Carbohydrate Metabolism
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Carbohydrate Metabolism






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Carbohydrate Metabolism Carbohydrate Metabolism Presentation Transcript

  • Principles of Energy Harvest
    • Endothermic
      • Photosynthesis
    • Exothermic
      • Glycolysis
      • Respiration
  • 6CO 2 + 6H 2 O 2840 kJ Energy As Heat Combustion of glucose in a bomb calorimeter Glucose
  • Aerobic Respiration
    • Products would be the same if the glucose were burned in a bomb calorimeter with oxygen
    • A redox reaction
    • Glucose is oxidized
    • Oxygen is reduced
    • Cells carry out a redox process in about 30 steps
    • Electrons associated with hydrogen atoms in glucose are transferred to oxygen
  • Redox reactions
    • Oxidation-reduction
    • OIL RIG (adding e- reduces + charge)
    • Oxidation is e- loss; reduction is e- gain
    • Reducing agent: e- donor
    • Oxidizing agent: e- acceptor
  • Redox Reactions
    • Reaction in which one substance transfers one or more electrons to another substance is called oxidation-reduction reaction
      • Redox for short
    • Gain or 1 or more electrons by atom, ion, or molecule is called reduction
    • Loss of 1 or more electrons by atom, ion, or molecule is called oxidation
  • Cellular respiration
    • Glycolysis: cytosol; degrades glucose into pyruvate
    • Kreb’s Cycle: mitochondrial matrix; pyruvate into carbon dioxide
    • Electron Transport Chain: inner membrane of mitochondrion; electrons passed to oxygen
  • Overview of Glycolysis
    • The Embden-Meyerhof (Warburg) Pathway
    • Discovered by Hans Buchner and Eduard Buchner when sucrose was found rapidly fermented into alcohol by yeast;
    • Essentially all cells carry out glycolysis
    • Enzyme driven
    • Site of glycolysis is in cytosol;
    • Ten reactions - same in all cells - but rates differ
    • Two phases:
      • First phase converts glucose to two G-3-P
      • Second phase produces two pyruvates
    • Products are pyruvate, ATP and NADH
    • Three possible fates for pyruvate
  • Glycolysis
    • 1 Glucose  2 pyruvate molecules
    • Energy investment phase : cell uses ATP to phosphorylate fuel
    • Energy payoff phase : ATP is produced by substrate-level phosphorylation and NAD+ is reduced to NADH by food oxidation
    • Net energy yield per glucose molecule : 2 ATP plus 2 NADH; no CO 2 is released; occurs aerobically or anaerobically
  • Kreb’s Cycle
    • If molecular oxygen is present…….
    • Each pyruvate is converted into acetyl CoA (begin w/ 2): CO2 is released; NAD+ ---> NADH; coenzyme A (from B vitamin), makes molecule very reactive
    • From this point, each turn 2 C atoms enter (pyruvate) and 2 exit (carbon dioxide)
    • Oxaloacetate is regenerated (the “cycle”)
    • For each pyruvate that enters: 3 NAD+ reduced to NADH; 1 FAD+ reduced to FADH2 (riboflavin, B vitamin); 1 ATP molecule
  • Electron transport chain
    • Cytochromes carry electron carrier molecules (NADH & FADH2) down to oxygen
    • Chemiosmosis : energy coupling mechanism
    • ATP synthase : produces ATP by using the H+ gradient (proton-motive force) pumped into the inner membrane space from the electron transport chain; this enzyme harnesses the flow of H+ back into the matrix to phosphorylate ADP to ATP (oxidative phosphorylation)
  • Review: Cellular Respiration
    • Glycolysis: 2 ATP (substrate-level phosphorylation)
    • Kreb’s Cycle: 2 ATP (substrate-level phosphorylation)
    • Electron transport & oxidative phosphorylation: 2 NADH (glycolysis) = 6ATP 2 NADH (acetyl CoA) = 6ATP 6 NADH (Kreb’s) = 18 ATP
    • 2 FADH2 (Kreb’s) = 4 ATP
    • 38 TOTAL ATP/glucose
  • 4 stages of aerobic respiration Stage 1: Glycolysis Stage 2: Formation of Acetyl coenzyme A Stage 3: The Citric Acid Cycle Stage 4: Electron transport chain
  • A Road Map for Cellular Respiration Cytosol Mitochondrion High-energy electrons carried by NADH High-energy electrons carried mainly by NADH Glycolysis Glucose 2 Pyruvic acid Krebs Cycle Electron Transport
  • Glycolysis and Fermentation
  • Glycolysis: Embden Meyerhof pathway
    • The pathway for lactate fermentation in muscle is the same pathway as alcohol fermentation, showing an underlying unity in biology.
