anaerobic metabolism (glycolysis and fermentation) only releases 7% of the energy in glucose, with...

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  • Anaerobic metabolism (glycolysis and fermentation) only releases 7% of the energy in glucose, with higher energy requirements Utilize aerobic metabolism (pyruvate dehydrogenase complex (PDH), Krebs Cycle (KC) to completely oxidize pyruvate to CO2.

    The PDH in the mitochondrial matrix connects glycolysis to KC by irreversible oxidative carboxylation of pyruvate to Acetyl CoA.(Dehydrogenase: an enzyme catalyzing removal of pairs of hydrogen atoms from specific substrates.

    Glycolysis is used for rapid ATP production :

    Rate of ATP formation in anaerobic is 100 times > ATP productionby oxidative phosphorylation.

    Note:

  • Krebs Cycle (KC)Also known as TCA cycle, or citric acid cycleReactions of KC occur in mitochondrial matrixCommon final degradative pathway for breakdown of monomers of CHO, fat and protein to CO2 and H20Electrons removed from acetyl groups and attached to NAD+ and FADSmall amount of ATP produced from substrate level phosphorylationKC also provides intermediates for anabolic functions (eg. gluconeogenesis)

  • Amphibolic Nature of TCA CycleSome compounds feed in and some are removed for other usesAnabolicCatabolic

  • Some General Features of TCA Cycle

    The enzymes that participate in the citric acid cycle are found in the mitochondrial matrix.

    Catabolic role Amino acids, fats, and sugars enter the TCA cycle to produce energy. Anabolic role TCA cycle provides starting material for fats and amino acids. Note: carbohydrates cannot be synthesized from acetyl-CoA by humans. Pyruvate---Acetyl CoA is one way!

    In contrast to glycolysis, none of the intermediates are phosphorylated but all are either di- or tricarboxylic acids.

  • Pyruvate transport and mitochondial structure:

    The mitochondria enclosed by a double mb. All of the glycolytic enzymes are found in the cytosol of the cell. Charged molecules such as pyruvate must be transported in and out of the mithochondria. Small charged molecules with M.wt. < 10000 can freely diffuse through outer mitochondrial mb. through aqueous channels called porins. A transport protein called pyruvate translocase specifically transports pyruvate through the inner mitochondrial mb. into the Mitochondrial matrix.

    outer

    membrane

    inner

    membrane

    matrix

    inter-

    membrane

    space

    mitochondrion

    cristae

  • Mitochondrial compartment:The matrix contains Pyruvate Dehydrogenase, enzymes of Krebs Cycle, and other pathways, e.g., fatty acid oxidation & amino acid metabolism.The outer membrane contains large channels, similar to bacterial porin channels, making the outer membrane leaky to ions & small molecules The inner membrane is the major permeability barrier of the mitochondrion. It contains various transport catalysts, including a carrier protein that allows pyruvate to enter the matrix. It is highly convoluted, with infoldings called cristae. Embedded in the inner membrane are constituents of the respiratory chain and ATP Synthase.

  • Entry of Pyruvate into the MitochondrionPyruvate translocase transports pyruvate into the mitochondria in symport with H+

  • Pyruvate Acetyl CoAPyruvate produced in cytosol and transported into mitochondriaCannot directly enter KCFirst converted to acetyl CoA by pyruvate dehydrogenase complexOxidative decarboxylation of pyruvate

  • Coenzyme: an organic cofactor required for the action of certain enzymes often containing a vitamin as a building block.

    high energy compound- Hydrolysis of thioesterbond more exergonic than ATP

    acetylCoA common breakdown product of CHO, FAs, AAs

    Coenzyme AReactive thiol group

  • Pyruvate Dehydrogenase Complex (PDH) *TPP is a derivative of thiamine (vitamin B1). Nutritional deficiency of thiamine leads to the disease beriberi. Beriberi affects especially the brain, because TPP is required for CHO metabolism, & the brain depends on glucose metabolism for energy.Limb weakness, heart disease (green vegetables, fruit, fresh meat)

    ** Flavin Adenine Dinucleotide is derived from the vitamin riboflavin

    EnzymeAbbreviatedProsthetic groupFunctionPyruvate dehydrogenaseE1Thiamine Pyrophosphate TPP*Decaboxylation and aldehyde group transferDihydrolipoyl transacetylaseE2Lipoamide, Co-ACarrier of hydrogens or acetyl groupDihydrolipoyl dehydrogenaseE3FAD**, NADElectron carriers

  • Reactions of the PDH Complex Reaction is irreversibleRegulation of E2 and E3 :Inhibitors: NADH, AcetylCoAActivators: NAD, CoAE1 by phos/dephosOxidized formAcetylated formReduced form

  • Enzymes and Reactions of the Citric Acid CycleMulti-step catalystCitrate synthaseAconitase Isocitrate Dehydrogenasealpha-Ketoglutarate DehydrogenaseSuccinyl-CoA SynthetaseSuccinate DehydrogenaseFumaraseMalate Dehydrogenase

  • Formation of citrateOxaloacetate condenses with acetyl CoA to form CitrateNon-equilibrium (irreversible) reaction catalysed by citrate synthase

