Enzyme Inhibition.

Introduction:

Enzymes are the organic biological catalysts, which speed up the rate of biochemical reactions without undergoing any change.
They are highly selective catalysts that greatly accelerate both the rate and specificity of metabolic reactions.
Many types of molecules exist which are capable of obstructing the activity of an individual enzyme.
An inhibitor is any molecule that acts directly on an enzyme to reduce its catalytic rate.
Some enzyme inhibitors are normal body metabolites that inhibit a particular enzyme while other inhibitors may be foreign substances, such as drugs or toxins.
The inhibition may be a part of the normal metabolic control of a pathway, a diseased condition or either a therapeutic measure.
The effect of enzyme inhibition could be either therapeutic or, at the other extreme, dangerous.
Enzyme inhibition is of two main types:

Irreversible inhibitors bind to the enzyme and inactivate it.
Inhibitors that bind irreversibly to an enzyme frequently form a covalent bond to an amino acid residue at or near the active site, inactivating the enzyme permanently.
Susceptible amino acid residues include Ser and Cys residues which have reactive –OH and –SH groups, respectively.
Some nonspecific inhibitors may cause physical or chemical change to the enzyme structure e.g. denaturation.
e.g

Organophosphorus compounds (Insecticides), covalently bond the active site of the enzyme acetylcholinesterase, irreversibly inhibiting the enzyme.
Penicillin inhibits the glycopeptide transpeptidase enzyme, which forms cross-links in the bacterial cell wall, irreversibly by covalently attaching to a “Ser” residue in the enzyme's active site.

Reversible inhibition can be overcome by removing the inhibitor from the enzyme.
Reversible enzyme inhibitors can be classified as either competitive or noncompetitive, and can be distinguished via a Lineweaver–Burk plot.

Competitive inhibitors compete with the substrate for the active site of the enzyme and form an enzyme–substrate complex.
A competitive inhibitor typically has close structural similarities to the normal substrate for the enzyme. Thus it competes with substrate molecules to bind to the active site.
As the enzyme can bind either a substrate or an inhibitor, but not both at the same time; binding to the inhibitor inhibits its activity.
The competitive inhibitor binds reversibly to the active site.
At high substrate concentrations the action of a competitive inhibitor is reversed because a sufficiently high substrate concentration will successfully compete out the inhibitor molecule in binding to the active site.
Many drugs work by mimicking the structure of the substrate of a target enzyme, and hence act as competitive inhibitors of the enzyme.

Non- competitive inhibitors bind to the enzyme or the enzyme–substrate complex at a site different from the active site, hence decreasing the activity of the enzyme.
A noncompetitive inhibitor binds reversibly at a site other than the active site and causes a change in the overall 3-D shape of the enzyme that leads to a decrease in the activity.
Since the inhibitor binds at a different site from the substrate, the enzyme may bind the inhibitor, the substrate or both the inhibitor and substrate together.
The effects of a non-competitive inhibitor cannot be overcome by increasing the substrate concentration, so there is a decrease in Vmax.