Types of reversible inhibition

There are three types of reversible inhibition competitive, uncompetitive, and noncompetitive. Most texts acknowledge only two kinds of inhibition—competitive and noncompetitive (or mixed). This approach makes it difficult to explain inhibition on an intuitive level, so we ll use all three types of inhibition and explain what the other nomenclature means in the last paragraph of this section. 

Reversible Inhibition One common type of reversible inhibition is called competitive (Fig. 6-15a). A competitive inhibitor competes with the substrate for the active site of an enzyme. While the inhibitor (I) occupies the active site it prevents binding of the substrate to the enzyme. Many competitive inhibitors are compounds that resemble the substrate and combine with the enzyme to form an El complex, but without leading to catalysis. Even fleeting combinations of this type will reduce the efficiency of the enzyme. By taking into account the molecular geometry of inhibitors that resemble the substrate, we can reach conclusions about which parts of the normal substrate bind to the enzyme. Competitive inhibition can be analyzed quantitatively by steady-state kinetics. In the presence of a competitive inhibitor, the Michaelis-Menten equation (Eqn 6-9) becomes... 

FIGURE 6-15 Three types of reversible inhibition, (a) Competitive inhibitors bind to the enzyme s active site, (b) Uncompetitive inhibitors bind at a separate site, blit bind only to the ES complex. K, is the equilibrium constant for inhibitor binding to E K is the equilibrium constant for inhibitor binding to ES. (c) Mixed inhibitors bind at a separate site, but may bind to either E or ES. 

Two other types of reversible inhibition, uncompetitive and mixed, though often defined in terms of one-substrate enzymes, are in practice observed only with enzymes having two or more substrates. An uncompetitive inhibitor (Fig. 6-15b) binds at a site distinct from the substrate active site and, unlike a competitive inhibitor, binds only to the ES complex. In the presence of an uncompetitive inhibitor, the Michaelis-Menten equation is altered to... 

Reversible inhibition that produces complete loss of catalytic activity is referred to as linear inhibition because the plots of K IV or 1/y versus [I] are straight lines. When some catalytic activity remains, even at saturating amounts of inhibitor, it is referred to as hyperbohc inhibition because these plots are nonlinear (this case will not be considered here). Both of these types of reversible inhibition are further classified according to the various apparent Michaelis-Menten parameters that are affected by the inhibitor. The two limiting cases are competitive inhibition and uncompetitive inhibition a third type is mixed inhibition, which includes as a special case noncompetitive inhibition. 

The most common type of reversible inhibition is when the inhibitor binds to the free enzyme in the substrate binding site (called the active site), which is known as competitive reversible inhibition. Competitive inhibition prevents the substrate from binding because of a competition between the substrate and inhibitor for binding to the active site (Scheme 1). Particularly in medicinal chemistry, another common expression of inhibition, in addition to the Ki, is the /C50 value, the concentration of an inhibitor that results in 50% inhibition of the enzyme in the presence of a specific concentration of substrate. The IC50 and Ki values for a competitive reversible inhibitor are roughly interconverted by the following expression (Eq. 1) (1-3)... 

The three most common types of reversible inhibition occurring in enzymatic reactions are competitive, uncompetitive, and noncompetitive. (See Problem P7-12b) The enzyme molecule is analogous to the heterogeneous catalytic surface in that it contains active sites. When competitive inhibition occurs, the substrate and inhibitor are usually similar molecules that compete for the same site on the enzyme. Uncompetitive inhibition occurs when the inhibitor deactivates the enzyme-substrate complex, usually by attaching itself to both the substrate and enzyme molecules of the complex. Noncompetitive inhibition occurs with enzymes containing at least two different types of sites. The inhibitor attaches to only one type of site and the substrate only to the other. Derivation of the rate laws for these three types of inhibition is shown on the CD-ROM. 

The curvature seen for reversible inhibition [Fig. 2.12 (a)] indicates that an inhibitor-binding equilibrium precedes the conversion of substrate to product. Three types of reversible inhibition may be distinguished. (1) Competitive inhibition occurs when the degree of inhibition decreases as substrate concentration increases and Vmax is unaffected. (2) Noncompetitive inhibition exists when the degree of inhibition does not vary with substrate concentration, and Km is unaffected. (3) Uncompetitive inhibition exists if the degree of inhibition increases as substrate concentration increases both Vmax and Km are affected. Uncompetitive inhibition is often thought of as a mixture of competitive and noncompetitive behavior. 

In a rather unusual type of reversible inhibition, uncompetitive inhibition, parallel lines are obtained when plots of 1/v against 1/[S] with and without the inhibitor are compared (see Figure 8-9) that is, both K , and V ax are decreased. Uncompetitive inhibition is due to a combination of the inhibitor with the ES complex. It is more common in two-substrate reactions, in which a ternary ESI complex forms after the first substrate has combined with the enzyme. 

