Cholinesterase binding

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. 

There is no correlation between AChE inhibition and the disposition of [ H]-soman, H)-DFP, and [ H]-sarin in brain (Kadar cf a/, 1985 Little etal., 1988). For example, the hypothalamus binds two to five times more OP compared to the striatum, but the striatum has more AChE activity than the hypothalamus. This suggests that in the hypothalamus, targets other than cholinesterase bind OP (Little et al., 1988). In a related experiment, binding of pH]-DFP to whole brain homogenate was decreased only 15% by preincubation with 1 pM eserine (a specific inhibitor of AChE and BChE), suggesting that only 15% of the DFP-Iabeled proteins are cholinesterases (Richards etal., 1999). 

Methyl paraoxon may also be made unavailable by binding to noncritical tissue and plasma constituents (Benke and Murphy 1975), including cholinesterase (Parkinson 1996). In addition, the parent compound is bound to albumin, in serum, as discussed previously in Section 3.4.2.4, but this binding does not appear to limit the availability of methyl parathion to the tissues, indicating that it is reversible. Tissue binding appears to be more important than serum binding (Braeckman et al. 1980, 1983). 

There is a second type of cholinesterase called butyrylcholinesterase, pseudocholinesterase, or cholinesterase. This enzyme is present in some nonneural cells in the central and peripheral nervous systems as well as in plasma and serum, the liver, and other organs. Its physiologic function is not known, but is hypothesized to be the hydrolysis of esters ingested from plants (Lefkowitz et al. 1996). Plasma cholinesterases are also inhibited by organophosphate compounds through irreversible binding this binding can act as a detoxification mechanism as it affords some protection to acetylcholinesterase in the nervous system (Parkinson 1996 Taylor 1996). 

The pollutant (xenobiotic) forms a stable covalent bond with its target. Examples include the phosphorylation of cholinesterases by the oxon forms of OPs, the formation of DNA adducts by the reactive epoxides of benzo[a] pyrene and other PAHs, and the binding of organomercury compounds to... 

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 13.3. An overview of the chemical events at a cholinergic synapse and agents commonly used to alter cholinergic transmission acetyl CoA, acetyl coenzyme A Ch, choline. Nicotine and scopolamine bind to nicotinic and muscarinic receptors, respectively (nicotine is an agonist while scopolamine is an antagonist). Most anti-Alzheimer drugs inhibit the action of the enzyme cholinesterase.

Famphur and other organophosphorus compounds are metabolized and excreted with greater efficiency by mammals than the target pests before these compounds can bind to and ultimately inhibit the cholinesterase enzyme (Randell and Bradley 1980). Mice, for example, degrade famphur rapidly. Less than 1 h after an intraperitoneal injection of 1 mg famphur/kg BW, only 8.34% of... 

Another different class of inhibitors binds covalently to specific amino acids in the enzyme and these are referred to as irreversible inhibitors. The organophosphorus compounds, of which nerve gases are examples, inactivate enzymes which rely on the hydroxyl group of serine residues for their activity, e.g. cholinesterase (EC 3.1.1.8). 

A variety of hydrolases catalyze the hydrolysis of acetylsalicylic acid. In humans, high activities have been seen with membrane-bound and cytosolic carboxylesterases (EC 3.1.1.1), plasma cholinesterase (EC 3.1.1.8), and red blood cell arylesterases (EC 3.1.1.2), whereas nonenzymatic hydrolysis appears to contribute to a small percentage of the total salicylic acid formed [76a] [82], A solution of serum albumin also displayed weak hydrolytic activity toward the drug, but, under the conditions of the study, binding to serum albumin decreased chemical hydrolysis at 37° and pH 7.4 from tm 12 1 h when unbound to 27 3 h for the fully bound drug [83], In contrast, binding to serum albumin increased by >50% the rate of carboxylesterase-catalyzed hydrolysis, as seen in buffers containing the hydrolase with or without albumin. It has been postulated that either bound acetylsalicylic acid is more susceptible to enzyme hydrolysis, or the protein directly activates the enzyme. 

The toxicity of the P-halidc anhydrides, like that of phosphoroxychloride (POCl3) and of other organophosphorus compounds discussed earlier in this section, is due to their high efficiency as irreversible inactivators of acetylcholinesterase [157]. The main target organs for the lethal effects of these chemical weapons are the brain and diaphragm. As for the detoxification of the P-halide anhydrides, it can occur by a number of biochemical mechanisms, namely chemical hydrolysis, enzymatic hydrolysis, and binding to hydrolases such as carboxylesterases, cholinesterases, and albumin [68][158][159]. 

Table 6.3 Brain MChR Binding and Brain and Plasma Cholinesterase Activities in Rainbow Trout (Oncorhynchus mykiss) Exposed to Sample Extracts and Controls. Reprinted from Petty et al. (2000), copyright (2000) reproduced with permission from Elsevier...

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. 

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