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Chapter 8 Chem 341 Suroviec Fall 2016 I. Overview • Metabolism – overall process through which living system acquire and use free energy to carry our various functions I. Overview • Catabolism • Anabolism A. Tropic Strategies • Autotropic – synthesize all their cellular constituents from simpler molecules – Chemolithotrophs – Photoautotrophs • Heterotrophs - Obtains free energy through oxidation of organic compounds II. Food, Fuel and Storage A. Intake of proteins, nucelic acids, polysaccharides and triacylglycerols • Digestion takes place by: – Salivary amylase – Gastric and pancreatic proteases – lipases II. Food, Fuel and Storage B. Cells – Take up digestion products through intestine C. Storage – Depends on monomer if stored or used immediately II. Food, Fuel and Storage D. Mobilization – Metabolic fuels – Broken down by processes that make free energy available II. Food, Fuel and Storage E. Adipose tissue mobilization F. Amino acid mobilization II. Food, Fuel and Storage G. Common Intermediates • Many steps required to break down monomeric compounds/build them up metabolic pathways II. Food, Fuel and Storage H. Small Molecules • NAD to NADH • FAD to FADH2 • Coenzyme A Images from Wikipedia III. Thermodynamic Requirements 1. 2. • Reactions need to be specific The entire set of reactions needs to be the thermodynamically favored Enzymes that catalyze near-equilibrium reactions tend to – act quickly – restore equilibrium concentrations – net rates of such reactions are effectively regulated by the relative concentration of substrates and products IV. ATP • Acts as energy conduit between high and low energy compounds • ATP is special for several reasons – Drives thermodynamically unfavorable reactions by cleavage of high energy bonds – Why is large amount of free energy released? IV. ATP A. How is ATP consumed • Early stages of nutrient breakdown • During physiological processes using ATP to drive reactions • Additionally in endergonic reaction the PPi to Pi + Pi B. Regenerate ATP • Catabolism – carbon in full molecules oxidized to CO2 • Anabolism – use O2 • Redox reactions are linked V. CAC Overview • Glycolysis converts to two C3 units. The free energy released in this process is harvested to synthesize ATP from ADP and Pi V. Overview A. Some pathways are irreversible B. Catabolic and anabolic pathways MUST differ C. Every metabolic pathway has a 1st committed step II. Glucose A. Glucose • • • 6 carbon sugar with aldehyde group form: OH group of the anomeric C is on OPPOSITE side of ring from CH2OH form: OH group of the anomeric C is on SAME side of ring from CH2OH II. Glucose C. Glycogenolysis – Only liver can make glucose available to the liver at large VI. Glycolysis • Stage I. Energy investment – • Glucose is phosphorylated and cleaved – Uses 2 ATP Stage II. Energy recovery – 2 molecules of glyceraldehyde-3phosphate converted to pyruvate – Produces 4 ATP VII. Reactions of Glycolysis A. Hexokinase Metabolically irreversible reaction B. Phosphoglucose Isomerase • Conversion of G6P to F6P C. Phosphofrutokinase • • PFK phosphorylates FBP Operates similar to hexokinase • • • Tetrameric enzyme R and T states in equilibrium ATP is both a substrate and and allosteric inhibitor C. PFK • • • Each PFK has 2 binding site – Substrate site – Inhibitor site Inhibitor site binds ATP only in T state Shifts equilibrium in favor of T at high ATP concentrations D. Aldolase • Catalyzes cleavage of FBP to form GAP and DHAP E. Triose Phosphate Isomerase • • • GAP continues down the glycolytic pathway DHAP and GAP are ketose-aldose isomers Final reaction Stage I F. Glyceraldehyde-3-Phosphate Dehydrogenase • • Exergonic reaction Synthesis of high energy 1,3-BPG G. Phosphoglycerate Kinase • • Bilobal with Mg2+ 1,3-BPG common intermediate whose consumption pulls reaction forward H. Phosphoglycerate Mutase • • • 3PG is converted to 2PG Phosphorylated His is needed to complete reaction 2,3-BPG