Lecture 13 (2009)

Lecture 13 (2009) - Midterm 2 (in class), TUE (5/19) Bring...

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Unformatted text preview: Midterm 2 (in class), TUE (5/19) Bring Calculator to Exam! Review Sessions Friday (5/15): Monday (5/18): ESSENTIALS Problem Sets Kleiber Hall, 5-7 p.m. Kleiber Hall, 5-7 p.m. posted 4-6 Lecture 13 Pentose-P Pathway and Calvin cycle Lipid Metabolism Introduction to lipids Degradation of fatty acids (-oxidation) oxidation Reactions of the Pentose Phosphate Pathway 1. Oxidation Phase (C6 C5 + CO2) Glucose-6-P Dehydrogenase (G6P + NADP+ Gluconate-6-P + NADPH) Lactonase (Hydrolysis of intramolecular ester, lactone) Gluconate-6-P Dehydrogenase (Gluconate-6-P + NADP+ Ru5P + CO2 + NADPH) Review 2. Isomerization Phase (C5 C5) Phosphopentose Isomerase (Ru5P R5P) Phosphopentose Epimerase (Ru5P Xu5P) 3. Rearrangement Phase (xC5 yC6) Transketolase (C2-Transfer, TPP-dependent) Transaldolase (C3-Transfer) Review Phase 1: Oxidative Reactions irreversible reactions regulation by allosteric inhibition of first reaction (NADPH) Glc-6-P Dehydrogenase Phase I CH2OPO32O H OH H OH OHH OH (-) NADPH NADP+ NADPH + H+ H2O H HO H 2 H CH2OPO32O H O OH H OH H OH 6-P-Glucono--lactone COOOH H OH OH CH2OPO326-P-Gluconate H H C OH O H H OH 3 H H NADP+ NADPH + H+ H COOOH O OH OH CH2OPO32- 1 Glc-6-P + CO2 OH CH2OPO32- Phase II Ribulose-5-P (Ru5P) p. 68 "Modular" Flexibility of Carbohydrate Metabolism Glucose Glycolysis - Gluconeogenesis Glucose-6-P Fructose-6-P GA-3-P Pyr PDH-TCA-ETC ATP Anaplerotic Reactions CO2 NADPH I Pentose Phosphate Pathway III TCA Intermediates ("C-Skeletons") II Ribulose-5-P Xylulose-5-P To meet cell type-specific needs for NADPH, ATP, NADPH ATP Ribose-5-P ribose and other sugars Scenario A: NADPH >> R5P Glucose Glycolysis/Gluconeogenesis Glucose-6-P Fructose-6-P GA-3-P PDH-TCA-ETC CO2 NADPH Pentose-P Pathway Examples Erythrocytes Macrophages Lens, cornea Ribulose-5-P p. 69 Scenario B: R5P >> NADPH Glucose Glycolysis/Gluconeogenesis Glucose-6-P Fructose-6-P GA-3-P PDH-TCA-ETC Pentose-P Pathway Examples Ribulose-5-P Rapidly dividing cells Ribose-5-P p. 70 Scenario C: NADPH + R5P Glucose Glucose-6-P Fructose-6-P GA-3-P PDH-TCA-ETC CO2 NADPH Pentose-P Pathway Examples Ribulose-5-P Rapidly dividing cells Ribose-5-P p. 70 Scenario D: NADPH + ATP Glucose Glycolysis Glucose-6-P Fructose-6-P GA-3-P PDH-TCA-ETC ATP CO2 NADPH Pentose-P Pathway Examples Liver cells Adipose tissue Mammary gland Ribulose-5-P p. 71 Scenario E: NADPH + ATP + C-Skeletons Glucose Anaplerotic Reactions Glycolysis Glucose-6-P Fructose-6-P GA-3-P PDH-TCA-ETC ATP CO2 NADPH Pentose-P Pathway TCA Intermediates ("C-Skeletons") Ribulose-5-P p. 71 Metabolism of diverse dietary sugars Glucose