Lecture 5 (2009)

Lecture 5 (2009) - Review Sessions for MT 1 FRI (4/17): Mon...

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Unformatted text preview: Review Sessions for MT 1 FRI (4/17): Mon (4/20): Kleiber Hall, 5 - 7 p.m. Kleiber Hall, 5 - 7 p.m. See ESSENTIALS for MIDTERM 1 Problem sets and Midterms of 2008 and 2007 posted on the "real" 103 website (My UCDavis) http://www.plantsciences.ucdavis.edu/bis103 MIDTERM 1 Next Tuesday (4/21 from 1:40 3:00 p.m.) Seating Assignments (last name initial) (A-H) (I-Z) Med Sci C 180 198 Young Hall Bring a calculator supporting log functions! Lecture 5 Glycolysis (Embden-Meyerhof Pathway) Cleavage of glucose and Substrate-level phosphorylation of ADP to ATP The "Powertrain" of Human Metabolism (The "Big Picture") CARBOHYDRATES PROTEINS LIPIDS Glucose Amino acids Fatty acids Oxaloacetate O2 Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP CO2 H2O Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 The "Powertrain" of Human Metabolism (Overview) CARBOHYDRATES PROTEINS LIPIDS Glucose Amino acids Fatty acids Oxaloacetate O2 Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Glycolysis CO2 H2O Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 Aerobic Glycolysis (Overview) Fischer projection-open chain CHO H HO H H OH H HO CHO OH CH2OH O 1 CH2OPO322 O 1 CH2OPO322 O DHAP 1 H OH OH CH2OH 2 H OH OH CH2OPO32HO H H H OH OH CH2OPO32- 3 HO 3 4 5 6 4 H OH OH CH2OPO32H 3 CH2OH + 4 HC 5 O ATP ADP H H ATP ADP H H 5 OH G-3-P Haworth projection Ring form GLC GLC-6-P F-6-P F-1,6-bisP 6 CH OPO 22 3 CH2OH H OH OH H OH O H OH H CH2OPO32O OH H OH OH O3POH2C H O OH CH2OH O3POH2C H O OH CH2OPO32- HPO42OH 1 ATP OH H 2 H OH H OH 3 ATP ADP H OH H 6 NAD+ NADH + H+ ADP 2 Molecules -O - C O O C O -O -O OPO32C O C O 10 O OPO32CH2 9 H OPO32- 8 H OH CH2OPO32- 7 H 3,4 2,5 1,6 C O OH CH3 ATP ADP H2O CH2OH ATP ADP CH2OPO32- PYR PEP 2-PGA 3-PGA 1,3 bisPGA p. 25 4 HC H O 5 OH G-3-P Reaction 6: The Big Deal! 6 CH OPO 22 3 23 6 NAD HPO42+ Glyceraldehyde-3-P dehydrogenase or Glyceraldehyde-3-P NAD+ oxidoreductase (phosphorylating) G= 1.3 NADH + H+ OPO32- H 3,4 2,5 1,6 C O OH CH2OPO32- 1,3 bisPGA p. 25 G/E Calculations on 6. Reaction in Glycolysis Summary of Chalk Board Calculations Glyceraldehyde-3-P + Pi + NAD+ 1,3-Bisphoshoglycerate + NADH + H+ Can be formally written as two reactions (coupled by enzyme): I. Glyceraldehyde-3-P + H2O + NAD+ 3-Phoshoglycerate + NADH + H+ II. 3-Phoshoglycerate + Pi 1,3-Bisphoshoglycerate + H2O Compare Go' of both reactions I. Glyceraldehyde-3-P + H2O + NAD+ 3-Phoshoglycerate + NADH + H+ Similar to oxidation of acetaldehyde to acetate (see Table 3, reactions 3 and 12) Acetaldehyde + H2O + NAD+ Go' = -nFEo Acetate + NADH + H+ Eo = EoOxidant EoReductant Eo = EoNAD+ EoAcetaldehyde Eo = - 0.32V (-0.58V) Eo = + 0.26V Go' = - 2 (electrons) x 96.5 kJmol-1V-1 x 0.26V Go' = - 50.2 kJmol-1 II. 3-Phoshoglycerate + Pi See Table 4 for Go' of 1,3-Bisphoshoglycerate + H2O Hydrolysis of 1,3-Bisphosphoglycerate (Go' = - 49.6 kJmol-1) or Formation of 1,3-Bisphosphoglycerate (Go' = + 49.6 kJmol-1) Conclusion: In a first approximation (because we are only looking at Go' values), the oxidation of glyceraldehyde-3-P to 3-phosphoglycerate yields about the same amount of energy (-50.2 kJmol-1) as is required to produce 1,3-bisphosphoglycerate from 3-phosphoglycerate and Pi (+49.6 kJmol-1). Again, these two reactions do not occur in isolation but are coupled or combined by the enzyme Glyceraldehyde-3-P Dehydrogenase. Therefore, the Go' (and in fact G) of the overall reaction is close to zero. The Mechanism of Reaction 6 Role of Thioesters in Energy Transduction Disclaimer: Do NOT memorize mechanism, understand what happens here! Esters versus Thioesters O R1 C Ester - O O R2 Resonance stabilization - R1 C O - R2 O R1 C - No resonance stabilization of thioesters (more "strained" molecules) S R2 Thioester Therefore, Go' of thioester hydrolysis is highly negative (about 30 kJ/mol). See Table 4. Mechanism of Glyceraldehyde-3-P Dehydrogenase CH2OPO3 2CHOH H C O- SH HC H O OH CH2OPO32B NAD Enzyme + + BH S NAD+ + Glyceraldehyde-3-P CH2OPO32CHOH Hydride removal to NAD+ H C O- S + HB NAD+ p. 29 CH2OPO3 2CHOH C O CH2OPO32CHOH C O O -O P OH O- HB + S NAD+ + S HB NADH + NAD NADH Thioester-linked substrate 2O3PO C H SH O OH CH2OPO32- NAD+ + B Enzyme + H+ 1,3-Bisphosphoglycerate p. 29 Fischer projection-open chain CHO H HO H H OH H HO CHO OH CH2OH O 1 CH2OPO322 O 1 CH2OPO322 O DHAP 1 H OH OH CH2OH 2 H OH OH CH2OPO32HO H H H OH OH CH2OPO32- 3 HO 3 4 5 6 4 H OH OH CH2OPO32H 3 CH2OH + 4 HC 5 O ATP ADP H H ATP ADP H H 5 OH G-3-P Haworth projection Ring form GLC GLC-6-P F-6-P F-1,6-bisP 6 CH OPO 22 3 CH2OH H OH OH H OH O H OH H CH2OPO32O OH H OH OH O3POH2C H O OH CH2OH O3POH2C H O OH CH2OPO32- HPO42OH 1 ATP OH H 2 H OH H OH 3 ATP ADP H OH H 6 NAD+ NADH + H+ ADP 2 Molecules -O - C O O C O -O -O OPO32C O C O 10 O OPO32CH2 9 H OPO32- 8 H OH CH2OPO32- 7 H 3,4 2,5 1,6 C O OH CH3 ATP ADP H2O CH2OH ATP ADP CH2OPO32- PYR PEP 2-PGA 3-PGA 1,3 bisPGA p. 25 2-Phosphoglycerate 3-Phosphoglycerate 1,3-Bisphosphoglycerate 2 Molecules - O C H O -O OPO32C O 8 OPO32H OH CH2OPO32- 7 H 3,4 2,5 1,6 C O OH CH2OH ATP ADP CH2OPO32- 2-PGA 3-PGA Go'= 1,3 bisPGA 19.1 G= +0.1 Substrate-level Phosphorylation Reaction 7: Phosphoglycerate kinase p. 25 2-Phosphoglycerate 3-Phosphoglycerate 1,3-Bisphosphoglycerate 2 Molecules - O C H O -O OPO32C O 8 OPO32H OH CH2OPO32- 7 H 3,4 2,5 1,6 C O OH CH2OH ATP ADP CH2OPO32- 2-PGA 3-PGA 1,3 bisPGA Reaction 8: Phosphoglycerate mutase (special isomerase) p. 25 Pyruvate (Pyruvic Acid) -O Phosphoenolpyruvate 2-Phosphoglycerate 2 Molecules - C O O C O -O C O 10 O OPO32CH2 9 H OPO32- CH3 ATP ADP H2O CH2OH PYR PEP Go'= 1.8 G= 1.1 2-PGA Reaction 9: Enolase (Glycerate-2-P hydro-lyase) p. 25 Pyruvate (Pyruvic Acid) -O Phosphoenolpyruvate 2-Phosphoglycerate 2 Molecules - C O O C O -O C