Lecture 20 (2009)

Lecture 20 (2009) - Final Review Sessions June 4 (123 Sci...

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Unformatted text preview: Final Review Sessions June 4 (123 Sci Lec, 5-7 pm), Abel June 5 (1001 Giedt Hall, 5-7 pm), TAs Final Exam SAT (June 6), 10:30 12:30 Seating Assignments (Last Name Initial) 198 Young: 1227 Haring: AH I Pe and Ph - Z Lecture 20 Principles of Metabolic Regulation Summer Break Regulation of Metabolism at the Cellular Level Principles of Regulation Basic strategy: conservation of chemical energy (ATP) ATP formation of reducing power (NADPH) NADPH generation of precursors (C-skeletons) ATP: anabolic reactions (biosynthesis) active transport muscle contraction signal amplification anabolic reactiosn (biosynthesis) redox homeostasis pathogen defense (ROS) NADPH: Control by Cellular Energy Status ATP + 0.5 ADP Energy Charge (EC) = ATP + ADP + AMP Rel. Rate ATP-generating reactions Catabolism EC = 0 (all AMP) EC = 1 (all ATP) Anabolism ATP-utilizing reactions 0 Energy Charge 0.9 1.0 Catabolic and Anabolic Pathways both thermodynamically favorable at all times both almost always distinct (chemically, spatially) rates governed mainly by activities of key enzymes key enzymes (regulatory enzymes) catalyze enzymes essentially, or physiologically, irreversible reactions Pathway Regulation 1. Amount of enzyme gene expression (de novo synthesis) enzyme removal (proteolysis) 2. Isoenzymes (different molecular forms) cellular compartmention tissue- or organ-specific expression developmental stage response to allosteric regulators 3. Catalytic activity allosteric regulation covalent modification Feedback Control ("Acceptor Control") Glucose PFK-1 PK Glycogen Glucose-6-P Pyruvate PDH Acetyl-CoA CS IDH KGA-DH NADH ADP ETC ATP Lactate Some Examples... Phosphofructokinase-1 (PFK) AMP (+) F2,6BP (+) ATP () Citrate () H+ () Pyruvate Kinase (PK) F1,6BP (+) ATP () Alanine () Acetyl-CoA () Pyruvate Dehydrogenase (PDH) AMP (+) ATP () NADH () Acetyl-CoA () Science (2009) 324:1029-1033 (May 29) Regulation of Metabolism at the Organismal Level Role of Hormones (Adrenaline, Glucagon, Insulin) Food Glucose (ketone bodies) Lactate Alanine Fatty acids, ketone bodies, branched amino acids (resting muscle) Fatty and keto acids Fatty acids, glycerol Glucose, fatty acids, ketone bodies We Detoxification BIS103 Hormonal Regulation coordination of metabolic activities of different organs circulation in blood (endocrine hormones) binding to specific receptors in target cells (high affinity) amplification cascades to activate enzymes enzyme activation by covalent modification desensitization (resetting of response system) integration of multiple (hormonal) signals Hormone-induced Activation of Adenylate Cyclase H H H H H Blood inactive Hormone Receptor Cell Membrane Cytosol GTP Adenylate Cyclase GDP G-Protein p. 110 H inactive Blood GTP Hormone Receptor Cell Membrane Cytosol GDP Adenylate Cyclase p. 110 H Blood active GTP Hormone Receptor Cell Membrane Cytosol Adenylate Cyclase ATP + H2O 3':5'-cAMP + PPi Second Messenger p. 110 Regulation of cAMP-dependent Protein Kinase A (PKA) NH2 N O O O -O P O P O P O OOON H H O H H O -O P OO O P O - NH2 N N N O -O P O OH H O H H H N N N NH2 N N N Adenylate cyclase O H O P -O H O O H H N OH H H PPi O- OH ATP H 2O O cAMP (cyclic AMP) AMP 2 HO P O- O- x4 Cyclic Nucleotide Phosphodiesterase