Glycolysis/Gluconeogenesis Glucose-6-P Fructose-6-P GA-3-P PDH-TCA-ETC Pentose-P Pathway C3 C4 C5 C6 C7 Ribulose-5-P Ribose-5-P CO2 Assimilation ("Fixation") in Photosynthesis O2 LIGHT ATP NADPH CO2 + H2O ATP NADH Photosynthesis Respiration NADP+ ADP + Pi H2O Reduced Organic Compounds NAD+ ADP + Pi Triose-P Glucose Sucrose Starch p. 58 Photophosphorylation (per mole O2) 8 Photons (~1,400-2,400 kJ) 2NADP+ + 2H2O PS 2NADPH + 2H+ + O2 12 H+out 12 H+out FoF1 12 H+in 12 H+in 3ATP + 3H2O 3ADP + 3Pi 3ATP + 2NADPH + CO2 + H2O 1/3 Triose-P + 3ADP + 2Pi + 2NADP+ 18ATP + 12NADPH + 6CO2 + H2O Glucose-P + 18ADP + 13Pi + 12NADP+ The Calvin Cycle (CO2 Fixation): Reactions 1. Carboxylation Phase (unique to Calvin cycle) Stroma 2. Reduction Phase (similar to gluconeogenesis) gluconeogenesis 3. Regeneration Phase (similar to pentose-P pathway) pathway Carbon Fixation in Photosynthesis (Calvin Cycle) 1. Carboxylation Phase Ribulose-1,5-bisP 2X 3-PGA CH2OPO 32CH2OPO 32C O CH2OPO 32C C OH ENZ OH C O HC OH CH2OPO 32COOHC OH CH2OPO 32- CO2 -OOC CH2OPO 32C OH ENZ H2O HC OH COO- HC OH HC OH CH2OPO 32- HC OH CH2OPO 32- Ribulose Bisphosphate Carboxylase/Oxygenase (RuBISCO) 3 x C5(-CHO) + 3 CO2 6 x C3(-COOH) p. 72 2. Reduction Phase (Segment of Gluconeogenesis) ATP COOHC OH CH2OPO32- ADP NADPH+H+ COOPO32HC OH CH2OPO 32- NADP+ CHO HC OH CH2OH C O Pi CH2OPO32- CH2OPO3 2- 3-PGA 1,3-bisPGA GA-3-P Triose-P DHAP Phosphoglycerate kinase NADP-glyceraldehyde-P dehydrogenase Triose-P isomerase p. 72 3 CO2 3 x C5(-CHO) + 3 CO2 6 x C3(-COOH) Carboxylation 6 x C3(-COOH) 6 x C3(-CHO) Reduction 3 x C5(-CHO) 5 x C3(-CHO) Regeneration (of acceptor) 1 x C3(-CHO) Net Triose 3. Regeneration Phase (Similar to Phase II and III of PPP) C3 Dihydroxyacetone-P Aldolase Glyceraldehyde-3-P C3 5 x C3(-CHO) 3 x C5(-CHO) Fructose-1,6-bisP Phosphatase Pi Fructose-6-P Glyceraldehyde-3-P Transketolase C3 C5 C3 Dihydroxyacetone-P Aldolase Erythrose-4-P Xylulose-5-P Seduheptulose-1,7-bisP Phosphatase Pi C3 C5 Glyceraldehyde-3-P Transketolase Seduheptulose-7-P Ribose-5-P Xylulose-5-P C5 Isomerase Epimerase Ribulose-5-P Kinase Ribulose-1,5-bisP CO2 Acceptor Molecule p. 73 Stoichiometry of CO2 Assimilation in the Calvin Cycle Carboxylation 6 CO2 (Ru1,5BP Carboxylase/Oxygenase or "Rubisco") Rubisco" (6 x 5 carbons) 6 Ru-1,5-BP 12 Phosphoglycerate 12 ATP (12 x 3 carbons) 6 ADP 6 ATP Calvin Cycle 6 Ru5P 12 ADP 12 NADPH Regeneration (PPP) Reduction (GNG) 12 NADP+ (10 x 3 carbons) 10 GA-3-P 12 GA-3-P 12 Pi (2 x 3 carbons) 2 GA-3-P Glucose or other carbohydrates p. 74 Photosynthetic Carbon Fixation UDP-Galactose Cellulose UDP-Glucose Starch Glucose-1-P Sucrose Glucose-6-P Fructose-6-P GA-3-P GNG ATP 3-PGA NADPH PPP Ribose-5-P Ribulose-5-P CO2 Carboxylation CARBOHYDRATES PROTEINS LIPIDS Glucose