O 10 O OPO32CH2 9 H OPO32- CH3 ATP ADP H2O CH2OH PYR Go'= 31.7 G= 23.0 PEP 2-PGA Keto "Locked" Enol Tautomerization Substrate-level Phosphorylation Reaction 10: Pyruvate kinase (ATP:enol-pyruvate phoshotransferase) p. 25 Fischer projection-open chain CHO H HO H H OH H HO CHO OH CH2OH O 1 CH2OPO322 O 1 CH2OPO322 O DHAP 1 H OH OH CH2OH 2 H OH OH CH2OPO32HO H H H OH OH CH2OPO32- 3 HO 3 4 5 6 4 H OH OH CH2OPO32H 3 CH2OH + 4 HC 5 O ATP ADP H H ATP ADP H H 5 OH G-3-P Haworth projection Ring form GLC GLC-6-P F-6-P F-1,6-bisP 6 CH OPO 22 3 CH2OH H OH OH H OH O H OH H CH2OPO32O OH H "Preparation" Phase (reactions 1-5) O3POH2C O H OH OH OH H CH2OH O3POH2C O H OH OH CH2OPO32- HPO42OH 1 ATP OH H OH 2 H 3 ATP ADP H OH H 6 NAD+ NADH + H+ ADP "Pay-off" Phase (reactions 6-10) 2 Molecules -O -O -O - C O O C O OPO32C O C O 10 O OPO32CH2 9 H OPO32- 8 H OH CH2OPO32- 7 H 3,4 2,5 1,6 C O OH CH3 ATP ADP H2O CH2OH ATP ADP CH2OPO32- PYR 2x PEP 2-PGA 3-PGA 2x 1,3 bisPGA p. 25 Overall Stoichiometry of Glycolysis Preparation Phase (reactions 1-5): 1Glc + 2ATP Pay-off Phase (ractions 6-10): 2GA3P + 2NAD+ + 2Pi + 4ADP Total Glycolysis (net result): 2Pyr + 2NADH + 2H+ + 4ATP + 2H2O 2GA3P + 2ADP 1Glc + 2NAD+ + 2Pi + 2ADP 2Pyr + 2ATP + 2NADH + 2H+ + 2H2O Glc Glucose; GA3P Glyceraldehyde-3-P; Pyr - Pyruvate Recurring Concepts/Themes Fischer projection-open chain CHO H HO H H OH H HO CHO OH CH2OH O 1 CH2OPO322 O 1 CH2OPO322 O DHAP 1 H OH OH CH2OH 2 H OH OH CH2OPO32HO H H H OH OH CH2OPO32- 3 HO 3 4 5 6 4 H OH OH CH2OPO32H 3 CH2OH + 4 HC 5 O ATP ADP H H ATP ADP H H 5 OH G-3-P Haworth projection Ring form GLC GLC-6-P F-6-P F-1,6-bisP 6 CH OPO 22 3 CH2OH H OH OH H OH O H OH H CH2OPO32O OH H OH OH O3POH2C H O OH CH2OH O3POH2C H O OH CH2OPO32- HPO42OH 1 ATP OH H 2 H OH H OH 3 ATP ADP H OH H 6 NAD+ NADH + H+ ADP 2 Molecules -O - C O O C O -O -O OPO32C O C O 10 O OPO32CH2 9 H OPO32- 8 H OH CH2OPO32- 7 H 3,4 2,5 1,6 C O OH CH3 ATP ADP H2O CH2OH ATP ADP CH2OPO32- PYR PEP 2-PGA 3-PGA 1,3 bisPGA General Concepts (derived from glycolysis) Intermediates in CHO metabolism are "phosphorylated" How to drive an unfavorable reaction forward? coupling to ATP hydrolysis coupling to more favorable reactions ("push" or "pull") Strategy to cleave a C-C bond (place a C=O next to it) Redox conversion of aldehydes-to-carboxylic acids Role of thioesters in energy conservation Production of ATP by "substrate-level" phosphorylation Aerobic Glycolysis Glucose 2NAD+ 2H2O 2ATP 2x Pyruvate 8NAD+ 2NADH + H+ Most (34) ATP O2 2ATP 6x CO2 8NADH + H+ H2O Anaerobic Glycolysis Glucose 2NAD+ 2H2O 2ATP 2x Pyruvate 8NAD+ 2NADH + H+ How to regenerate NAD+ in the absence of oxygen? 