Competitive inhibition, enzymes

Glucose-6-phosphatase is another enzyme competitively inhibited by galactose-l-phosphate (15). The inhibition of hepatic glucose-6-phos-phatase is probably important in relation to hypoglycemia. 

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... 

In the case of competitive inhibition, the equilibrium between the enzyme, E, the inhibitor, 1, and the enzyme-inhibitor complex, El, is described by the equilibrium constant Ki. 

Reversible inhibition is characterized by an equiUbrium between enzyme and inhibitor. Many reversible inhibitors are substrate analogues, and bear a close relationship to the normal substrate. When the inhibitor and the substrate compete for the same site on the enzyme, the inhibition is called competitive inhibition. In addition to the reaction described in equation 1, the competing reaction described in equation 3 proceeds when a competitive inhibitor I is added to the reaction solution. 

The three most common types of inhibitors in enzymatic reactions are competitive, non-competitive, and uncompetitive. Competitive inliibition occurs when tlie substrate and inhibitor have similar molecules that compete for the identical site on the enzyme. Non-competitive inhibition results in 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. Uncompetitive inhibition occurs when the inhibitor deactivates the enzyme substrate complex. The effect of an inhibitor is determined by measuring the enzyme velocity at various... 

The enzyme succinate dehydrogenase (SDH) is competitively inhibited by malo-nate. Figure 14.14 shows the structures of succinate and malonate. The structural similarity between them is obvious and is the basis of malonate s ability to mimic succinate and bind at the active site of SDH. However, unlike succinate, which is oxidized by SDH to form fumarate, malonate cannot lose two hydrogens consequently, it is unreactive. 

Generally inhibitors are competitive or non-competitive with substrates. In competitive inhibition, the interaction of the enzyme with the substrate and competitive inhibitor instead of the substrate can be analysed with the sequence of reactions taking place as a result, a complex of the enzyme-inhibitor (El) is formed. The reaction sets at equilibrium and the final step shows the product is formed. The enzyme must get free, but the enzyme attached to the inhibitor does not have any chance to dissociate from the El complex. The El formed is not available for conversion of substrate free enzymes are responsible for that conversion. The presence of inhibitor can cause the reaction rate to be slower than the ordinary reaction, in the absence of the inhibitor. The sequence of reaction mechanisms is ... 

In such inhibition, the inhibitor and die substrate can simultaneously bind to the enzyme. The nature of the enzyme-inhibitor-substrate binding has resulted in a ternary complex defined as EIS. The Ks and Kt are identical to the corresponding dissociation constants. It is also assumed that the EIS does not react further and is unable to deliver any product P. The rate equation for non-competitive inhibition, unvAX, is influenced ... 

In non-competitive inhibition, the substrate (S) and inhibitor (I) have equal potential to bind to the free enzyme (E). The inhibitor forms a ternary complex with enzyme-substrate (ES) whereas the substrate will form another ternary complex with enzyme-inhibitor (El). Since the non-competitive inhibitor had no effect on the binding of substrate to the enzyme, the Km value remained consistent (or unchanged). There are two different ways for the formation of ESI ternary complex this complex would not form the product and therefore was decreased. Non-competitive inhibitor had no effect on substrate binding or the enzyme-substrate affinity, therefore the apparent rate constant (K ) was unchanged.5 A possible reason for product inhibition was because of the nature of 2-ethoxyethanol,... 

The first member of this class, acarbose, was introduced in the early 1990s. a-Glucosidase inhibitors slow the intestinal process of carbohydrate digestion by competitive inhibition of the activity of a-glucosidase enzymes located in the brush border of the enterocytes... 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

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]. 

The second B. thuringiensis toxin, the /3-exotoxin has a much broader spectrum encompassing the Lepidoptera, Coleoptera and Diptera. It is an adenine nucleotide, probably an ATP analogue which acts by competitively inhibiting enzymes which catalyse the hydrolysis of ATP and pyrophosphate. This compound, however, is toxic when administered to mammals so that commercial preparations of the B. thuringiensis 5-endotoxin are obtained from strains which do not produce the j8-exotoxin. 

Competitive inhibition is important in biological control mechanisms for instance, if the product assumes the role of an inhibitor. The enzyme invertase catalyzes the hydrolysis of sucrose into glucose and fructose. As glucose is a competitive inhibitor, it ensures that the reaction does not proceed too far. 

A large number of amino acid transporters have been detected by isolating mutations which selectively inactivate one permease without altering enzyme activities involving the corresponding amino acid. Competitive inhibition, kinetics and regulatory behaviour have also been used as criteria to distinguish one transport system from another (see section 4.2). 

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... 

Muldoon et al. developed a monoclonal-based competitive inhibition enzyme-linked immunosorbent assay (cELISA) for sulfadimethoxine. The group compared... 

Figure 3.2 Cartoon representations of the three major forms of reversible inhibitor interactions with enzymes (A) competitive inhibition (B) noncompetitive inhibition (C) uncompetitive inhibition. Source-. From Copeland (2000).

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