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Binding of inhibitors

In this chapter we described the thermodynamics of enzyme-inhibitor interactions and defined three potential modes of reversible binding of inhibitors to enzyme molecules. Competitive inhibitors bind to the free enzyme form in direct competition with substrate molecules. Noncompetitive inhibitors bind to both the free enzyme and to the ES complex or subsequent enzyme forms that are populated during catalysis. Uncompetitive inhibitors bind exclusively to the ES complex or to subsequent enzyme forms. We saw that one can distinguish among these inhibition modes by their effects on the apparent values of the steady state kinetic parameters Umax, Km, and VmdX/KM. We further saw that for bisubstrate reactions, the inhibition modality depends on the reaction mechanism used by the enzyme. Finally, we described how one may use the dissociation constant for inhibition (Kh o.K or both) to best evaluate the relative affinity of different inhibitors for ones target enzyme, and thus drive compound optimization through medicinal chemistry efforts. [Pg.80]

Most often the binding of inhibitors to enzymes is measured by their effects on the velocity of the enzyme catalyzed reaction. In the absence of inhibitor, the velocity is defined by the Michaelis-Menten equation (Chapter 2) ... [Pg.261]

Considerable use has been made of the thermodynamic perturbation and thermodynamic integration methods in biochemical modelling, calculating the relative Gibbs energies of binding of inhibitors of biological macromolecules (e.g. proteins) with the aid of suitable thermodynamic cycles. Some applications to materials are described by Alfe et al. [11]. [Pg.363]

In partial (hyperbohc) mixed inhibition (O Figure 4-12d), binding of inhibitor to a site distinct from the active site results in altered affinity of enzyme for substrate (by a factor, ot) as well as a change (by a factor, /i) in the rate at which product can be released from ESI. The effects of a partial mixed inhibitor on a Lineweaver-Burk plot depend upon the actual values, and on the relative values, of ot and fl. Once again, inhibitor plots can intersect the control plot above or below, but not on, the oeaxis, and to the left or to the right of, but not on, the y-axis. Because Vmax cannot be driven to zero, a maximum Lineweaver-Burk slope is reached at infinitely high inhibitor concentrations beyond which no further increase occurs. [Pg.123]

Irreversible inhibition should be more correctly termed difficult-to-reverse inhibition because any inhibition due to the binding of inhibitor molecules can be reversed theoretically by lowering the concentration of inhibitor to zero. The exceptions are some protease inhibitors (e.g. the serpins) since, once the inhibitor-enzyme complex is formed, it is destroyed by phagocytosis. It is, therefore, a specific form of irreversible inhibition (Box 3.4). [Pg.46]

This binding of inhibitor at allosteric site (Fig. 16.3) changes the shape of the active site in such a way that substrate cannot recognise it. [Pg.164]

Research in this field is ongoing aiming to understand the mechanism of action of kinetic inhibitors. Lee and Englezos (2005) showed that inclusion of polyethylene oxide (PEO) to a kinetic inhibitor solution was found to enhance by an order of magnitude the performance of the hydrate inhibitor. Binding of inhibitor molecules to the surface of hydrate crystals was considered to be the key aspect of the mechanism of kinetic inhibition (Anderson et al.,... [Pg.37]

The activity of eucaryotic transcriptional activators can be regulated by the binding of low molecular weight effectors, as well as by the binding of inhibitor proteins (see 1.3.2.3). The most significant example for transcriptional activators regulated by low molecular weight effectors are the nuclear receptors, which will be discussed in more detail in chapter 4. [Pg.59]

Regulation of Enzyme Activity by Binding of Inhibitor and Activator Proteins... [Pg.98]

If an inhibitor binds not only to free enzyme but also to the enzyme substrate complex ES, inhibition is noncompetitive. In this case, S and I do not mutually exclude each other and both can be bound to the enzyme at the same time. Why does such an inhibitor slow an enzymatic reaction In most instances, the structure of the inhibitor does not show a close similarity to that of substrate, which suggests that the binding of inhibitors is at an allosteric site, that is, at a site other than that of the substrate. The inhibition of the enzyme may result from a distortion of the three-dimensional structure of the enzyme which is caused by the binding of the inhibitor. This distortion may be... [Pg.473]

As well as being irreversibly inactivated by heat or chemical reagents, enzymes may be reversibly inhibited by the noncovalent binding of inhibitors. There are four main types of inhibition. [Pg.67]

Dye-sensitized photooxidation of methionine occurs selectively in strong formic or acetic acid media (131). All four methionine residues in RNase-A appear to be converted to sulfoxides under these conditions. The product still showed 13% of the initial activity in the Kunitz RNA assay at pH 5 [see, however, Neumann et al. (ISO)]. Apparently an oxygen atom can be accommodated next to each Met sulfur atom in a structure closely resembling that of the native enzyme. The 3 buried tyrosine residues appeared to have been largely normalized. It would be interesting to know if the binding of inhibitors returned these to the buried condition. [Pg.683]

Summary of Chemical Shift and pK Changes on Binding of Inhibitors to RNase ... [Pg.764]

Ab initio quantum mechanical calculations of binding of inhibitors to surfaces have been tried, but it is too much at the moment for the software to be able to give an answer in a reasonable time with such large molecules, and better to depend upon... [Pg.194]

Finally, an important point which distinguishes covalent activation and allosteric activation should be mentioned. That is their different mode of deactivation. In the first case we have a distinct class of enzymes, the phosphatases, which deactivate and reverse phosphorylation, whereas in the second case deactivation is regulated by dissociation of the activator or binding of inhibitors. [Pg.133]


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See also in sourсe #XX -- [ Pg.285 ]




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