    • Gustav Embden
    • Otto Meyerhof
    • Jacob Parness
    1922 Nobel Prize
  • Related metabolic processes
  • Fate of Pyruvate
  • 2 Pyruvic acid Overview of Glycolysis
  • GLYCOLYSIS Glucose ATP hexokinase ADP Glucose 6-phosphate p hosphogluco- i somerase Fructose 6-phosphate ATP phosphofructokinase ADP Fructose 1,6- bis phosphate aldolase triose phosphate isomerase Dihydroxyacetone Glyceraldehyde phosphate 3-phosphate
  • Glyceraldehyde 3-phosphate glyceraldehyde NAD + + P i 3-phosphate NADH + H + dehydrogenase 1,3- Bis phosphoglycerate   ADP phosphoglycerate kinase ATP 3-Phosphoglycerate phosphoglyceromutase 2-Phosphoglycerate enolase H 2 O Phospho enol pyruvate ADP pyruvate kinase ATP Pyruvate
  • Glycolysis: 1
  • Glycolysis: stage 1 The three steps of stage 1 begin with the phosphorylation of glucose by hexokinase Energy used, none extracted
  • ATP ADP glucose glucose 6-phosphate ∆ G o = -16.7 kJ/mole Step 1: Adding a phosphate Enzyme: hexokinase
  • Phosphoryl transfer reaction. Kinases transfer phosphate from ATP to an acceptor. Hexokinase has a more general specificity in that it can transfer phosphate to other sugars such as mannose. Δ G°’= -4.0 kcal mol-1
  • Glucose phosphorylation: step 1 Glucose is a relatively stable molecule and is not easily broken down. The phosphoylated sugar is less stable. ATP serves as both source of phosphate and energy needed to add phosphate group to the molecule.
  • Induced fit in hexokinase Conformation Changes on binding glucose, the two lobes of the enzyme come together and Surround the substrate
  • Step 2: Isomerization glucose 6-phosphate fructose 6-phophate aldose to ketose isomerization reversible,  G°´= 1.7 kJ/mole 6 carbon ring 5 carbon ring Enzyme: phosphoglucoisomerase
  • The conversion of an aldose to a ketose . Phosphoglucose Isomerase Δ G°’= .40 kcal mol-1
  • Formation of fructose-6-phosphate: step 2 by phosphoglucose isomerase The enzyme opens the ring, catalyzes the isomerization, and promotes the closure of the five member ring.
  • Step 3: Second phosphorylation
    • second ATP investment
    • highly exergonic, essentially irreversible ,
    •  G°´= -14.2 kJ/mole
    fructose 1,6 bisphosphate ATP ADP fructose 6-phosphate Enzyme: phosphofructokinase
  • Phosphofructokinase-1 PFK Δ G°’= -3.4 kcal mol -1 The 2 nd investment of an ATP in glycolysis. Bis means two phosphate groups on two different carbon atoms. Di means two phosphate groups linked together on the same carbon atom. PFK is an important allosteric enzyme regulating the rate of glucose catabolism and plays a role in integrating metabolism.
  • Formation of fructose 1,6-bisphosphate: step 3 by phosphofructokinase (PFK): an allosteric enzyme that regulates the pace of glycolysis.
  • Allosteric Enzymes
    • Part II. Allosteric Regulation
    • Control of Enzyme Activity by Non-Covalent Modifiers is usually called allosteric regulation since the modifier binds to the enzyme at a site other than the active site but alters the shape of the active site. Allosteric is a word derived from two Greek words: 'allo' meaning other and 'steric' meaning place or site; so allosteric means other site and an 'allosteric enzyme' is one with two binding sites - one for the substrate and one for the allosteric modifier molecule, which is not changed by the enzyme so it is not a substrate. The molecule binding at the allosteric site is not called an inhibitor because it does not necessarily have to cause inhibition - so they are called modifiers. A negative allosteric modifier will cause the enzyme to have less activity, while a positive allosteric modifier will cause the enzyme to be more active. In order for allosteric regulation to work, the enzyme must be multimeric (ie. a dimer, trimer, tetramer etc.). The concept is easily illustrated using a dimer as the model system, but it applies equally well to higher order multimers such as trimers and tetramers, etc.