2ATP 6x CO2 8NADH + H+ Anaerobic Glycolysis Glucose 2NAD+ 2H2O 2ATP 2x Pyruvate 2NADH + H+ ??? Reduction of the endproduct of glycolysis (Pyr)! Fermentation Fates of Pyruvate in Anaerobic Glycolysis (Fermentation) A. Lactic Acid Fermentation -O C -O C O O 11 O HO H CH3 NADH + H+ NAD+ CH3 Pyruvate Lactate p. 30 The "Powertrain" of Human Metabolism (Overview) CARBOHYDRATES PROTEINS LIPIDS Glucose Amino acids Fatty acids Oxaloacetate O2 Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Glycolysis CO2 H2O Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 B. Alcoholic (Ethanolic) Fermentation -O C O H 12 O CH3 13 O CH2OH CH3 CO2 NADH + H + NAD + CH3 Pyruvate Acetaldehyde Ethanol Decarboxylation of an -keto acid (here: pyruvate) p. 30 Decarboxylation of - and -Keto Acids and -Hydroxy Acids -OH acids Examples are malate, isocitrate, 6-phosphogluconate O Oconverts when bound to enzyme, requires NAD or NADP -keto acids Example is acetoacetate O O- C CHOH CHOH R C CHOH C R O Keto group No cofactor is required for the decarboxylation p. 31 Decarboxylation of - and -Keto Acids and -Hydroxy Acids -keto acids Examples of this type are pyruvate (Pyr) and -ketoglutarate (-KGA) Carboxyl group that will leave as CO 2 Keto group O C C OO CH2 R Decarboxylation requires the cofactor thiamin pyrophosphate (TPP) p. 31 The TPP Coenzyme Thiamine Pyrophosphate (TPP) Thiamine (Vitamin B1) NH2 CH3 C N CH2 N HC H3C N S O O C CH2CH2 O O P O O P O p. 32 TPP-dep. Decarboxylation of -Keto Acids CH3 C CH3 O TPP +N C C OH COOH Pyruvate COOH CH3 C CH3 O TPP +N C C OH COOH Pyruvate COOH Similar to "-Keto Acid" CO2 CH3 C CH3 O TPP +N C C OH COOH Pyruvate H Hydroxyethyl-TPP ("Acetaldehyde") Mechanism of Pyruvate Decarboxylase (PDC) CH3 C R1 N C H S C R2 R1 N CH3 C C C S R2 CH3 + -O C O O C CH3 HB B R1 N C C H3C C R2 SO C O- H TPP carbanion Pyruvate OH CH3 C R1 N C S C R2 CH3 CH3 CO2 H R2 R1 C H3C OH S H H3C OH N C S CH3 C C R2 HB B R1 N C C H3C C S H R2 R1 N C C + H H3C C O OH Acetaldehyde p. 33 The "Powertrain" of Human Metabolism (Overview) CARBOHYDRATES PROTEINS LIPIDS Sucrose Lactose Fructose Mannose Glycerol Galactose Starch Glucose Amino acids Fatty acids Oxaloacetate O2 Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Glycolysis CO2 H2O Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 Hydrolysis of Sucrose and Lactose CH2OH H OH OH H O H OH O HOH2C H H OH H glucosyl Sucrose O OH CH2OH fructosyl glucose (1 2) fructose p. 34 CH2OH H OH O H glucosyl OH Lactose CH2OH OH OH OH O O H OH galactosyl galactose (1 4) glucose p. 34 Metabolism of Fructose, Mannose, and Glycerol A. Fructose CH2OH O HO H H OH H OH CH2OH 1 ATP ADP CH2OH O HO H H OH H OH CH2OPO32- Fructose F-6-P CH2OPO32O Dihydroxyacetone-P CH2OH OR CH2OH O HO H H OH H OH CH2OH 14 ATP ADP CH2OPO32O 15 HO H H OH H OH CH2OH (DHAP) + CHO OH H CH2OH 16 CHO H OH CH2OPO32- Fructose F-1-P ATP Glyceraldehyde ADP GA-3-P p. 35 B. Mannose HO HO H H CHO H H OH OH CH2OH 1 ATP ADP HO HO H H CHO H H OH OH CH2OPO32- 20 CH2OH O HO H H OH H OH CH2OPO32- Mannose Mannose-6-P (M-6-P) F-6-P p. 35 C. Glycerol CH2OH OH CH2OH 17 CH2OH OH CH2OPO32- 18 CH2OH O CH2OPO 32- ATP ADP Glycerol-3-P NAD+ NADH + H+ DHAP Glycerol p. 35 ...
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