C R R C 2 C + 2 R 4 cAMP H 2O Inactive PKA Active PKA C R Catalytic subunit Regulatory subunit p. 111 Activation Cascade for Glycogen Phosphorylase H Blood Adenylate Cyclase GTP Hormone Receptor Cell Membrane Cytosol H20 ATP PPi 3':5'-cAMP Cyclic Nucleotide Phosphodiesterase 5'AMP C R R C PKA (inactive) C C PKA (active) cAMP cAMP cAMP R R cAMP p. 112 C R R C PKA (inactive) C C PKA (active) cAMP cAMP cAMP R R cAMP ATP ADP (+) Ca 2+ Phosphorylase b kinase (active) ATP ADP Phosphorylase b kinase (inactive) Glycogen synthase (active) Glycogen synthase (inactive) Pi Protein phosphatase H20 Pi Protein phosphatase H20 ATP ADP ATP ADP Phosphorylase b (inactive) Phosphorylase a (active) Protein phosphatase inhibitor (inactive) Protein phosphatase inhibitor (active) Pi Protein phosphatase H20 Pi Protein phosphatase H20 Glycogen phosphorolysis p. 112 Hormone ("first messenger") Hormone Receptor Adenylate Cyclase Desensitization (Resetting) GTPase activity (G protein) Hydrolysis of cAMP cAMP ("second messenger") Protein Kinase A Glycogen phosphorylase kinase Glycogen phosphorylase Glycogen Reserve Allosteric Control of Glycogen Phosphorylase b HPO43- (+) AMP (-) ATP (-) Glc-6-P Glycogen phosphorylase b + Glucose-1-P p. 113 Target Proteins for cAMP-dependent Protein Kinase A F6P-2-kinase Triacylglycerol lipase (+) (+) F2,6BP-2-phosphatase Pyruvate kinase (-) Protein Kinase A Glycogen synthase (-) Phosphorylase b kinase (+) Protein Phosphatase Inhibitor Protein (+) Phosphorylase b Phosphorylase a p. 113 Adrenaline (Epinephrine): The "Fight-or-Flight" Hormone produced in adrenal mulla derived from tyrosine (see p. 103) prepares peripheral organs for bursts of activity Heart beat goes up, blood pressure increases increased oxygen delivery Glucagon secretion (+), Insulin secretion (-) reinforces adrenaline effect Adrenaline Fatty acid mobilization (+) Glycogen degradation (+) Glycolysis (+) Energy Glycogen degradation (+) Gluconeogenesis (+) Glycolysis (-) Hormonal Regulation of Mammalian Metabolism Adrenaline Target tissues: Muscle (M), Adipose (A), Liver (L) Target Enzyme (+) Glycogen phosphorylase (-) Glycogen synthase (+) Phosphofructokinase-2 (-) Phosphofructokinase-2 Metabolic Effect (+) Glycogen degradation (M, L) (+) Glycolysis (M) (+) Gluconeogenesis (L) (-) Glycolysis (L) (+) Fatty acid mobilization (A) (+) Glucagon secretion (-) Insulin secretion (+) Triacylglycerol lipase p. 115 We BIS103 Heart does not store glycogen (very little) or lipids Many mitochondria (50% of cell volume) Completely aerobic at all times (depends on oxygen!) oxygen! If oxygen delivery is blocked (e.g., blood clots), heart muscles will die (heart attack) attack large store of glycogen (75% of total) >50% of oxygen consumption, resting >90% of oxygen consumption, contracting (glucose preferred fuel) ATP (<5 sec) Anaerobic (45-80 sec) Aerobic (> 2 min) Creatine~P (10-15 sec) Peak Consumption Homeostasis of Blood Glucose Levels Glucagon secreted by islet cells of pancreas peptide hormone maintains blood glucose levels (increase) increase Insulin secreted by islet cells of pancreas peptide hormone maintains blood glucose levels (decrease) decrease very active respiratory metabolism (~ 20% of total oxygen consumed) uses normally only glucose as fuel (~70% of daily intake; no fuel stores) can switch to ketone bodies when necessary (minimizes protein degradation) cannot