Allosteric modulator examples

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Allosteric regulatory molecules are small molecular weight compounds which may be coenzymes (NAD+, ATP, etc.) or intermediate substrates, possibly generated by enzymes found within the same pathway as the regulated enzyme. Alternatively, the allosteric modulator may be generated within another, perhaps complementary, pathway. For example, a regulator may be stimulatory for a catabolic route and at the same time inhibitory for the opposing anabolic pathway. 

The most responsive regulation of amino acid synthesis takes place through feedback inhibition of the first reaction in a sequence by the end product of the pathway. This first reaction is usually irreversible and catalyzed by an allosteric enzyme. As an example, Figure 22-21 shows the allosteric regulation of isoleucine synthesis from threonine (detailed in Fig. 22-15). The end product, isoleucine, is an allosteric inhibitor of the first reaction in the sequence. In bacteria, such allosteric modulation of amino acid synthesis occurs as a minute-to-minute response. 

An example of negative allosteric modulation is the case of the antidepressants, which act as neurotransmitter reuptake blockers for the neurotransmitters norepinephrine and serotonin. This has already been discussed in Chapter 2. When the neurotransmitters norepinephrine and serotonin bind to their own selective receptor sites, they are normally transported back into the presynaptic neuron, as shown in Figure 2-23- Thus the empty reuptake carrier (Fig. 2—20) binds to the neurotransmitter (Fig. 2—21) to begin the transport process (Fig. 2—23). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter (represented as an icon in Figs. 2—22 and 2—24), this causes the neurotransmitter to no longer be able to bind there, thereby blocking synaptic re-... 

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