Ret er.stble inhibition, in contrast with irreversible inhibition, is acterized by a rapid dissociation of the enzyme-inhibitor complex. In the type of reversible inhibition called competitive inhibition, an enzyme can bind substrate (forming an ES complex) or inhibitor 1) but not both (ESI). The competitive inhibitor often resembles the substrate and binds to the active site of the enzyme (Figure 8.15). The substrate is thereby prevented from binding to the same active site. A competitive inhibitor dimmishes the rate oj catalysis by reducing the pro-por/ion of enzyme molecules bound to a substrate. At any given inhibitor concentration, competitive inhibition can be relieved by increasing... 

In textbooks dealing with enzyme kinetics, it is customary to distinguish four types of reversible inhibitions (i) competitive (ii) noncompetitive (iii) uncompetitive and, (iv) mixed inhibition. Competitive inhibition, e.g., given by the product which retains an affinity for the active site, is very common. Non-competitive inhibition, however, is very rarely encountered, if at all. Uncompetitive inhibition, i.e. where the inhibitor binds to the enzyme-substrate complex but not to the free enzyme, occurs also quite often, as does the mixed inhibition, which is a combination of competitive and uncompetitive inhibitions. The simple Michaelis-Menten equation can still be used, but with a modified Ema, or i.e. ... 

Enzyme inhibition may be reversible or irreversible. Irreversible inhibitors usually bind covalently to enzymes. In reversible inhibition, the inhibitor can dissociate from the enzyme. The most common types of reversible inhibition are competitive, uncompetitive, and noncompetitive. 

The three most common types of reversible inhibition occurring in enzymatic reaction.s are cotnpeiitive, uncompetitive, and noncompetitive. The enzyme molecule is analogous to a heterogeneous catalytic surface in that it contains active sites. When competitive inhibition occurs, the substrate and... 

The second case are reversible or noncolvalent inhibitors. If an inhibitor binds reversibly at the same site as the substrate, the inhibition is referred to as competitive. In other words for competitive inhibition - inhibitor (I) binds only to E, not to the enzyme substrate complex ES. For noncompetitive inhibition - inhibitor (I) binds either to E and/or to ES. A further type of reversible inhibition, uncompetitive, occurs when the inhibitor binds only to the complex enzyme-substrate ES and not to the free enzyme. This is a very rare case and sometimes is even referred to as a hypothetical case. 

Mechanisms of CYP inhibition can be broadly divided into two categories reversible inhibition and mechanism-based inactivation. Depending on the mode of interaction between CYP enzymes and inhibitors, reversible CYP inhibition is further characterized as competitive, noncompetitive, uncompetitive, and mixed (Ito et al., 1998b). Evaluation of reversible inhibition of CYP reactions is often conducted under conditions where M-M kinetics is obeyed. Based on the scheme illustrated in Fig. 5.1, various types of reversible inhibition are summarized in Table 5.1. Figure 5.1 depicts a simple substrate-enzyme complex during catalysis. In the presence of a reversible inhibitor, such a complex can be disrupted leading to enzyme inhibition. 

The three types of reversible inhibitions can be differentiated by double reciprocal rate plots, that ... 

In practice, the most common type of reversible inhibition relevant to httman P450s and drag metabolism is the competitive mechanism. Uncompetitive irrhibition is very rare one (non-P450) example is the inhibition of steroid 5a-reductase by the drag finasteride [194], An example of noncompetitive inhibition is that of cholesterol blocking the oxidation of nifedipine and quinidine by P450 3A4, even though cholesterol is also a substrate for the enzyme [157]. 

An inhibitor is a compound that decreases the rate of an enzyme-catalyzed reaction. Moreover, this inhibition can be reversible or irreversible. Reversible enzyme inhibition can be competitive, uncompetitive, or linear mixed type, each affecting Ks and Vmax in a specific fashion. In this chapter, each type of reversible inhibition is discussed in turn. This is followed by two examples of strategies used to determine the nature of the inhibition as well as to obtain estimates of the enzyme-inhibitor dissociation constant (Ki). 

In this type of reversible inhibition, a compound interacts with the enzyme-substrate complex at a site other than the active site. 

In conclusion, it can be stated that the three types of reversible inhibition are kinetically distinguishable by plots of reaction rate versus substrate concentration using the procedure developed by Lineweaver and Burk (Fig. 2.30). 

Reversible inhibition is a phenomenon whereby the noncovalent binding of inhibitors competes either directly or indirectly with the substrate binding and modulates the enzyme activity. The strength of inhibition is measured by fCj (= [E][I]/[EI]). Three main types of reversible inhibitions are usually recognizable... 

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