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Cholinesterases binding sites

Specific structure-function relationships. For example, certain structural domains are responsible for binding to the nicotinic receptor and muscarinic receptor. Also, structural modifications that block the binding site for one receptor subtype result in a selectivity of the drug for the other subtype. In the same way. modifications that result in steric hindrance to the cholinesterase binding site will confer cholinesterase resistance. [Pg.84]

The enzyme choline esterase has been shown to have two binding points on its protein surface for these substances—one site for the quaternary ammonium group and one for X. This enzyme catalyzes the hydrolysis of an ester at the X position. From a consideration of the structure of the (2-chloroethyl)trimethylammonium chloride derivatives which were active as plant growth substances, a similar protein-binding site in the plant has been postulated. This site would have a point of attachment for both the ammonium cation and the X constituent of the molecule. This postulated site in the plant is thus similar, but not identical, to cholinesterase, which is an enzyme not known to occur in plants. There is no direct proof for this hypothetical site in the plant. [Pg.147]

A polymorphism in serum cholinesterase is one of the oldest polymorphisms known. It leads to prolonged muscle relation or prolonged paralysis after administration of the muscle relaxant succinylcholine. Several mutants occur, the most common is a point mutation causing the substitution of glycine for aspartic acid at position 70. This variant shows defective binding of choline esters to the anionic binding site but has normal activity with neutral or positively charged esters. There also numerous other variants, many with partial or complete loss of activity. [Pg.213]

Hase (H16) studied the effect of pH on the hydrolysis of acetylcholine by horse serum cholinesterase, and his results have been reanalyzed by Laidler (L5) and extensively discussed by Dixon and Webb (D21). The relationship between pH and the rate of hydrolysis of acetylcholine has been used to obtain information on the structure of the active site of the enzyme (B19, W28). Acetylcholine is a particularly suitable substrate for these studies since it does not change its charge in the pH range studied. Similar pH-activity curves have been obtained using other substrates for cholinesterase (H23, S20, P19). Moreover the pH dependence of enzymic activity varies with the buffer system (K3). By investigating the effect of pH and sodium chloride concentration on the rate of hydrolysis of ben-zoylcholine by human plasma cholinesterase, Kalow (K6) deduced that for this substrate, each enzyme molecule contains at least two binding sites which differ in their dependence on pH. Michaelis constants and maximum hydrolysis velocities were measured for each of the two binding sites, and pK values of the enzyme-substrate complexes were found to be 5.2, 6.7, and 9.2 for one site, and 5.2, 7.0, 8.4, and 8.8 for the other. [Pg.55]

The discovery that organophosphates such as diisopropyl fluoro-phosphate (DFP) inhibit cholinesterase by irreversible phosphorylation of a basic group at the esteratic site led to the use of P P]DFP to ascertain the chemical nature of the DFP-binding site. Jansz et al. (J2) found that the structure of the P peptide of horse serum cholinesterase was Phe-Glu-Ser-Ala-Gly-Ala-Ala-Ser This indicated the serine hydroxyl as the... [Pg.55]

Note that the kinetic interactions of substrates with AChE and BuChE are in reality more complex than portrayed in Fig. 5. Both cholinesterases have been shown to display substrate inhibition and activation, depending on the incubation condilion.s (Masson et ai., 2004). probably as a result of the presence of a binding site separate from the active site, termed the peripheral anionic site (Changeux. 1966 Taylor and Radic, 1994 Barak et ai., 1995 Soreq and Seidman,... [Pg.212]

It appears that, generally, sialic acid is not a part of an antigenic determinant (atropinesterase and orosomucoid) nor a functioning part of a catalytic or binding site ( i-antitrypsin, atropinesterase, cemloplasmin, and serum cholinesterase). However, sialic acid does seem to play a role in transport ( i-antitrypsin). This effect is discussed more fully later in this chapter. Johnson et al. (1970) found that removal of sialic acid residues from the copper-containing protein cemloplasmin had no effect on its kinetic properties as an oxidase. They concluded that the terminal sialic acid residues do not influence the stmcture and function of the active sites in cemloplasmin. [Pg.279]

Phenyl tetrahydroisoquinoline scaffold was selected as it was proven to be a convenient peripheral site binder [27]. There is a growing interest in developing multitarget-directed drugs and particularly new potent dual-binding site, AChE inhibitors are able to exert a dual action [33] (inhibition of cholinesterase activity and inhibition of AChE-mediated Ap deposition) [34]. The results of the m-AChE-directed syntheses of heterodimeric huprine-based inhibitors are summarized vide Table 2.1). [Pg.30]

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)... Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)...
Reversible cholinesterase inhibitors form a transition state complex with the enzyme, just as acetylcholine does. These compounds are in competition with acetylcholine in binding with the active sites of the enzyme. The chemical stracture of classic, reversible inhibitors physostigmine and neostigmine shows their similarity to acetylcholine. Edrophonium is also a reversible inhibitor. These compounds have a high affinity with the enzyme, and their inhibitory action is reversible. These inhibitors differ from acetylcholine in that they are not easily broken down by enzymes. Enzymes are reactivated much slower than it takes for subsequent hydrolysis of acetylcholine to happen. Therefore, the pharmacological effect caused by these compounds is reversible. [Pg.187]

Acetylcholinesterase can be inhibited by two general mechanisms. In the first mechanism, positively charged quaternary ammonium compounds bind to the anionic site and prevent ACh from binding—a simple competitive inhibition. In the second mechanism, the agents act either as a false substrate for the cholinesterase or directly attack the esteratic site in both cases they covalently modify the esteratic site and non-competitively prevent further hydrolytic activity. Either mechanism can be effective in preventing the hydroly-... [Pg.126]


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See also in sourсe #XX -- [ Pg.175 , Pg.176 , Pg.177 , Pg.178 , Pg.199 ]




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