  • Glycolysis: stage 2 Two 3-carbon fragments are produced from one 6-carbon sugar No energy used or extracted
  • Step 4: Cleavage to two triose phosphates Reverse aldol condensation ; converts a 6 carbon atom sugar to 2 molecules, each containing 3 carbon atoms. Enzyme: aldolase
  • Aldol Condensation
    • An Aldol condensation is an organic reaction in which an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone .
    • Aldol condensations are important in organic synthesis , providing a good way to form carbon– carbon bonds . The Robinson annulation reaction sequence features an aldol condensation; the Wieland-Miescher ketone product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms . In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or " aldol " ( ald ehyde + alcoh ol ), a structural unit found in many naturally occurring molecules and pharmaceuticals.
    • Enol: An organic compound containing a hydroxyl group bonded to a carbon atom, which in turn is doubly bonded to another carbon atom.
  • Cleavage of six-carbon sugar: step 4
  • Glycolysis: 2
  • Step 5: Isomerization of dihydroxyacetone phosphate H 2 C-OH C=O CH 2 -O- P dihydroxyacetone glyceraldehyde phosphate 3-phosphate Enzyme: triose-phosphate isomerase
  • Salvage of three-carbon fragment: step 5
  • Glycolysis: stage 3 The oxidation of three-carbon fragments yields ATP Energy extracted, 2x2 ATP
  • Glycolysis: 3
  • Step 6: Formation of 1,3-Bisphosphoglycerate Done in two steps glyceraldehyde 3-phosphate 1,3 bisphosphoglycerate Enzyme: glyceraldehyde-3-phosphate dehydrogenase addition of phosphate, oxidation, production of NADH, formation of high energy compound
  • The fate of glyceraldehyde 3-phosphate Stage 3: The energy yielding phase. Glyceraldehyde 3-phosphate DH Δ G°’ = 1.5 kcal mol -1 1,3-BPG has a high phosphoryl-transfer potential. It is a mixed anhydride. An aldehyde is oxidized to carboxylic acid and inorganic phosphate is transferred to form acyl-phosphate. NAD + is reduced to NADH. Notice, under anaerobic conditions NAD + must be re-supplied.
  • Glyceraldehyde 3-phosphate dehydrogenase Active site configuration
  • Step 7: Transfer of phosphate to make ATP Formation of ATP from 1,3-Bisphosphoglycerate: Enzyme: phosphoglycerate kinase first substrate level phosphorylation, yielding ATP 2 1,3 bis PG yield 2 ATPs, thus ATP yield = ATP input high free energy yield,  G°´= -18.8kJ/mole drives several of the previous steps
  • 7: Phosphoglycerate Kinase Substrate-level phosphorylation Δ G°’ = -4.5 kcal mol -1 ATP is produced from P i and ADP at the expense of carbon oxidation from the glyceraldehyde 3-phosphate DH reaction. Remember: 2 molecules of ATP are produced per glucose. At this point 2ATPs were invested and 2ATPs are produced.
  • Two-process reaction Aldehyde Acid
  • Step 8: Phosphate shift setup - shifts phosphate from position 3 to 2 - reversible , ΔG  = + 4.6 kJ/mole Enzyme: phosphoglycerate mutase
  • Phosphate shift Phosphoglycerate mutase Δ G°’ = 1.1 kcal mol -1
  • Step 8: Rearrangement
  • Step 9: Removal of Water leadsto formation of double bond little energy change in this reaction, ΔG  = + 1.7 kJ/mole because the energy is locked into enolphosphate. Phosphate group attached by unstable bond, therefore high energy Enzyme: enolase
  • Generation of second very high energy compound by a dehydration reaction Enolase Δ G°’ = .4 kcal mol -1 Dehydration reaction PEP the energy is locked into the high energy unfavorable enol configuration by phosphoric acid ester
  • An enol phosphate is formed: step 9 Dehydration elevates the transfer potential of the phosphoryl group, which traps the molecule in an unstable enol form Enol: molecule with hydroxyl group next to double bond
  • Step 10: Formation of Pyruvate & ATP Enzyme: pyruvate kinase phosphoenolpyruvate pyruvate second substrate level phosphorylation yielding ATP highly exergonic reaction, irreversible , ΔG  = -31.4 kJ/mole.