use fatty acids (blood-brain barrier) 5 mM (blood) ~ 1 mM (brain) Glucose < 2.2 mM (blood) ~ 0.05 mM (brain) = KM of hexokinase Danger Zone Secreted in response to low blood glucose Glucagon Not muscles Glucose Fatty acid mobilization (+) Glycogen degradation (+) Gluconeogenesis (+) Glycogen synthesis (-) Glycolysis (-) Fatty acid synthesis (-) Hormonal Regulation of Mammalian Metabolism Glucagon Target tissues: Liver (L), Adipose tissue (A) Target Enzyme (+) Glycogen phosphorylase (-) Glycogen synthase (+) Fru-2,6-BP phosphatase (-) Pyruvate kinase (+) Fru-2,6-BP phosphatase (+) Triacylglycerol lipase Metabolic Effect (+) Glycogen degradation (L) (-) Glycogen synthesis (L) (-) Glycolysis (L) (+) Gluconeogenesis (L) (+) Fatty acid mobilization (A) p. 115 Glucose Insulin Secreted in response to high blood glucose TAG synthesis (+) Glucose uptake (+) Glycogen synthesis (+) Glycolysis (+) Acetyl-CoA synthesis (+) Fatty acid synthesis (+) Glycogen degradation (-) Gluconeogenesis (-) Glucose uptake (+) Glycogen synthesis (+) Glycolysis (+) Acetyl-CoA synthesis (+) Protein synthesis (+) Glycogen degradation (-) Hormonal Regulation of Mammalian Metabolism Insulin Target tissues: Muscle (M), Adipose (A), Liver (L) Target Enzyme (+) Glucose transporter (GLUT4) (+) Glucokinase (+) Glycogen synthase (-) Glycogen phosphorylase (+) Phosphofructokinase-2 Metabolic Effect (+) Glucose uptake (M, A) (+) Glucose uptake (L) (+) Glycogen synthesis (L, M) (-) Glycogen degradation (L, M) (+) Glycolysis (L, M) (-) Gluconeogenesis (L) (+) Acetyl-CoA production (L, M) (+) Fatty acid synthesis (L) (+) Triacylglycerol synthesis (A) (+) PDH complex (+) Acetyl-CoA carboxylase (+) Lipoprotein lipase p. 115 Glucose regulation of insulin secretion by pancreatic cells Isoenzymes of Glucose Transporters (GLUT) V GLUT 4 (muscles, adipocytes) GLUT 1/3 (most tissues) GLUT 2 (liver, pancreatic cells) 1 5 ~15 Blood Glucose [mM] Insulin Receptor and Signaling H H H H Insulin Receptor H H Insulin Receptor Blood PI-3K Insulin Insulin Receptor Receptor Cytosol P PIP3 PKB P PIP2 P IRS-1 P GSK3 (inactive) P IRS-1 P MAPKKK (Raf-1) GSK3 (active) MAPKK (MEK) MAPK GS (inactive) P GS (active) Transcription Factors p. 114 Glycogen Synthesis Target Genes (e.g., Glucokinase) Fasting and Starvation Lean (70 kg) Circulating Fuels Glycogen Proteins Body Fat (TAG) 23 g (0.1 kcal) 225 g (0.9 kcal) 6 kg (24 kcal) 15 kg (141 kcal) Obese (140 kg) 25 g (0.11 kcal) 230 g (0.92 kcal) 8 kg (32 kcal) 80 kg (752 kcal) Estimated Survival 3 months 14 months Overnight fast Liver glycogen depleted maintain blood glucose Blood glucose drops glucagon Mobilization of triacylglycerides liver, muscles Liver: gluconeogenesis (glycerol, glucogenic amino acids urea) Liver: OAA drops ketogenesis brain, heart, skeletal muscles Prolonged Starvation Ketogenesis (mobilization of triacylglycerides ketone bodies) Degradation of nonessential proteins (skeletal muscles) Endphase When body fat depleted, degradation of essential proteins Organ failure Relative Concentrations in Blood During Fasting/Starvation Glucose Ketone bodies Fatty acids 2d 4d 6d I paaardon Dr. Abel BIS 103 Game Over! ...
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This note was uploaded on 09/06/2009 for the course BIS 103 taught by Professor Abel during the Spring '08 term at UC Davis.

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