Enzymes 2014 class
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Transcript of Enzymes 2014 class
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Enzyme Inhibitors
Routes to Rational Drug Design
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Topics For Discussion
What are Enzymes
How do Enzymes work
How do we study enzymes
What are Enzyme Inhibitors
How does understanding how an enzyme works allow the rational design of drugs
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What Are Enzymes
• Protein
• Catalyst
• Responsible for nearly all of the chemical reactions that take place in a living cell
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What is a Catalyst
• Accelerate the rate of a chemical reaction
• Are not consumed by the reaction
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Rates of Chemical Reaction
• What determines the rate of a chemical reaction?
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Reaction Rates
• First… what determines if a reaction goes at all?
• Must consider the ΔG for the reaction
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Reaction Coordinate
Gib
bs
Fre
e E
ne
rgy
Conversion of S to P
S
P
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Reaction Direction
• Reactions only proceed spontaneously in the direction given if the ∆G is negative
• But just because the reaction is spontaneous, doesn’t mean that it goes at any measurable rate
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Transition State Theory
• Consider the conversion of S to P• -dS/dt = k[S]• Transition state theory proposes that in the
[S] there is a distribution of energetic forms and one such form is referred to as the transition state between S and P.
• The reaction only proceeds through this form
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Transition State Theory
• So that the rate of the reaction really is
-dS/dt = k[S*] where S* is the transition state.
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[S*]
• So how much [S*] is present
K* = [S*]/[S] where K* is the equilibrium constant between the transition state and the ground state
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Transition State Concentration• So one can express the [S*] as a function of
the K* and the [S] [S*] = K*[S]
• And since ΔG* = -RTlnK*• [S*] = e- ΔG*/RT [S]• And therefore the rate of the reaction would
be -d[S]/dt = ke- ΔG*/RT [S]• The term in red is the rate constant for the
reaction.
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• G = free energy at any moment
• G0 = standard-state free energy
• R = ideal gas constant = 8.314 J/mol-K
• T = temperature (Kelvin)
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Reaction Rate
• Therefore the magnitude of the ∆G* determines the rate of the reaction
• The lower this value is the faster the reaction goes
• Therefore, for an enzyme to catalyze a reaction it must lower the transitions state free energy (transition state activation energy)
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Consider this Reaction
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Why does the reaction go slowly?
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What Could Help the Reaction Go Faster
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What Else Could Make It Go Faster
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But High Acid Concentrations are not “Biological”
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Where Do These General Acids/General Bases and
Electrostatic Groups Come From
Proteins are linear polymers of amino acids
Some of the Amino Acids have side chains with functional groups.
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Another Way to Accelerate a Reaction
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Covalent Nucleophilic Catalysis
The reaction mechanism has changed
Forms a covalent intermediate
But at the end the reaction is the same
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How Enzymes Catalyze Reactions
• General acid/general base
• Electrostatic
• Change the reaction mechanism
• Proximity and orientation effects
• Entropy considerations
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How Do We Study Enzymes
Enzyme Kinetics
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Enzymatic Reactions
• Enzyme = E
• Substrate = S
• Product = P
• Velocity = ΔP/ ΔT (where T = time)
E + S → P
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Michaelis Menten Equation
Also: 1/v = (Km + S)/Vmax(S)
or = Km/Vmax + 1/Vmax
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Inhibitors
• Why would you want to inhibit an enzyme
• What are the different kinds of enzyme inhibitors
• How can you know what kind of inhibitor a molecule is
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Competitive Inhibition
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Non-competitive Inhibition
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Uncompetitive Inhibition
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What Kind of Inhibition would this Compound Give?
• Competitive?
• Non-competitive?
• Un-competitive?
• Other?
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Transition State Analogues
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Saqinivir bound to HIV protease
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