Enzymes allosteric binding

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

Figure 8.9 Allosteric enzymes. The binding of an activator stabilizes the enzyme in an active form while the binding of an inhibitor distorts the active site, causing a loss of activity.

Fig. 16.3 Non-competitive inhibitor changes the actiue site of enzyme cfter binding at allosteric site.

The regulation of ribonucleotide reductase is complex. The substrate-specificity and activity of the enzyme are controlled by two allosteric binding sites (a and b) in the R1 subunits. ATP and dATP increase or reduce the activity of the reductase by binding at site a. Other nucleotides interact with site b, and thereby alter the enzyme s specificity. 

Water-soluble peptide and amine hormones (insulin and epinephrine, for example) act extracellularly by binding to cell surface receptors that span the plasma membrane (Fig. 23-4). When the hormone binds to its extracellular domain, the receptor undergoes a conformational change analogous to that produced in an allosteric enzyme by binding of an effector molecule. The conformational change triggers the downstream effects of the hormone. 

Figure 9-13 (A) An enzyme with binding sites for allosteric inhibitor I and activator J. Conformer A binds inhibitor I strongly but has little affinity for activator J or for substrate S. Conformer B binds S and catalyzes its reaction. It also binds activator J whose presence tends to lock the enzyme in the "on" conformation B. Conformers A and B are designated T and R in the MWC model of Monod, Wyman, and Changeux.80 (B) Inhibited and activated dimeric enzymes.

It is also predicted that an allosteric inhibitor should bind noncooperatively to an enzyme that binds its substrates cooperatively, since the inhibitor binds to the predominant T state. The converse should be true for activators binding to multiple binding sites in the R state. 

Covalent modification requires an enzyme to control an enzyme. Allosterism requires only a binding site on an enzyme that interacts (via an equilibrium) with a particular small molecule. 

Allosteric binding can manifest itself in many ways, and feedback inhibition is just one example. Entire proteins can bind an allosteric site, and sometimes allosteric binding enhances an enzyme s activity. 

Two mechanisms that are commonly employed in altering enzyme activity are covalent modification and allosteric regulation. Covalent modification is an enzymatically catalyzed reaction that involves the reversible formation of a covalent bond between a small molecule and a specific amino acid side chain(s) on an enzyme that affects its activity. Allosteric regulation of an enzyme s activity involves noncovalent binding of a small molecule at a site other than the active site that alters the enzyme s activity. Unlike the limited examples of covalent modification that have been discovered (see Table 15-1), a wide variety of small molecules have been found to regulate the activity of particular enzymes allosterically. 

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