotein (VLDL) • The newly-synthesized fatty acids are combined with glycerol-3- phosphate (a glycolytic intermediate) to generate
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