    Inhibited by:ATPNADHSuccinyl-CoACitrate - competitive inhibitor of oxaloacetate

  • Citrate isocitrate

    Citrate isomerised to isocitrate in two reactions (dehydration and hydration)Equilibrium reactions catalysed by aconitaseResults in interchange of H and OH. Changes structure and energy distribution within molecule. Makes easier for next enzyme to remove hydrogen

  • isocitrate -ketoglutarateIsocitrate dehydrogenated and decarboxylated to give -ketoglutarateNon-equilibrium reactions catalysed by isocitrate dehydrogenaseResults in formation of: NADH + H+CO2Stimulated by isocitrate, NAD+, Mg2+, ADP, Ca2+Inhibited by NADH and ATP

  • -ketoglutarate succinyl CoASeries of reactions result in decarboxylation, dehydrogenation and incorporation of CoASHNon-equilibrium reactions catalysed by -ketoglutarate dehydrogenase complexResults in formation of: CO2 +NADHHigh energy bondStimulated by Ca2+Inhibited by NADH, ATP, Succinyl CoA

  • Succinyl CoA succinateEquilibrium reaction, the succinyl thioester of CoA =energy rich bond.Results in formation of: CoA-SH , GTP

    GTP + ADP GDP + ATP( nucleoside diphosphokinase)

  • Succinate fumarate Oxidation of succinate to fumarate reduces FAD to FADH2Succinate dehydrogenated to form fumarateEquilibrium reaction catalysed by succinate dehydrogenase. Only Krebs enzyme contained within inner mitochondrial membraneResults in formation of FADH2.

  • Fumarate malate Addition of water to the double bond, to make the alcoholFumarate hydrated to form malateEquilibrium reaction catalysed by fumaraseResults in redistribution of energy within molecule so next step can remove hydrogen

  • Malate oxaloacetateOxidation of Malate to Oxaloacetate reduces NAD+ to NADH

    Malate dehydrogenated to form oxaloacetateEquilibrium reaction catalysed by malate dehydrogenaseResults in formation of NADH + H+

  • All of the carbons that are input as Pyruvate are released as CO2. This is as highly oxidized as carbon can get.

    Oxidative decarboxylation: each time a CO2 is produced one NADH is produced.

    Locations of CO2 release:1. Pyruvate dehydrogenase: Pyruvate to Acetyl-CoA2. Isocitrate dehydrogenase: Isocitrate to a-ketoglutarate3. alpha-ketoglutarate dehydrogenase:a-ketoglutarate to succinyl-CoA

  • Acetyl CoA is completely oxidized to CO2

    Oxidation occurs in four reactions that transfer electrons (ashydrogen atoms) to electron accepting coenzymes (NAD+, FAD) other reactions in the cycle rearrange electrons to facilitate the transfer. initially, 2C acetyl portion of acetyl CoA + 4C oxaloacetate to form citrate (6 carbons). a bond rearrangement in citrate is followed by 2 oxidative decarboxylation reactions which transfer electrons to NAD+ and release 2 carbons as electrona high energy phosphate bond in GTP is generated in the next step by substrate level phosphorylation

  • Summary of TCA Cycle Reactionsacetyl CoA oxidized to 2CO2 4 electron pairs3NADH 1FADH21GTPCoupled to oxidative phosphorylation

  • Regulation of PDH complex 1- inhibition by end products (NADH, Acetyl CoA). Increased levels of acetyl CoA and NADHinhibit E2, E3 in mammals and E. coli.2- Feed back regulation by nucleotides (GTP)

  • 3- Regulation by reversible phosphorylation phosphorylation/dephosphorylation of E12-3 molecules in complex

  • Regulation of Krebs CycleCycle always proceeds in same direction due to presence of 3 non-equilibrium reactions catalysed byCitrate synthase - NADH, ATP, citrate, succinyl CoA + NAD+, ADPIsocitrate dehydrogenase - NADH, ATP+ NAD+, ADP, Ca2+-ketoglutarate dehydrogenase - NADH, Succinyl CoA + NAD+, Ca2+

  • Regulation of Krebs CycleFlux through KC increases during exercise3 non-equilibrium enzymes inhibited by NADHKC tightly coupled to ETCIf NADH decreases due to increased oxidation in ETC flux through KC increasesIsocitrate dehydrogenase and -ketoglutarate dehydrogenase also stimulated by Ca2+Flux increases as contractile activity increases

  • *****Figure 13.3Citric acid cycle. For each acetyl group that enters the pathway, two molecules of CO2 are released, the mobile coenzymes NAD+ and ubiquinone (Q) are reduced, one molecule of GDP (or ADP) is phosphorylated, and the acceptor molecule (oxaloacetate) is re-formed.*Figure 13.3Citric acid cycle. For each acetyl group that enters the pathway, two molecules of CO2 are released, the mobile coenzymes NAD+ and ubiquinone (Q) are reduced, one molecule of GDP (or ADP) is phosphorylated, and the acceptor molecule (oxaloacetate) is re-formed.*Figure 13.3Citric acid cycle. For each acetyl group that enters the pathway, two molecules of CO2 are released, the mobile coenzymes NAD+ and u

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