Compounds that are non-competitive inhibitors bind to the enzyme—substrate complex, rather than to the enzyme itself. The enzyme—substrate—inhibitor complex reacts only slowly to form enzyme—product—inhibitor, so the effect of a non-competitive inhibitor is to slow down the rate at which the enzyme catalyses the formation of product. The reaction sequence can be written as:
Enz + S + I ^ Enz-S + I ^ Enz-S-I ^ Enz-P-I ^ Enz + P + I
Because there is no competition between the inhibitor and the substrate for binding to the enzyme, increasing the concentration of substrate has no effect on the activity of the enzyme in the presence of a non-competitive inhibitor. The Km of the enzyme is unaffected by a non-competitive inhibitor, but the Vmax is reduced. Figure 2.13 shows the s/v and double-reciprocal plots for an enzyme incubated with several concentrations of a non-competitive inhibitor.
A non-competitive inhibitor would be the choice for use as a drug when the aim is either to increase the concentration of substrate in the cell or to reduce the rate at which the product is formed, as, unlike a competitive inhibitor, the accumulation of substrate has no effect on the extent of inhibition.
Although most enzymes are proteins, many contain small non-protein molecules as an integral part of their structure. These may be organic compounds or metal ions. In either case, they are essential to the function of the enzyme, and the enzyme has no activity in the absence of the metal ion or coenzyme.
When an organic compound or metal ion is covalently bound to the active site of the enzyme it is usually referred to as a prosthetic group; compounds that are tightly
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Figure 2.13 Substrate/velocity and Lineweaver—Burk double-reciprocal plots for an enzyme incubated with varying concentrations of a non-competitive inhibitor.
but not covalently bound are referred to as coenzymes. Like the enzyme itself, the coenzyme or prosthetic group participates in the reaction, but at the end emerges unchanged. Sometimes the coenzyme is chemically modified in the reaction with the first substrate, then restored to its original state by reaction with the second substrate. This would be a ping-pong reaction (section 220.127.116.11); transaminases (section 18.104.22.168) catalyse a ping-pong reaction in which the amino group from the first substrate forms an amino derivative of the coenzyme as an intermediate step in the reaction.
Some compounds that were historically considered as coenzymes do not remain bound to the active site of the enzyme, but bind and leave in the same way as other substrates. Such compounds include the nicotinamide nucleotide coenzymes (NAD and NADP) and coenzyme A. Although they are not really coenzymes, they are present in the cell in very much smaller concentrations than most substrates, and are involved in a relatively large number of reactions, so that they turn over rapidly.
Table 2.1 shows the major coenzymes, the vitamins they are derived from and their principal metabolic functions.
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