Enzymes and Metabolism

Enzymes and MetabolismParts of Chapter 2, and 24Figure 2.11 Patterns of chemical reactions.

ExampleAmino acids are joined together toform a protein molecule. ExampleGlycogen is broken down to releaseglucose units. ExampleATP transfers its terminal phosphategroup to glucose to form glucose-phosphate.

Bonds are both made and broken(also called displacement reactions).

Bonds are broken in largermolecules, resulting in smaller,less complex molecules. (c) Exchange reactions(b) Decomposition reactions(a) Synthesis reactionsSmaller particles are bondedtogether to form larger,more complex molecules.Amino acidmoleculesProteinmoleculeGlucosemoleculesGlycogenGlucoseAdenosine triphosphate (ATP)Adenosine diphosphate (ADP)Glucosephosphate++

ExampleAmino acids are joined together toform a protein molecule. (a) Synthesis reactionsSmaller particles are bondedtogether to form larger,more complex molecules.Amino acidmoleculesProteinmolecule.

ExampleGlycogen is broken down to releaseglucose units. Bonds are broken in largermolecules, resulting in smaller,less complex molecules. (b) Decomposition reactionsGlucosemoleculesGlycogen.

ExampleATP transfers its terminal phosphategroup to glucose to form glucose-phosphate.Bonds are both made and broken(also called displacement reactions).(c) Exchange reactionsGlucoseAdenosine triphosphate (ATP)Adenosine diphosphate (ADP)Glucosephosphate++.

Secondary structure:The primary chain formsspirals (-helices) andsheets (-sheets).Tertiary structure:Superimposed on secondary structure.-Helices and/or -sheets are folded upto form a compact globular moleculeheld together by intramolecular bonds.Quaternary structure:Two or more polypeptide chains, eachwith its own tertiary structure, combineto form a functional protein.Tertiary structure of prealbumin(transthyretin), a protein thattransports the thyroid hormonethyroxine in serum and cerebro-spinal fluid.Quaternary structure of afunctional prealbumin molecule.Two identical prealbumin subunitsjoin head to tail to form the dimer.Amino acidAmino acidAmino acidAmino acidAmino acid

-Helix: The primary chain is coiledto form a spiral structure, which isstabilized by hydrogen bonds.

-Sheet: The primary chain zig-zags backand forth forming a pleated sheet. Adjacentstrands are held together by hydrogen bonds.(a) Primary structure: The sequence of amino acids forms the polypeptide chain.(b) (c) (d)Figure 2.19a Levels of protein structure.

(a) Primary structure: The sequence of amino acids forms the polypeptide chain.Amino acidAmino acidAmino acidAmino acidAmino acidFigure 2.19b Levels of protein structure.

a-Helix: The primary chain is coiledto form a spiral structure, which isstabilized by hydrogen bonds.b-Sheet: The primary chain zig-zags backand forth forming a pleated sheet. Adjacentstrands are held together by hydrogen bonds.(b) Secondary structure:The primary chain forms spirals (a-helices) and sheets (b-sheets)..

Tertiary structure of prealbumin(transthyretin), a protein thattransports the thyroid hormonethyroxine in serum and cerebro-spinal fluid.(c) Tertiary structure: Superimposed on secondary structure. a-Helices and/or b-sheets are folded up to form a compact globular molecule held together by intramolecular bonds..

Quaternary structure ofa functional prealbuminmolecule. Two identicalprealbumin subunitsjoin head to tail to formthe dimer.(d) Quaternary structure: Two or more polypeptide chains, each with its own tertiary structure, combine to form a functional protein.Figure 2.20 Enzymes lower the activation energy required for a reaction to proceed rapidly.

Activationenergy requiredLess activationenergy requiredWITHOUT ENZYMEWITH ENZYMEReactantsProductProductReactantsFigure 2.21 Mechanism of enzyme action.

Substrates (S)e.g., amino acidsEnzyme (E)Enzyme-substratecomplex (E-S)Enzyme (E)Product (P)e.g., dipeptideEnergy isabsorbed;bond isformed. Water isreleased.Peptidebond1 Substrates bind at active site. Enzyme changes shape to hold substrates in proper position.2 Internalrearrangements leading to catalysis occur.3 Product isreleased. Enzyme returns to original shape and is available to catalyze another reaction.Active site+.

