Competitive inhibition examples

Example CD7-4 Derive a Rate Law For Non-Competitive Inhibition Example CD7-5 Match Eadie Plots to the Different Types of Inhibition... 

Relatively unambiguous monotonic SARs also occur where activity depends on the ionization of a particular functional group. A classic example (Fig. 5) is that of the antibacterial sulfonamides where activity is exerted by competitive inhibition of the incorporation of j -amin ohenzoic acid into foHc acid (27). The beU-shaped relationship is consistent with the sulfonamide acting as the anion but permeating into the cell as the neutral species. 

A recent example is the substrate analogue thymidine 5 -[a,P-iaiido]triphosphate [141171-20-2] (TMPNPP) (2) which competitively inhibits the human iaimunodeficiency vims-1 (HIV-1) reverse transcriptase (HIV-1 RT) with a iC value of 2.4 micromolar ]lM) (9). The substrate is thymidine 5 -triphosphate... 

Succinate Dehydrogenase—A Classic Example of Competitive Inhibition... 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

Product inhibition studies are used to complement kinetic analyses and to distinguish between ordered and random Bi-Bi reactions. For example, in a random-order Bi-Bi reaction, each product will be a competitive inhibitor regardless of which substrate is designated the variable substrate. However, for a sequential mechanism (Figure 8-11, bottom), only product Q will give the pattern indicative of competitive inhibition when A is the variable substrate, while only product P will produce this pattern with B as the variable substrate. The... 

It should be remembered that some of the established antioxidants have other metabolic roles apart from free-radical scavenging. The finding of reduced antioxidant defences in diabetes, for example, may not be prima fascie evidence of increased oxidative stress, since alternative explanations may operate. For example, this may reflect a response to reduced free-radical activity as su ested by the results of a previous study (Collier et al., 1988). In the case of ascorbate, an alternative explanation has been proposed by Davis etal. (1983), who demonstrated competitive inhibition of ascorbate uptake by glucose into human lymphocytes. This view is supported by the similar molecular structure of glucose and ascorbic acid (see Fig. 12.4) and by a report of an inverse relationship between glycaemic control and ascorbate concentrations in experimental diabetes in rats. Other investigators, however, have not demonstrated this relationship (Som etal., 1981 Sinclair etal., 1991). 

In the case of competitive inhibition, the substrate is displaced by a substance which has greater affinity for the enzyme (or receptor protein) than its natural substrate. For example, a competitive inhibitor (or antagonist) will try to occupy the binding sites such that the enzyme is prevented from exerting its normal activity on the substrate. It is assumed here that the binding between inhibitor and... 

A variety of biochemical and molecular mechanisms have been described to explain how PUFAs can modulate immune cell fate and function. The primary mechanism of action of dietary n-3 PUFAs involves the replacement of AA in the lipid membrane of the cells with either EPA or DHA. This, in effect, competitively inhibits the oxygenation of AA by the COX enzymes. For example, the EPA-induced suppression in the production of AA-derived eicosanoids is followed by a subsequent increase in the production of those from EPA. Generally, the EPA-derived eicosanoids are considered to be much less potent than those from AA, thus explaining, at least partially, the anti-inflammatory effects of PUFAs. A similar mechanism of action can be demonstrated for DHA, either directly or by retroconversion to EPA. 

Slightly more complex are constraints with respect to the feasible intervals that are induced by interactions between metabolites. Until now, all saturation parameters were chosen independently, using a uniform distribution on a given interval We emphasize that this choice indeed samples the comprehensive parameter spaces, and for all samples, there exists a system of explicit differential equations that are consistent with the sampled Jacobian. However, obviously, not all rate equations can reproduce all sampled values. In particular, competition between substrates for a single binding site will prohibit certain combinations of saturation values to occur. For example, consider an irreversible monosubstrate reaction with competitive inhibition (see Table II) ... 