allosteric inhibitor of deoxyhemoglobin I. Enolase • • • 2PG dehydrated to PEP Needs Mg2+ F- inhibitor of reaction J. Pyruvate Kinase • • • • PEP is cleaved via PK to form pyruvate Forms ATP Step 1: ADP nucleophilically attacks the PEP, forms ATP Step 2: Enolpyruvate tautomerizes to pyruvate 3 products of glycolysis • • • ATP – Investment of 2 ATP per glucose – Generation of 4 ATP NADH – Glucose oxidized – 2 NAD+ reduced to NADH – Electron transport Pyruvate – 2 molecules are produced – Complete oxidation to CO2 done in citric acid cycle VIII. Fermentation • Pyruvate – Aerobic conditions • completely oxidized to CO2 and H2O – Anaerobic conditions • converted to reduced end product to reoxidize NADH A. Homolactic Fermentation • • Demand for ATP high Supply of oxygen is low B. Alcoholic Fermentation • • Forms CO2, ethanol and NAD+ TPP is essential cofactor of pyruvate decarboxylase IX. Control of Glycolysis • • • • Glycolysis operates continuously in most tissues Flux must vary to meet needs How do we determine to flux control mechanisms? One 3 reactions of glycolysis potentially control it: – Hexokinase – Phosphofrucokinase – Pyrivate kinase X. Gluconeogenesis Gluconeogenesis is the formation of new glucose molecules from precursors in the liver Precursor molecules include lactate, pyruvate, and -keto acids Gluconeogenesis Reactions Reverse of glycolysis except the three irreversible reactions From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press X. Gluconeogenesis Figure 8.11 Carbohydrate Metabolism: Gluconeogenesis and Glycolysis From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press X. Gluconeogenesis Figure 8.11 Carbohydrate Metabolism: Gluconeogenesis and Glycolysis From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press Section 8.2: Gluconeogenesis Gluconeogenesis Reactions Continued Three bypass reactions: 1. Synthesis of phosphoenolpyruvate (PEP) 2. Conversion of fructose-1,6-bisphosphate to fructose6-phosphate 3. Formation of glucose from glucose-6-phosphate From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press X. Gluconeogenesis Gluconeogenesis Substrates Three of the most important substrates for gluconeogenesis are: 1. Lactate 2. Glycerol Alanine Figure 8.12 Cori Cycle From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press X. Gluconeogenesis Gluconeogenesis Regulation Substrate availability Hormones (e.g., cortisol and insulin) Figure 8.14 Allosteric Regulation of Glycolysis and Gluconeogenesis From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press X. Gluconeogenesis Gluconeogenesis Regulation Continued Allosteric enzymes (pyruvate carboxylase, pyruvate carboxykinase, fructose-1,6bisphosphatase, and glucose-6-phosphatase) + Figure 8.14 Allosteric Regulation of Glycolysis and Gluconeogenesis From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press XI. Pentose Phosphate Pathway Glucose-6-phosphate dehydrogenase Pentose Phosphate Pathway Gluconolactonase Figure 8.15a The Pentose Phosphate Pathway (oxidative) From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press XI. Pentose Phosphate Pathway 6-phosphogluconate dehydrogenase Pentose Phosphate Pathway: Oxidative Figure 8.15a The Pentose Phosphate Pathway (oxidative) From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press XI. Pentose Phosphate Pathway Pentose Phosphate Pathway: Nonoxidative Figure 8.15b The Pentose Phosphate Pathway (nonoxidative) From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press X. Pentose Phosphate Pathway Pentose Phosphate Pathway Figure 8.16 Carbohydrate Metabolism: Glycolysis and the Phosphate Pathway From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press Metabolism of Other Important Sugars Figure 8.17 Carbohydrate Metabolism: Galactose Metabolism From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press Metabolism of Other Important Sugars Figure 8.17 Carbohydrate Metabolism: Other Important Sugars From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press