Substrates competitive inhibitors resembling

Three important classes of inhibitors are shown in Table 1-8-3. Competitive inhibitors resemble the substrate and compete for binding to the active site of the enzyme. Noncompetitive inhibitors do not bind at the active site. They bind to regulatory sites on the enzyme. Irreversible inhibitors inactivate the enzyme similar to removing enzyme from the assay. 

B. Competitive inhibitors resemble the substrate in structure and bind reversibly... 

The answer is a. (Murray, pp 48-73. Scriver, pp 4571-4636. Sack, pp 3—17. Wilson, pp 287-317.) Competitive inhibitors resemble the structure of the substrate and compete with the substrate to bind to the active site of the enzyme. For this reason, fC increases with increasing inhibitor concentration, while V,-, remains the same. That is, Vnwt can be reached at substrate concentrations sufficiently high to overcome the inhibitor. Since the x axis intercept represents —l/K and they axis intercept represents l/Tmax, only curves A, X, and D show changes in K with no changes in Vnwt- When -i/K is interpreted properly, the highest K value is given by curve A. 

A competitive inhibitor resembles the substrate in its chemical structure and is able to combine with the enzyme to form an enzyme-inhibitor complex. In so doing it competes with the substrate for the active sites of the enzyme, and formation of the enzyme-substrate complex is inhibited. This type of inhibition may be reversed by the addition of excess substrate, which displaces the inhibitor, forming normal enzyme-substrate complexes. One of the best-known examples is provided by the sulphonamide drugs. The synthesis of folic acid from p-aminobenzoic acid (PABA) is a vital metabolic process in the bacteria controlled by these drugs. The similarity between PABA and sulphanUamide, released by the sulphonamides, is obvious ... 

The effects of competitive inhibitors, which typically resemble substrates, are overcome by raising the concentration of the substrate. Noncompetitive inhibitors lower but do not affect K. ... 

The value of K, is then the concentration of inhibitor needed to double the value of Km. Effective concentrations of substrate and competitive inhibitor can be compared by means of these two constants. As a rule, competitive inhibitors bear, in their chemical structure, a resemblance to the substrate, and they tend to be much more specific in their action than non-competitive inhibitors. It is evident that a small value of K, relative to Kra denotes an efficient, competitive inhibitor. 

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... 

Competitive inhibitors often closely resemble in some respect the substrate whose reactions they inhibit and, because of this structural similarity, compete for the same binding site on the enzyme. The enzyme-inhibitor complex either lacks the appropriate reactive groups or is held in an unsuitable position with respect to the catalytic site of the enzyme which results in a complex which does not react (i.e. gives a dead-end complex). The inhibitor must first dissociate before the true substrate may enter the enzyme and the reaction can take place. An example is malonate, which is a competitive inhibitor of the reaction catalysed by succinate dehydrogenase. Malonate has two carboxyl groups, like the substrate, and can fill the substrate binding site on the enzyme. The subsequent reaction, however, requires that the molecule be reduced with the formation of a double bond. If malonate is the substrate, this cannot be achieved without the loss of one of the carboxy-groups and therefore no reaction occurs. 

Since a competitive inhibitor has a strong structural resemblance to the substrate, both the inhibitor and substrate compete for the active site of an enzyme. The formation of an enzyme-inhibitor complex reduces the amount of enzyme available for interaction with the substrate and, as a result, the rate of reaction decreases. A competitive inhibitor normally combines reversibly with enzyme. Therefore, the effect of the inhibitor can be minimized by increasing the substrate concentration, unless the substrate concentration is greater than the concentration at which the substrate itself inhibits the reaction. The mechanism of competitive inhibition can be expressed as follows ... 

Competitive, reversible inhibitors are the most common type of inhibitor developed for pharmaceutical use. If the substrate of an enzyme is known, then a competitive inhibitor will likely somewhat resemble the substrate. The search for an inhibitor will typically start with molecules of similar structure to the substrate. Because enzymes theoretically bind most strongly to a transition state, competitive inhibitors are often designed to resemble a transition state or a high energy intermediate along the reaction coordinate. These types of drugs are called transition state analogues or transition state inhibitors. 

Another way to reduce the supply of deoxynucleotides for cell replication is to target the reduction of dihydrofolate to tetrahydrofo-late. Folate antagonists are used in antimicrobial and anticancer chemotherapy. These compounds are competitive inhibitors of dihydrofolate reductase because they resemble the natural substrate. For example, methotrexate is used in antitumor therapy. 

A competitive inhibitor of an enzyme will typically structurally resemble a substrate of the enzyme. Thus malonate (methanedicarboxylate OOC-CH2-COO ) is structurally similar to succinate (ethanedicarboxylate OOC CH2 CH2 COO ) and is a competitive inhibitor of the oxidoreductase succinate dehydrogenase that catalyses the reaction ... 

Competitive inhibitors often structurally resemble the substrate of the enzyme (structural analogues). For example, methotrexate is a competitive inhibitor of the enzyme dihydrofolate... 

Compounds that resemble the substrate dosely may bind at or very close to the active site, but the inhibitor is not capable of being turned over catalytically. This form of inhibition, in which substrate and inhibitor compete for the same site, and where it is not possible for both to bind simultaneously, is called competitive inhibition (Figure 8-7). The rate equation for reaction in the presence of a competitive inhibitor, expressed in the form of the linearised double redprocal Lineweaver-Burk plot, is shown in Eqn. 8.27. 

Noncompetitive inhibitions result from combination of the inhibitor with an enzyme form other than the one the substrate combines with, and one that is present at both high and low levels of the substrate. An example is a dead-end inhibitor resembling the first substrate in an ordered mechanism. It is competitive versus A, but noncompetitive versus B, because B cannot prevent the binding of the inhibitor to free enzyme. In a random mechanism, an inhibitor binding at one site is noncompetitive versus a substrate binding at another site. 

Succinylacetone, which accumulates in this disease, has a structural resemblance to ALA and is therefore a competitive inhibitor of ALAD. Consequently, its substrate ALA accumulates and excess amounts are excreted in urine. Patients with hereditary tyrosinemia suffer neurological crises very similar to attacks of acute porphyria. They can be treated with heme infusions. ... 

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... 

An inhibition (/) decreases enzymes activity, causing the rate of reaction to decrease competitively or noncompetitively (7). A competitive inhibitor has a strong structural resemblance to the substrate. Therefore, both the inhibitor and substrate compete for the active site of an enzyme as... 

The enzyme is unable to bind both S and I at the same time and in competitive inhibition, the enzyme-inhibitor complex El does not react with substrate S. Competitive inhibitors often resemble substrate structurally. As an example we can mention malonate, which is an inhibitor for dehydrogenation of succinate of a enzyme succinic dehydrogenase and resembles the structure of succinate (Figure 6.35)... 

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