Fundamentals of Medicinal Chemistry

Energy

Substrate

TS

Product

Reaction ordinate

E−S complex

E−P complex

TS 1

TS 2

TS 3

Uncatalysed reaction

energy changes

Enzyme catalysed

reaction energy

changes

Figure A7.1 The effect of an enzyme on the minimum energy pathway of a simple enzyme

catalysed reaction involving a single substrate. (TS¼transition state.) The heights of the energy

barriersts 1 ,ts 2 andts 3 will vary depending on which step in the enzyme controlled route is the

rate controlling step

The chemical activity of a cell must be controlled in order for the cell to

function correctly. Enzymes offer a means of controlling that activity in that

they can be switched from active to inactive states by changes induced in their

conformations. Compounds that modulate the action of enzymes and other

molecules by these conformational changes are known asregulators,modulators

oreffectors. These compounds may switch on (activators) or switch off (inhibi-

tors) an enzyme. They may be generally classified for convenience as either

compounds that covalently modify the enzyme or allosteric regulators. The

former type of regulation involves the attachment of a chemical group to the

enzyme by covalent bonding, which may either inactivate or activate an enzyme.

Allosteric control involves the reversible binding of a compound to an allos-

teric site referred to as aregulatory siteon the enzyme. These compounds may

be either one of the compounds involved in the metabolic pathway (feedback

regulators) or a compound that is not a product of the metabolic pathway. In

both cases, the binding usually results in conformational changes, which either

activate or deactivate the enzyme. Proenzymes also act as a form of enzyme

control.

254 APPENDIX 7 ENZYMES