Stage 1 Digestion in GI tract lumen to absorbable forms.Transport via blood totissue cells.Stage 2 Anabolism (incorporation into molecules) and catabolism of nutrients to form intermediates within tissue cells.Stage 3 Oxidative breakdown of products of stage 2 in mitochondria of tissue cells. CO2 is liberated, and H atoms removed are ultimately delivered to molecular oxygen, formingwater. Some energy released isused to form ATP.Catabolic reactionsAnabolic reactionsGlycogenPROTEINSProteinsFatsCARBOHYDRATESGlucoseFATSAmino acidsGlucose and other sugarsGlycerolFatty acidsPyruvic acidAcetyl CoAInfrequentCO2NH3HKrebscycle Oxidativephosphorylation(in electron transport chain)O2H2O

Via oxidativephosphorylationVia substrate-levelphosphorylationMitochondrionMitochondrialcristaeCytosolKrebscycleGlucoseGlycolysisPyruvicacidElectron transportchain and oxidativephosphorylationChemical energy (high-energy electrons)1 During glycolysis, each glucose molecule is broken down into two molecules of pyruvic acid in the cytosol.2 The pyruvic acid then enters the mitochondrial matrix, where the Krebs cycle decomposes it to CO2. During glycolysis and the Krebs cycle, small amounts of ATP are formed by substrate-level phosphorylation.3 Energy-rich electrons picked up bycoenzymes are transferred to the elec-tron transport chain, built into the cristae membrane. The electron transport chain carries out oxidative phosphorylation, which accounts for most of the ATP generated by cellular respiration.Chemical energy

To Krebscycle(aerobicpathway)22Glucose4 ADP2 Lactic acid2 Pyruvic acidPhase 1SugarActivationGlucose is activated by phosphorylationand converted to fructose-1, 6-bisphosphate Fructose-1,6-bisphosphateDihydroxyacetonephosphateGlyceraldehyde3-phosphatePhase 2SugarCleavageFructose-1, 6-bisphosphate is cleaved into two 3-carbon fragmentsPhase 3Sugar oxidationand formationof ATPThe 3-carbon frag-ments are oxidized (by removal of hydrogen) and 4 ATP molecules are formed2 ADPCarbon atomPhosphate2 NAD+2 NAD+NADH+H+NADH+H+GlycolysisElectron trans-port chain and oxidativephosphorylationKrebscycle

Krebs cycleNAD+NAD+GDP +NAD+FADNAD+NADH+H+CytosolMitochondrion(matrix)NADH+H+FADH2NADH+H+Citric acid(initial reactant)Isocitric acidOxaloacetic acid (pickup molecule)Malic acidSuccinic acidSuccinyl-CoAGTPADPCarbon atomInorganic phosphateCoenzyme A Acetyl CoAPyruvic acid from glycolysisTransitionalphaseFumaric acidNADH+H+CO2CO2CO2-Ketoglutaric acidElectron trans-port chain and oxidativephosphorylationGlycolysisKrebscycle

IntermembranespaceInnermitochondrialmembraneMitochondrialmatrixNADH + H+NAD+FAD(carryingfrom food)FADH2KrebscycleGlycolysisElectron transportchain and oxidativephosphorylationElectron Transport ChainChemiosmosisADP +2 H+ +Electrons are transferred from complex to complex and some of their energy is used to pump protons (H+) into the intermembrane space, creating a proton gradient.ATP synthesis is powered by the flow of H+ back across the inner mitochondrial membrane through ATP synthase.ATPsynthase12

GlycolysisKrebscycleElectron trans-port chain and oxidativephosphorylationEnzymeComplex IEnzymeComplex IIIEnzymeComplex IVEnzymeComplex IINADH+H+FADH2Free energy relative to O2 (kcal/mol)Figure 24.12 Energy yield during cellular respiration.

MitochondrionCytosol2AcetylCoAElectron transportchain and oxidativephosphorylationGlucoseGlycolysisPyruvicacidNet +2 ATPby substrate-levelphosphorylation+ about 28 ATPby oxidativephosphorylation+2 ATPby substrate-levelphosphorylationElectronshuttle across mitochondrialmembraneKrebscycle(4 ATP2 ATPused foractivationenergy)2 NADH + H+2 NADH + H+6 NADH + H+2 FADH2About32 ATPMaximumATP yieldper glucose10 NADH + H+ x 2.5 ATP2 FADH2 x 1.5 ATPFigure 24.15 Metabolism of triglycerides.

ElectrontransportCholesterolStored fatsin adiposetissueDietary fatsGlycerolGlycolysisGlucoseGlyceraldehydephosphatePyruvic acidAcetyl CoACO2 + H2O+SteroidsBile saltsFatty acidsKetonebodiesTriglycerides(neutral fats)CertainaminoacidsKetogenesis (in liver)Catabolic reactionsAnabolic reactionsLipogenesisKrebscycle bFigure 24.16 Transamination, oxidative deamination, and keto acid modification: processes that occur when amino acids are utilized for energy.

