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Chapter 3. DRUG TARGETS: ENZYMES. Naming enzymes. Root + ase ClassificationReaction Type Catalyzed Oxidoreductases Oxidation Reduction Reactions Transferases Group transfer Reactions Hydrolases Hydrolysis Reactions Lyases Addition or removal of groups to form double bonds - PowerPoint PPT Presentation
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ch 3
DRUG TARGETS: ENZYMESChapter 3 Naming enzymes Root + ase
ClassificationReaction Type CatalyzedOxidoreductasesOxidation Reduction ReactionsTransferasesGroup transfer ReactionsHydrolasesHydrolysis ReactionsLyasesAddition or removal of groups to form double bondsIsomerasesIntramolecular group transfersLigasesJoining two substrates
Structure and function of enzymes Globular proteins acting as the bodys catalysts Speed up time for reaction to reach equilibrium Lower the activation energy of a reaction
Example:LDH = Lactate dehydrogenase (enzyme)NADH2 = Nicotinamide adenosine dinucleotide (reducing agent & cofactor)Pyruvic acid = Substrate
Lowering the activation energy of reaction Structure and function of enzymesAct. energyTransition stateWITHOUT ENZYMEProductStartingmaterialEnergy
WITH ENZYMEProductStartingmaterialEnergyG
Newtransition stateGAct. energyEnzymes lower the activation energy of a reaction but DG remains the same
Methods of enzyme catalysis Provides a reaction surface (the active site)
Provides a suitable environment (hydrophobic)
Brings reactants together
Positions reactants correctly for reaction
Weakens bonds in the reactants
Provides acid / base catalysis
Provides nucleophilic groups Structure and function of enzymes The active site Hydrophobic hollow or cleft on the enzyme surface
Accepts reactants (substrates and cofactors)
Contains amino acids which:- bind reactants (substrates and cofactors)- catalyse the reactionENZYMEActive siteActive site Substrate binding Active site is nearly the correct shape for the substrate Binding alters the shape of the enzyme (induced fit) Binding strains bonds in the substrate Binding involves intermolecular bonds between functional groups in the substrate and functional groups in the active site Induced fitInduced fitSubstrate
S Substrate binding Ionic H-bonding van der Waals
Bonding forcesExample
SEnzymeActive sitevdwinteractionionicbondH-bondPhe
SerOH
AspCO2
Substrate binding Ionic H-bonding van der Waals
Bonding forcesExample - Binding of pyruvic acid in LDHH-BondPossible interactionsvdw-interactionsOHH3N
Ionic bondH-Bond
van der Waals
Ionic
Substrate binding Induced fit - Active site alters shape to maximise intermolecularbonding Bonding forcesIntermolecular bonds not optimum length for maximum bonding
Intermolecular bond lengths optimisedSusceptible bonds in substrate strainedSusceptible bonds in substrate more easily broken
SPhe
SerOH
AspCO2
Induced fitSPhe
SerOH
AspCO2
Substrate bindingExample - Binding of pyruvic acid in LDHOHH3N
OOO Substrate bindingExample - Binding of pyruvic acid in LDHOHH3N
p bondweakened
Catalysis mechanismsHistidine
Acid/base catalysisNucleophilic residues
Non-ionizedActs as a basic catalyst(proton 'sink')IonizedActs as an acid catalyst(proton source)
L-Serine
L-Cysteine Catalysis mechanismsOHSer
H2OOHSerHO
Serine acting as a nucleophile Catalysis mechanismsMechanism for chymotrypsin to hydrolyses peptide bondsCatalytic triad of serine, histidine and aspartateChymotrypsinNNOHHOOSerHisAsp..::Catalysis mechanismsMechanism for chymotrypsinProteinNHCOProtein::ChymotrypsinNNOHHOOSerHisAsp..:: Catalysis mechanismsMechanism for chymotrypsin
ChymotrypsinNNHHOOSerHisAsp:: Catalysis mechanismsMechanism for chymotrypsin
ChymotrypsinNHOOSerHisAsp:: Catalysis mechanismsMechanism for chymotrypsin
ChymotrypsinNNHOOSerHisAsp::: Catalysis mechanismsMechanism for chymotrypsin
ChymotrypsinNNHOOSerHisAsp::: Catalysis mechanismsMechanism for chymotrypsin
ChymotrypsinNHOOSerHisAsp:: Catalysis mechanismsMechanism for chymotrypsin
ChymotrypsinNNOHHOOSerHisAsp..:: Catalysis mechanismsMechanism for chymotrypsin
Overall process of enzyme catalysisSE
ESPE
EP
PEE + PESE + SE Binding interactions must be strong enough to hold the substrate sufficiently long for the reaction to occur Interactions must be weak enough to allow the product to depart Implies a fine balance Designing molecules with stronger binding interactions results in enzyme inhibitors which block the active site Regulation of enzymes Many enzymes are regulated by agents within the cell Regulation may enhance or inhibit the enzyme The products of some enzymes may act as inhibitors Usually bind to a binding site called an allosteric binding siteExample
ACTIVE SITE (open)ENZYMEEnzymeRegulation of enzymes Inhibitor binds reversibly to an allosteric binding site Intermolecular bonds are formed Induced fit alters the shape of the enzyme Active site is distorted and is not recognised by the substrate Increasing substrate concentration does not reverse inhibition Inhibitor is not similar in structure to the substrateAllostericbinding siteActive site (open)ENZYMEEnzyme
InducedfitActive siteunrecognisableAllostericinhibitor Regulation of enzymes Enzymes with allosteric sites are often at the start of a biosynthetic pathway Enzyme is controlled by the final product of the pathway Final product binds to the allosteric site and switches off enzyme
PPP
Biosynthetic pathwayFeedback controlInhibitionPS
(open)ENZYMEEnzymeProteinkinaseCell Regulation of enzymes External signals can regulate the activity of enzymes (e.g. neurotransmitters or hormones) Chemical messenger initiates a signal cascade which activates enzymes called protein kinases Protein kinases phosphorylate target enzymes to affect activity
Example
AdrenalineSignal cascade
Phosphorylase b (inactive)Phosphorylase a (active)
Glycogen
Glucose-1-phosphate
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