    • Substrate level phosphorylation is the synthesis of ATP from ADP that is not linked to the electron transport system.
    Pyruvate Kinase 2 nd example of substrate level phosphorylation. The net yield from glycolysis is 2 ATP Δ G°’ = -7.5 kcal mol -1 unstable Enol form  more stable keto form PEP
  • Maintaining Redox Balance NAD + must be regenerated for glycolysis to proceed Glycolysis is similar in all cells, the fate of pyruvate is variable
  • Diverse fates of pyruvate To citric acid cycle
  • The Conversion of Glucose to Pyruvate Glucose + 2 P i + 2 ADP + 2 NAD + -> 2 pyruvate + 2 ATP + 2 NADH +2 H + The Energy released from the anaerobic conversion of glucose to pyruvate is -47kcal mol -1 . Under aerobic conditions much more chemical bond energy can be extracted from pyruvate. The question still remains: How is NAD + supplied under anaerobic conditions? Or how is redox balance maintained?
  • Under anaerobic conditions pyruvate is converted to lactate. Exercising muscle is an example. The NAD + that is consumed in the glyceraldehyde 3-phosphate reaction is produced in the lactate DH reaction. The redox balance is maintained. The activities of glyceraldehyde 3-phosphate DH and Lactate DH are linked metabolically. What happens to the lactate after a run?
  • ATP
  • In anaerobic yeast, pyruvate->ethanol Pyruvate is decarboxylated. Acetaldehyde is reduced.
  • Variations on a theme in alcoholic fermentation. Here also, there is no net oxidation reduction.
  • Enzyme Classification Dehydrogenase - oxidizes substrate using cofactors as electron acceptor or donor (pyruvate dehydrogenase) Reductase- adds electrons from some reduced cofactor (enoyl ACP reductase) Kinase- phosphorylates substrate (hexokinase)  Hydrolases - uses water to cleave a molecule Phosphatase- hydrolyzes phosphate esters (glucose-6-phosphatase) Esterase (lipase)- hydrolyzes esters (those that act on lipid esters are lipases) (lipoprotein lipase) Thioesterases - hydrolyzes thioesters Thiolase- uses thiol to assist in forming thioester (β-ketothiolase) Isomerases- interconversions of isomers
  • Stage 2: The Krebs Cycle
    • The Krebs cycle completes the breakdown of sugar
    • In the Krebs cycle, pyruvic acid from glycolysis is first “prepped” into a usable form, Acetyl-CoA
    Acetyl-CoA (acetyl-coenzyme A) CO 2 pyruvic acid acetic acid 2 Pyruvic acid Acetic acid Coenzyme A Acetyl-CoA (acetyl-coenzyme A) CO 2
  • input output ADP NAD+ FAD Figure 6.11 Input 3 NAD  FAD Krebs Cycle Output 2 CO 2 1 2 3 4 5 6
  • Figure 6.12 Protein complex Electron carrier Inner mitochondrial membrane Electron flow Electron transport chain ATP synthase Electron Transport Chain
  • Stage 3: Electron Transport
    • Electron transport releases the energy your cells need to make the most of their ATP
    • The molecules of electron transport chains are built into the inner membranes of mitochondria
      • The chain functions as a chemical machine that uses energy released by the “fall” of electrons to pump hydrogen ions across the inner mitochondrial membrane
      • These ions store potential energy
  • Adding Up the ATP from Cellular Respiration Figure 6.14 Cytosol Mitochondrion Glycolysis Glucose 2 Pyruvic acid 2 Acetyl- CoA Krebs Cycle Electron Transport by direct synthesis by direct synthesis by ATP synthase Maximum per glucose:
  • Figure 6.13 Food Polysaccharides Fats Proteins Sugars Glycerol Fatty acids Amino acids Amino groups Glycolysis Acetyl- CoA Krebs Cycle Electron Transport
  • ATP hydrolysis and synthesis