Amino acids Fatty acids Other Carbohydrates Oxaloacetate GNG Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Glycolysis PPP PDH TCA Cycle ETC Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 Lipid Review Carbohydrates Chemically well-defined group: [CH2O]n Low "energy density" (partially oxidized) oxidized (hydrated: ~ 2 g H2O/g CHO) Rapidly accessible (water-soluble) Stored glycogen: ~25,000 kJ (lasts ~ 1 day) day Lipids Chemically diverse compounds (water insoluble) insoluble Higher "energy density" (2x) (highly reduced) reduced (no hydration) Slower to mobilize (inert, osmotically inactive) Stored fats: > 400,000 kJ (lasts > 1 month) month Major Lipid Classes Structural Fatty acid-containing lipids Isoprenoids (assembled from C5 units, e.g., steroids) Functional Storage lipids (fats, oils) Membrane lipids Pigments (carotenoids) Co-factors, Vitamins Hormones, Signals Fatty Acids Nomenclature of Fatty Acids 3 24 10 4 2 1 COOH COOH COOH COOH 24 24 9 24:0 COOH 24:1(cis9) 12 18 Linoleic Acid 9 COOH 18:2(9,12) 20 17 14 11 8 5 COOH 20:5(5,8,11,14,17) Eicosapentaenoic Acid (EPA) Omega-3 Fatty Acid Melting Point (Co) Essential fatty acids for humans Cholesterol "Isoprene" Unit (5 carbons) Water Cholesterol Polar Membrane Lipids Water Triacylglycerides = Triglycerides = Fats = Neutral Fats Some Functions of Triglycerides Energy/carbon storage Thermogenesis (heat) Insulation (cold) Physical protection Storage for lipophilic vitamins/hormones Serum lipids 4 tons of fat Degradation of Dietary and Storage Fats Triacylglycerides are the major energy source for: Liver (~80%) Heart Resting skeletal muscles Migrating birds Hibernating animals Absorption of Dietary Fats Redistribution of Excess Lipids Lipoproteins Storage Lipids Adipocytes Mobilization of Storage Lipids Adipocyte TAG FAs Serum Albumin CO2 FAs Consumer Cell Transport of Fatty Acids into Mitochondria Fatty Acid Activation (Cytosol) Fatty Acid + CoA + ATP Acyl-CoA + AMP + PPi PPi + H2O 2 Pi Acyl-CoA Synthetase (specific for length of FAs) Pyrophosphatase Combined Go' = -34 kJ/mol Cost of fatty acid activation: 2 ATP (why?) AMP + 2ATP ATP + 2ADP p. 75 Transport of Fatty Acids into Mitochondria Outer Membrane Intermembrane Space Inner Membrane Matrix Acyl-CoA Carnitine Transporter Acyl-CoA -Oxidation CoA-SH O-Acyl Carnitine CoA-SH "Committed" Step Carnitine acyltransferase I (-) Malonyl-CoA Reciprocal regulation of fatty acid synthesis and degradation Carnitine acyltransferase II p. 75 Transport of Fatty Acids into Mitochondria O OH H3C N+ CH3 - O CH3 Carnitine O O CoA R S Acyl-CoA R C O H C 3 N + O OH H C 3 N+ Carnitine + CH3 -O O CH3 -O + HS CoA CH3 CH3 O-Acyl carnitine CoA p. 75 -Oxidation of Saturated Fatty Acids O C OCoA + ATP AMP + PPi O C S CoA