Drug Targets - 2

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  • Created by: LBCW0502
  • Created on: 26-09-19 09:38
Describe the structure and function of enzymes (1)
Proteins act as the body's catalyst. Speed up time for reaction to reach equilibrium. Lower activation energy of a reaction. Structure - made up of amino acids (COOH, NH2, H and variable group, peptide bonds CONH)
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Describe the structure and function of enzymes (2)
E.g. pyruvate converted to lactate using NADH as a reducing agent and lactate dehydrogenase enzyme
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How do enzymes appear to make reactions go only one way in biochemistry if they just make equilibrium happen faster?
A, B, C, D and E are equilibrium. If E was removed from equilibrium (insoluble macromolecule, excreted from cell), then the process will become linear
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What is the function of enzymes?
Lowers the activation energy of a reaction (but delta G remains the same). Kinetic (not thermodynamic) effect
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What is the method of enzyme catalysis?
Provides a place for the chemical reaction (active site). Provides hydrophobic and polar binding opportunities for substrates. Bring reactants together in correct alignment for reaction. May weaken bonds in reactants. Provide acid/base catalysis
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Describe features of the active site (1)
Hollow or cleft on the enzyme surface (can be hydrophobic or polar or more likely have both polar/non-polar regions). Accepts reactants (substrates and cofactors)
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Describe features of the active site (2)
Contains amino acids with appropriate side chains that bind reactants (substrates and cofactors), catalyse the reaction
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Describe features of substrate binding - induced fit (1)
Active site is nearly the correct shape for the substrate. Binding alters shape of enzyme (induced fit). Binding will strain bonds in substrate
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Describe features of substrate binding - induced fit (2)
Binding involves intermolecular bonds between functional groups in the substrate and functional groups in the active site and hydrophobic interactions between enzyme and substrate
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What are the bonding forces involved in the substrate binding to the active site of an enzyme?
Ionic, H bonding, and van der Waals (e.g. binding of pyruvic acid in LDH
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Describe features of catalysis mechanisms (1)
Acid/base catalysis. Histidine, pKa 7, 50% ionised at physiological pH. Non-ionised (acts as basic catalyst, proton/sink). Ionised (acts as acid catalyst, proton/source). Nucleophilic residues (L-serine, L-cysteine, key residues, proteases).
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Describe features of catalysis mechanisms (2)
Serine can act as a nucleophile (catalytic mechanisms)
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How does an enzyme lower the activation energy of the transition state?
Protease enzyme hydrolyses amide bond in a peptide. Carbon of amide is sp2 hybridised (planar). Carbon of gem-diol is sp3 hybridised (tetrahedral). Transition state is similar to gem-diol intermediate. Groups bind/stabilise gem-diol (lower Ea)
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Describe features of transition state inhibitors (1)
Gem-diol stabilised by an interaction with an enzymic aspartate. Sp3 alcohol should bind with higher affinity to protease than the substrate (not stable structure in animal)
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Describe features of transition state inhibitors (2)
Changing N to C stabilises structure (basis of life-saving drugs e.g. HIV protease inhibitors class) - all transition state inhibitors. Position of amide carbonyl in peptide substrate. Interactions of hydroxy group with aspartates
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Describe features of transition state inhibitors (3)
E.g. saquinavir, nelfinavir, atazanavir, indinavir etc.
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What is the overall process of enzyme catalysis? (1)
E + S <-> ES <-> EP <-> E + P. Binding interactions must be strong enough to hold the substrate sufficient long for reaction occur and weak enough to allow product to depart. Implies fine balance
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What is the overall process of enzyme catalysis? (2)
Drug design - design molecules with stronger binding interactions and lacking reactive groups results in enzyme inhibitors which block the active site
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Describe features of competitive (reversible) inhibitors (1)
Inhibitor binds reversibly to the active site. Intermolecular bonds are involved in binding. No reaction occurs with the inhibitor. Inhibition depends on the strength of inhibitor binding and inhibitor concentration
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Describe features of competitive (reversible) inhibitors (2)
Substrate is blocked from active site. Increasing substrate concentration reverses inhibition. Inhibitor likely to be similar in structure to the substrate
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Give an example of a competitive (reversible) inhibitor
Inhibitor bonds adjacent to NADH, enzyme function blocked
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Describe features of non-competitive (irreversible) inhibitors
Inhibitor bonds irreversibly to the active site. Covalent bond formed between the drug and the enzyme. Substrate is blocked from the active site. Increasing substrate concentration doesn't reverse inhibition
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Give an example of a non-competitive (irreversible) inhibitor
Lysine methyl transferase inhibitor. Enamide moiety acids as a Michael acceptor for cysteine side chains (S). (Covalent inhibitors often have toxicity issues due to presence of reactive functionality like electrophiles)
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What is allostery? (1)
Spatially separate binding sites in a protein are functionally coupled so binding at one site influences binding at the other
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What is allostery? (2)
Binding at one site (allosteric site) changes the conformation of the protein so that binding at the other site (effector site) is decreased or increased). Biological function is to achieve greater control over biochemical pathways
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What are the four types of allostery? (1)
Allosteric inhibitors (reduce bind of enzyme substrate). Allosteric promoters (enhance binding of enzyme substrate). Allosteric inhibitors (reduce binding of natural agonist). Allosteric enhancers (enhance binding of natural agonists)
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What are the four types of allostery? (2)
Historically, allosteric ligands have been found by accident. Structural biology/computational chemistry is enabling rational discovery of new sites
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Describe features of non-competitive (reversible) allosteric inhibitors (1)
Inhibitor binds reversibly to the allosteric site. Intermolecular bonds formed. Induced fit alters enzyme shape. Active site distorted/not recognised by substrate. Increasing substrate concentration doesn't reverse inhibition
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Describe features of non-competitive (reversible) allosteric inhibitors (2)
Inhibitor not similar to substrate structure. Rare form of enzyme inhibition
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Give an example of an non-competitive allosteric inhibitor
Cathepsin K - cysteine protease overactive in arthritis. Enzyme inhibited
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Describe the structure and function of enzymes (2)

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E.g. pyruvate converted to lactate using NADH as a reducing agent and lactate dehydrogenase enzyme

Card 3

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How do enzymes appear to make reactions go only one way in biochemistry if they just make equilibrium happen faster?

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Card 4

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What is the function of enzymes?

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Card 5

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What is the method of enzyme catalysis?

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