Enzyme Inhibition

Enzyme inhibitors bind to enzymes and decrease their activity. Enzyme activators bind to enzymes and increase their activity. Molecules that decrease the catalytic activity of enzymes can come in various forms, including reversible or irreversible inhibition. Reversible inhibition can be competitive, non-competitive, or uncompetitive.

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Reversible Enzyme Inhibition

Competitive inhibitors

  • Competitive inhibition: Inhibitor resembles the substrate and thus competes with it for the binding site at the active center of the enzyme.
    • Inhibitor binds at the active center, blocking the substrate from interacting with the binding site.
    • Inhibitor can be overcome through an excess of the substrate; therefore, this inhibition is reversible.
    • Decreases affinity of the enzyme for the substrate
  • As affinity decreases, the Km value increases, since an increased substrate concentration is required to obtain the half-maximal velocity.
  • Vmax is not changed, however.
  • Changes in Michaelis-Menten curve:
    • The increase in Km will cause the curve to shift to the left of the graph.
    • The reaction will eventually reach Vmax but will require much higher substrate concentrations to do so.
    • The curve shifts to the left without changing the height of the curve.
  • Changes in Lineweaver-Burk plot:
    • The increase in Km will also lead to an increase in -1/Km, shifting the x-intercept to the left.
    • The lack of change in Vmax causes the y-intercept to remain unchanged. 
    • These changes cause the line to appear “more vertical” and to cross the original plot at the y-intercept.

Non-competitive inhibitors

  • Non-competitive inhibition: Inhibitor does not have a similar shape to the substrate because it binds to and inhibits the enzyme outside of the active center, usually at the allosteric site.
    • Substrate can thus continue to bind to the active center but is not converted due to the additional binding of the inhibitor.
    • Non-competitive inhibition can be reversible or irreversible.
    • Substrate excess does not displace the inhibitor.
  • The number of functional enzyme-substrate complexes decreases.
  • This decreases Vmax, while Km remains the same.
  • Changes in Michaelis-Menten curve:
    • Decreasing Vmax leads to a downward shift in the height of the curve.
    • Km remains the same, so the curve does not shift on the x-axis.
  • Changes in Lineweaver-Burk plot:
    • Decreasing the Vmax leads to an increase in 1/Vmax, causing the y-intercept to be higher.
    • Since Km does not change, the x-intercept of -1/Km will also remain the same.
    • These changes cause the curve to appear “more vertical” with the new line, creating a V shape with the original line, with the point at the x-intercept.

Uncompetitive inhibitors

  • Uncompetitive inhibition: rare form of enzyme inhibition characterized by specific binding at the enzyme-substrate complex
    • The inhibitor also binds outside the active center, but only if the enzyme-substrate complex is already formed.
    • The result is a reversible conformational change and thus inactivation of the enzyme.
    • Prevents release of the substrate from the binding site.
  • Km is reduced as the inhibitor makes the reaction favor the enzyme-substrate complex, creating an initial increase in reaction rate.
  • Vmax is also reduced as the enzyme is prevented from forming products.
  • Changes in Michaelis-Menten curve:
    • Decreasing Km leads to a slight right shift in the curve.
    • Decreasing Vmax leads to a downward shift in the height of the curve.
  • Changes in Lineweaver-Burk plot:
    • Decreasing Km causes -1/Km to also decrease and shifts the x-intercept to the right.
    • Decreasing the Vmax leads to an increase in 1/Vmax, causing the y-intercept to be higher.
    • The line will shift to the right and appear parallel to and above the initial line.

Irreversible Enzyme Inhibition

Suicide inhibitors

  • Suicide inhibitors irreversibly bind to the active site of the enzyme via covalent binding.
  • Bind at the same site as competitive inhibitors, but have permanent results in a noncompetitive manner
  • Vmax drops to zero and no amount of substrate is allowed to bind.
  • Example: penicillin drugs acting on bacterial penicillin binding proteins

Allosteric Effects

  • Allosteric regulation: most common form of regulation; performed by allosteric ligand/effectors
  • Ligands bind outside the active center of the enzyme, namely at the allosteric center, leading to conformational change and activation or deactivation of the enzyme, depending on the substrate’s ability to fit the new shape.
  • In allosteric enzymes, 2 state forms can be distinguished:
    • The inactive T-form (tensed), stabilized by allosteric inhibitors
    • The active R-form (relaxed), stabilized by allosteric activators
  • Often, the substrate itself represents an allosteric activator and promotes the R-condition for its own implementation.
    • Positive cooperativity: The first substrate facilitates the binding of the second substrate.
    • Negative cooperativity: The binding of the first substrate complicates the binding of the second substrate.
  • Depending on the nature of the allosteric effector, Vmax, Km, or both values can be changed.
  • Allosteric regulation is most important for rate-limiting enzymes.
  • Changes in Michaelis-Menten curve:
    • Allosteric enzymes have a sigmoidal curve when plotted in this way.
    • Km values are usually significantly higher for allosteric enzymes.
    • Allosteric inhibitors move the reaction toward the right side of the curve.
    • Allosteric activators move the reaction toward the left side of the curve.
  • Changes in Lineweaver-Burk plot with activation: 
    • Activation can increase V0 of the reaction leading to a decrease in 1/Vmax and causing a downward shift of the y-intercept.
    • Activation can also lead to a decrease in Km and therefore a decrease in -1/Km, causing the x-intercept to shift to the right.
    • Either way, the new line will appear “more horizontal” compared with the original line.

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