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Lecture 7

BIOL 200 Lecture Notes - Lecture 7: Thiol, Phenyl Group, Threonine

Biology (Sci)
Course Code
BIOL 200
Mathieu Roy

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Traditionally reversible enzyme inhibitors have been classified as competitive, uncompetitive, or
non-competitive, according to their effects on Km and Vmax. These different effects result from
the inhibitor binding to the enzyme E, to the enzymesubstrate complex ES, or to both,
respectively. The division of these classes arises from a problem in their derivation and results in
the need to use two different binding constants for one binding event. The binding of an inhibitor
and its effect on the enzymatic activity are two distinctly different things, another problem the
traditional equations fail to acknowledge. In noncompetitive inhibition the binding of the
inhibitor results in 100% inhibition of the enzyme only, and fails to consider the possibility of
anything in between. [7] The common form of the inhibitory term also obscures the relationship
between the inhibitor binding to the enzyme and its relationship to any other binding term be it
the MichaelisMenten equation or a dose response curve associated with ligand receptor binding.
To demonstrate the relationship the following rearrangement can be made:
The mechanism of partially competitive inhibition is similar to that of non-competitive, except
that the EIS complex has catalytic activity, which may be lower or even higher (partially
competitive activation) than that of the enzymesubstrate (ES) complex. This inhibition typically
displays a lower Vmax, but an unaffected Km value. Uncompetitive inhibition occurs when the
inhibitor binds only to the enzymesubstrate complex, not to the free enzyme; the EIS complex
is catalytically inactive. This mode of inhibition is rare and causes a decrease in both Vmaxand
the Km valueSubstrate and product inhibition is where either the substrate or product of an
enzyme reaction inhibit the enzyme's activity. This inhibition may follow the competitive,
uncompetitive or mixed patterns. In substrate inhibition there is a progressive decrease in activity
at high substrate concentrations. This may indicate the existence of two substrate-binding sites in
the enzyme. At low substrate, the high-affinity site is occupied and normal kinetics are followed.
However, at higher concentrations, the second inhibitory site becomes occupied, inhibiting the
enzyme. Product inhibition is often a regulatory feature in metabolism and can be a form
of negative feedback.Slow-tight inhibition occurs when the initial enzymeinhibitor complex EI
undergoes isomerisation to a second more tightly held complex, EI*, but the overall inhibition
process is reversible. This manifests itself as slowly increasing enzyme inhibition. Under these
conditions, traditional MichaelisMenten kinetics give a false value for Ki, which is time
dependent. The true value of Ki can be obtained through more complex analysis of the on (kon)
and off (koff) rate constants for inhibitor association. See irreversible inhibition below for more
As enzymes have evolved to bind their substrates tightly, and most reversible inhibitors bind in
the active site of enzymes, it is unsurprising that some of these inhibitors are strikingly similar in
structure to the substrates of their targets. An example of these substrate mimics are the protease
inhibitors, a very successful class of antiretroviral drugsused to treat HIV. The structure
of ritonavir, a protease inhibitor based on a peptide and containing three peptide bonds, is shown
on the right. As this drug resembles the protein that is the substrate of the HIV protease, it
competes with this substrate in the enzyme's active site.Enzyme inhibitors are often designed to
mimic the transition state or intermediate of an enzyme-catalyzed reaction. This ensures that the
inhibitor exploits the transition state stabilising effect of the enzyme, resulting in a better binding
affinity (lower Ki) than substrate-based designs. An example of such a transition state inhibitor is
the antiviral drug oseltamivir; this drug mimics the planar nature of the ring oxonium ion in the
reaction of the viral enzyme neuraminidase
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