carnitine CoA O C carnitine CoA carnitine R O C S CoA Acyl CoA R Free fatty acids Free fatty acid:CoA ligase (acyl CoA synthetase) R Inner mitochondrial membrane Acyl CoA R Inner mitochondrial membrane Acyl carnitine p. 76 O C S-CoA Old Problem: How to break a C-C bond? Same Answer: Introduce a carbonyl function! C C C O C O C C O How? Look at TCA Cycle! The Tricarboxylic Acid (TCA) Cycle CoA-SH + H+ ACETYL-CoA H2O O C ScoA H3C CH2COOHO COOCH2COOCITRATE H2O CH2COOC COOCHCOO - H2O 2 2 1 CH2COOH COOHC COOOH NAD ISOCITRATE cis-aconitate enzyme-bound O C COO H2C COO- 3 NADH + H CO2 OXALOACETATE NADH + H+ 8 NAD CH2COOH H C COOO -KETOGLUTARATE COO HO C H H C H COOMALATE 7 CoASH 5 - 4 NAD + CoA-SH NADH + H + CO2 H -OOC C C COOH FADH2 6 H2O COOCH2 CH2 COOFAD SUCCINATE CH2COOH H C ScoA O GTP GDP + Pi SUCCINYL-CoA FUMARATE p. 45 R Mitochondrial matrix 1 O C S CoA FAD FADH2 O C S CoA -Oxidation of Saturated Fatty Acids Acyl CoA Acyl CoA:FAD oxidoreductase Acyl-CoA Dehydrogenase Acyl- R 2 -OXIDATION trans-2-enoyl CoA H H2O L-3-hydroxyacyl CoA hydro-lyase Enoyl-CoA Hydratase Enoyl- R OH Additional rounds of -oxidation 3 O C S CoA NAD+ NADH + H O C S CoA + L-3()-hydroxyacyl CoA O L-3-hydroxyacyl CoA:NAD+ oxidoreductase -hydroxyacyl-CoA Dehydrogenase hydroxyacyl3 ()-ketoacyl CoA R 4 O R C S CoA + CoA 3-Keto acyl CoA: CoA acyltransferase (Thiolase) Acyl-CoA acetyltransferase Acyl- O H3C C S CoA Acetyl CoA Acyl CoA ( 2 carbons) TCA Cycle p. 76 Model of the Electron Transport Chain (ETC) Glycerol-3-P Shuttle Outer Mitochondrial Membrane 4H+ + + + G3P DHAP FADH2 4H+ + + + + 2H+ Intermembrane space + + + + + + + + + + + + + + Cyt c I II - - - - - Q III - - E TF FADH2 TCA-Cycle Fatty acid degradation (-oxidation) F0 IV - - - - - - - FADH2 Succinate Fumarate F1 O2 + 2H+ H2O ADP + Pi ATP NADH + H+ NAD+ H+ Matrix ETF Electron-transferring Flavoprotein p. 55 How much ATP can be generated by -Oxidation, the TCA and ETC? Example: Stearic Acid (18:0) 1. Fatty Acid Activation Stearic Acid (18:0) + ATP + CoA Stearoyl-CoA + AMP + PPi PPi + H2O 2Pi 2. -Oxidation (8 rounds) Stearoyl-CoA (18:0) + 8FAD + 8H2O + 8NAD+ + 8CoA 9Acetyl-CoA + 8NADH + 8FADH2 3. TCA Cycle (9 rounds) 9Acetyl-CoA + 18H2O 27NADH + 9FADH2 + 9ATP + 18CO2 4. Electron Transport Chain 35NADH + 17FADH2 + 26O2 105ATP + 34ATP + 52H2O ATP Yield 148 ATP 2 ATP (fatty acid activation) = 146 ATP per 18:0 8.2 ATP per carbon of fatty acid Compare to glucose oxidation: 38 ATP per hexose 6.3 ATP per carbon of carbohydrate Water Yield (!) 52H2O (ETC) 18H2O (TCA) 8H2O (-Oxid.) = 26H2O per 18:0 ~1.6 gram H2O per gram fatty acid ...
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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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