Principles of Biochemistry

8.2.3.6.2. Noncompetitive inhibitor

A non-competitive inhibitor doesn't attach itself to the active site, but attaches somewhere else on the enzyme. By attaching somewhere else it affects the structure of the enzyme and so the way the enzyme works. Because there isn't any competition involved between the inhibitor and the substrate, increasing the substrate concentration won't help. Non competitive inhibitors bind reversibly to both the free enzyme and the ES complex to form the inactive complex El and ESI:

E + I ↔ EI

ES + I ↔ ESI

The inhibitor doesn't affect the ability of the substrate to bond with the active site, but stops it reacting once it is there. The inhibitor causes the shape of the active sit. The inhibitor attaches to a side group in the protein chain, and affects the way the protein folds into its tertiary structure. That in turn changes the shape of the active site. If the shape of the active site changes the substrate can't attach to it any more. Some non-competitive inhibitors attach irreversibly to the enzyme, and therefore stop it working permanently. Others attach reversibly.

e.g Heavy metal poisoning

Compounds containing heavy metals such as lead, mercury, copper or silver are poisonous. This is because ions of these metals are non-competitive inhibitors for several enzymes.Silver ions react with -SH groups in the side groups of cysteine residues in the protein chain:

There isn't enough electro negativity difference between silver and sulphur for a full ionic bond and so the bond can be considered as covalent. If the cysteine residue is somewhere on the protein chain which affects the way it folds into its tertiary structure, then altering this group could have an effect on the shape of the active site, and so stop the enzyme from working.The 2+ ions from, for example, mercury, copper or lead can behave similarly - also attaching themselves to the sulphur in place of the hydrogen.