Cooperative allosteric enzymes

Not all enzymes show the simple hyperbolic dependence of rate of reaction on substrate concentration shown in Figure 2.8. Some enzymes consist of several separate protein chains, each with an active site. In many such enzymes, the binding of substrate to one active site causes changes in the conformation not only of that active site, but of the whole multi-subunit array. This change in conformation affects the other active sites, altering the ease with which substrate can bind to the other active sites. This is cooperativity — the different subunits of the complete enzyme cooperate with each other. Because there is a change in the conformation (or shape) of the enzyme molecule, the phenomenon is also called allostericity (from the Greek for 'different shape'), and such enzymes are called allosteric enzymes.

Figure 2.11 shows the change in rate of reaction with increasing concentration of substrate for an enzyme that displays substrate cooperativity. At low concentrations of substrate, the enzyme has little activity. When one of the binding sites becomes occupied, this causes a conformational change in the enzyme and so increases the ease with which the other sites can bind substrate. Therefore, there is a steep increase in the rate of reaction with increasing concentration of substrate. Of course, once all the sites become saturated, the rate of reaction cannot increase any further with increasing concentration of substrate; the enzyme achieves its maximum rate of reaction.

Enzymes that display substrate cooperativity are often important in controlling the overall rate of metabolic pathways (section 10.2.1). Their rate of reaction is extremely sensitive to the concentration of substrate. Furthermore, this sensitivity can readily be modified by a variety of compounds that bind to specific regulator sites on the enzyme and affect its conformation, so affecting the conformation of all of the active sites of the multi-subunit complex, and either activating the enzyme at low concentrations of substrate by decreasing cooperativity or inhibiting it by increasing cooperativity.

Allosteric Enzyme Sigmoid

[substrate]

Figure 2.11 The substrate dependence of an enzyme showing subunit cooperativity — a sigmoid curve. For comparison the hyperbolic substrate dependence of an enzyme not showing substrate cooperativity is shown as a dotted line.

[substrate]

Figure 2.11 The substrate dependence of an enzyme showing subunit cooperativity — a sigmoid curve. For comparison the hyperbolic substrate dependence of an enzyme not showing substrate cooperativity is shown as a dotted line.

2.3.4 INHIBITION OF ENZYME ACTIVITY

Inhibition of the activity of key enzymes in metabolic pathways by end-products or other metabolic intermediates is an important part of metabolic integration and control (section 10.2). In addition, many of the drugs used to treat diseases are inhibitors of enzymes. Some act by inhibiting the patient's enzyme, so altering metabolic regulation; others act by preferentially inhibiting key enzymes in the bacteria or other organisms that are causing disease.

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