Another type of inhibitor combines with the enzyme at a site which is often different from the substrate-binding site and as a result will inhibit the formation of the product by the breakdown of the normal enzyme-substrate complex. Such non-competitive inhibition is not reversed by the addition of excess substrate and generally the inhibitor shows no structural similarity to the substrate. Kinetic studies reveal a reduced value for the maximum activity of the enzyme but an unaltered value for the Michaelis constant (Figure 8.7). There are many examples of non-competitive inhibitors, many of which are regarded as poisons because of the crucial role of the inhibited enzyme. Cyanide ions, for instance, inhibit any enzyme in which either an iron or copper ion is part of the active site or prosthetic group, e.g. cytochrome c oxidase (EC 1.9.3.1). 

Rate constants for the reaction of cytochrome f with inorganic oxidants are independent of pH when it is between 6.5-8.0 [150]. At pH < 6.5 protonation does have an effect, and with for example [Co(phen)3] there is a decrease and [Fe(CN)g] an increase in rate constants. From the kinetics cytochrome f shows no association with positively charged [Co(phen)j], and no competitive inhibition is observed with [Pt(NH3)6]" or [(NH3)5CoNH2Co(NH3)5] " [150]. It is possible therefore to study the effect of these reagents on the reaction of cytochrome f(II) with PCu(II), which... 

For example, experimental data might reveal that a novel enzyme inhibitor causes a concentration-dependent increase in Km, with no effect on and with Lineweaver-Burk plots indicative of competitive inhibition. Flowever, even at very high inhibitor concentrations and very low substrate concentrations, it is observed that the degree of inhibition levels off when some 60% of activity still remains. Furthermore, it has been confirmed that only one enzyme is present, and all appropriate blank rates have been accounted for. It is clear that full competitive inhibition cannot account for such observations because complete inhibition can be attained at infinitely high concentrations of a full competitive inhibitor. Thus, it is likely that the inhibitor binds to the enzyme at an allosteric site. 

Thereafter, a reference text such as Enzyme Kinetics (Segel, 1993) should be consulted to determine whether or not the proposed mechanism has been described and characterized previously. For the example given, it would be found that the proposed mechanism corresponds to a system referred to as partial competitive inhibition, and an equation is provided which can be applied to the experimental data. If the data can be fitted successfully by applying the equation through nonlinear regression, the proposed mechanism would be supported further secondary graphing approaches to confirm the mechanism are also provided in texts such as Enzyme Kinetics, and values could be obtained for the various associated constants. If the data cannot be fitted successfully, the proposed reaction scheme should be revisited and altered appropriately, and the whole process repeated. 

Full and partial competitive inhibitory mechanisms, (a) Reaction scheme for full competitive inhibition indicates binding of substrate and inhibitor to a common site, (b) Lineweaver-Burk plot for full competitive inhibition reveals a common intercept with the 1/v axis and an increase in slope to infinity at infinitely high inhibitor concentrations. In this example, Ki = 3 pM. (c) Replot of Lineweaver-Burk slopes from (b) is linear, confirming a full inhibitory mechanism, (d) Reaction scheme for partial competitive inhibition indicates binding of substrate and inhibitor to two mutually exclusive sites. The presence of inhibitor affects the affinity of enzyme for substrate and the presence of substrate affects the affinity of enzyme for inhibitor, both by a factor a. (e) Lineweaver-Burk plot for partial competitive inhibition reveals a common intercept with the 1/v axis and an increase in slope to a finite value at infinitely high inhibitor concentrations. In this example, Ki = 3 pM and = 4. (f) Replot of Lineweaver-Burk slopes from (e) is hyperbolic, confirming a partial inhibitory mechanism... 

The first stage occurs in the cytoplasm, which results in the synthesis of precursor units—uridindiphospho-A -acetyhnuramyl pentapeptide. Such an antibiotic, for example, cycloserine, the drug most frequently used to treat tuberculosis, blocks synthesis of cell membranes at this stage by competitive inhibition of the stage of introducing alanine into a pentapeptide. 

Product inhibition is another example of such an inhibition mechanism of enzyme reactions, and is due to a structural similarity between the substrate and the product. The mechanism of competitive inhibition in a unimolecular irreversible reaction is considered as follows ... 

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