Krebscycle OxidativedeaminationTransaminationAmino acid + Keto acid(a-keto-glutaric acid)Keto acid + Amino acid (glutamic acid)Keto acidmodificationModifiedketo acidEnter Krebscycle in body cellsLiverKidneyBlood During transamination an amine group is switched from an amino acid to a keto acid. During ketoacid modification the keto acids formed during transamination are altered so they can easily enter the Krebs cycle pathways.NH3 (ammonia)UreaUrea In oxidative deamination, the amine group of glutamic acid is removed as ammonia and combined with CO2to form urea. CO2123Excreted in urineFigure 24.18 Interconversion of carbohydrates, fats, and proteins.

ProteinsProteinsCarbohydratesFatsExcretedin urineGlycogenGlucoseGlucose-6-phosphateGlyceraldehyde phosphatePyruvic acidAcetyl CoAAmino acidsKeto acidsTriglycerides (neutral fats)Lactic acidKetonebodiesGlycerol and fatty acidsNH3Krebscycle UreaFigure 24.17 Carbohydrate-fat and amino acid pools.

Pool ofcarbohydrates and fats(carbohydrates fats)Dietary proteinsand amino acidsFood intakeSome lost via cellsloughing, hair lossExcretedin urine Some lost via surfacesecretion, cell sloughingExcretedvia lungs Dietary carbohydratesand lipidsUreaComponentsof structural and functionalproteinsNitrogen-containingderivatives(e.g., hormones,neurotransmitters)Structuralcomponents of cells (membranes,etc.)Specialized derivatives(e.g., steroids, acetylcholine); bile saltsCatabolizedfor energyStorageformsPool of freeamino acidsNH3CO2Figure 24.19a Major events and principal metabolic pathways of the absorptive state.

(a) Major events of the absorptive stateMajor energy fuel:glucose (dietary)Liver metabolism:amino acids deaminated and used for energy or stored as fatMajor metabolic thrust:anabolism and energy storageAminoacidsProteinsGlycogenGlucoseGlucoseAmino acidsKeto acidsFatsCO2 + H2O +TriglyceridesGlycerol andfatty acidsCO2 + H2O+

(b) Principal pathways of the absorptive stateAmino acidsProteinKetoacidsFatsFatsFatsGlucoseGlycogenGlycogenProteinGlucoseGlucoseGastrointestinaltractIn liver:In all tissues:In adiposetissue:GlucoseFattyacidsFattyacidsGlyceraldehyde-phosphateGlycerolGlycerolFattyacidsIn muscle:CO2 + H2O+CO2 + H2O+

StimulatesTargets tissue cells Beta cells ofpancreatic isletsBlood glucoseBlood insulinActive transportof amino acidsinto tissue cellsFacilitated diffusionof glucose intotissue cells Protein synthesisCellularrespirationEnhances glucoseconversion to:CO2 + H2O+ Fatty acids+glycerolGlycogenInitial stimulusPhysiological responseResultFigure 24.20 Insulin directs nearly all events of the absorptive state.26Figure 24.21a Major events and principal metabolic pathways of the postabsorptive state.

(a) Major events of the postabsorptive stateMajor energy fuels:glucose provided by glycogenolysis and gluconeogenesis, fatty acids, and ketonesLiver metabolism:amino acids converted to glucoseMajor metabolic thrust:catabolism and replacement of fuels in bloodAminoacidsProteinsGlycogenGlucoseFatty acidsand ketonesGlucoseAmino acidsKeto acidsGlucoseTriglyceridesGlycerol andfatty acidsCO2 + H2O+

(b) Principal pathways of the postabsorptive stateAmino acidsAmino acidsFatty acidsGlycerolFattyacids +glycerolKetonebodiesBlood glucoseGlucoseKetoacidsKeto acidsStoredglycogenGlycogenProteinPyruvic andlactic acidsFatFatPyruvic andlactic acidsIn nervoustissue:In liver:In most tissues:In adipose tissue:In muscle:CO2 + H2O+CO2 + H2O+CO2 + H2O+CO2 + H2O+1222333444Figure 24.21b Major events and principal metabolic pathways of the postabsorptive state.28

Plasma glucose(and rising amino acid levels)StimulatesPlasma glucagonPlasma fatty acidsLiverAlpha cells ofpancreatic isletsStimulatesglycogenolysisand gluconeogenesisNegative feedback:rising glucose levels shut off initial stimulusStimulatesfat breakdownReduces, inhibitsIncreases, stimulatesAdipose tissueInitial stimulusPhysiological responseResultFat used by tissue cells= glucose sparingPlasma glucose(and insulin)Figure 24.22 Glucagon is a hyperglycemic hormone that stimulates a rise in blood glucose levels.29Table 24.4 Thumbnail Summary of Metabolic Reactions

30Table 24.5 Profiles of the Major Body Organs in Fuel Metabolism

31Table 24.6 Summary of Normal Hormonal Influences on Metabolism

32Table 24.7 Summary of Metabolic Functions of the Liver (1 of 2)

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Table 24.7 Summary of Metabolic Functions of the Liver (2 of 2)34