ENZYME INHIBITION

Enzyme Inhibition

Enzyme inhibitors are the agents that interfere with the catalysis and slow down or even halt the reactions. There are 2 broad classes of enzyme inhibitors:

1.      Reversible

2.      Irreversible

Reversible inhibition: is characterized by a rapid dissociation of the enzyme inhibitor complex. Reversible inhibition can be:

Ø  Competitive

Ø  Uncompetitive

Ø  Mixed / non competitive

Competitive Inhibition: In this type of inhibition a competitive inhibitor competes with the substrate for an active site of enzyme; as a result inhibitor occupies the active site and prevents the interaction of substrate with the enzyme. The competitive inhibitors are the compounds having similarity with substrate and thus they combine with enzyme to form EI (enzyme inhibitor) complex.

This theory can be better justified by the example in case of medical science; in which the therapy is based upon the competition at the active site and is used to treat patients who ingest a solvent, methanol which is usually found in the gas line antifreeze. The enzyme alcohol dehydrogenase found in our liver converts methanol to formaldehyde and results in damage to the tissues and in severe cases it causes blindness. The reason behind this blindness is that eyes are quite sensitive to formaldehyde.

The medical therapy here is to give intravenous infusion of ethanol to the patients because ethanol competes effectively with the methanol as an alternative substrate for the enzyme alcohol dehydrogenase. In other words ethanol acts as a competitive inhibitor to ethanol and the effect of ethanol can be nullified as its concentration decrease over time as the dehydrogenase enzyme converts ethanol into acetaldehyde. So intravenous infusion should be given at a rate that maintains a controlled concentration in the blood stream for several hours. This will slow down the production of formaldehyde and ultimately kidneys will excrete out the methanol harmlessly in the urine.

Uncompetitive inhibition: can be distinguished by the fact that inhibitor binds only to the enzyme substrate complex. This type of inhibition cannot be overcome by addition of more substrates.

E + S              ES                   E + P

                        +

                        I

                   

                       

                  ESI complex

UNCOMPETITIVE INHIBITION

Mixed inhibition: the inhibitor will bind at a site distinct from the substrate active site but it will bind to either ES or E

Non competitive inhibition: the inhibitor and substrate can bind simultaneously to an enzyme molecule at different binding sites. This inhibition cannot be overcome by increasing the substrate concentration.

Both mixed and uncompetitive can be observed only for the enzymes with 2 or more substrates.

Irreversible inhibition: here the inhibitors will covalently bind to the enzyme and provides an alternative approach: they will modify the functional groups which can then be identified. Basically irreversible inhibition is important to determine what functional groups are required for enzymic activity and X-ray crystallography is the best approach. Irreversible inhibitors can be divided into 2 categories:

Suicide inhibitors: which are modified substrates that provide the most specific means to modify an enzyme active site. The inhibitors bind to the enzyme as substrates. The catalytic mechanism then generates intermediate that inactivates the enzyme through covalent modification. The fact that enzyme participates in its own irreversible inhibition; that’s why it is called as suicide inhibitor.

Affinity labels: are molecules that are structurally similar to the substrates for the enzyme and that covalently bind to the active site residues. Thus they are specific for the enzyme active site.