Acetylcholinesterase properties

In the body, metrifonate converts to the active metaboUte dichlorvos, (2,2-dichlorovinyl dimethyl phosphate), which is responsible for the inhibition of the enzyme acetylcholinesterase in the susceptible worm. This effect alone is unlikely to explain the antischistosomal properties of metrifonate (19). Clinically, metrifonate is effective only against infection caused by S. haematobium. Metrifonate is administered in three doses at 2-wk intervals (17). The dmg is well tolerated. Side effects such as mild vertigo, nausea, and cramps are dose-related. This product is not available in the United States. The only manufacturer of metrifonate is Bayer A.G. of Leverkusen, Germany. 

Grigg, M.E., Tang, L., Hussein, A.S. and Selkirk, M.E. (1997) Purification and properties of monomeric (Gl) forms of acetylcholinesterase secreted by Nippostrongylus brasiliensis. Molecular and Biochemical Parasitology 90, 513-524. 

Hussein, A.S., Chacon, M.R., Smith, A.M., Tosado-Acevedo, R. and Selkirk, M.E. (1999a) Cloning, expression and properties of a non-neuronal secreted acetylcholinesterase from the parasitic nematode Nippostrongylus brasiliensis. Journal of Biological Chemistry 274, 9312-9319. 

Hussein, A.S., Grigg, M.E. and Selkirk, M.E. (1999b) Nippostrongylus brasiliensis. characterisation of a somatic amphiphilic acetylcholinesterase with properties distinct from the secreted enzymes. Experimental Parasitology 91, 144-150. 

Toutant, J.-P. (1989) Insect acetylcholinesterase catalytic properties, tissue distribution and molecular forms. Progress in Neurobiology 32, 423 46. 

Cholinesterases are subdivided into acetylcholinesterase and cholinesterase, one with a narrow, the other with broad substrate specificity [109-112], Both enzymes exist in multiple molecular forms distinguishable by their subunits association (Fig. 2.4). The hydrodynamic properties of these associations have allowed globular (G) and asymmetric (A) forms to be distinguished. The G forms can be hydrophilic (water-soluble, and excreted into body fluids) or amphiphilic (membrane-bound). The homomeric class exists... 

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

Table 10.4 Pharmacological properties of selected acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer s disease... 

Galantamine is a reversible inhibitor of acetylcholinesterase that also possesses nicotinic receptor agonist properties, and which is used in mild-to-moderate dementia in Alzheimer s disease. 

Oxime reactivators (R-CH N0H) are weak acids that partly Ionize at biologic pH. This property allows them to function as nucleophiles and displace organophosphate moieties from inhibited acetylcholinesterase. It also makes them vulnerable to decomposition by other mechanisms in the body. 

Individual cholinesterase inhibitors differ in their selectivity, mechanism of inhibition of acetylcholinesterase (Schneider 2001), and pharmacokinetic properties (outlined in Table 7-2). 

The frequent occurrence of sialylated enzymes, or even of multiple forms, which are sometimes tissue-dependent, with a varying number of sialyl residues as, for example, in y-glutamyltranspeptida.se (EC 2.3.2.2),456,457 is not yet fully understood. Although the activity of most of these enzymes is not influenced by removal of sialic acid,454 the activity of monoamine oxidase A (EC 1.4.3.4) of outer mitochondrial membranes of rat liver has been shown to be destroyed by treatment with sialidase438 the substrate specificity of acetylcholinesterase (EC 3.1.1.7) is altered,459 the kinetic properties of human acid and alkaline phosphatases (EC 3.1.3.1 and 3.1.3.2) are changed, and the stability of a-D-galactosidase (EC 3.2.1.22) is drastically lowered.415 In these cases, an influence of sialyl residues on the conformation of the enzyme is assumed, but awaits firm evidence. 

The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical. 

This area is a development in the usage of NDDO models that emphasizes their utility for large-scale problems. Structure-activity relationships (SARs) are widely used in the pharmaceutical industry to understand how the various features of biologically active molecules contribute to their activity. SARs typically take the form of equations, often linear equations, that quantify activity as a function of variables associated with the molecules. The molecular variables could include, for instance, molecular weight, dipole moment, hydrophobic surface area, octanol-water partition coefficient, vapor pressure, various descriptors associated with molecular geometry, etc. For example, Cramer, Famini, and Lowrey (1993) found a strong correlation (r = 0.958) between various computed properties for 44 alkylammonium ions and their ability to act as acetylcholinesterase inhibitors according to the equation... 

The toxicity of organophosphoric esters for insects and mammals is associated with inhibition of cholinesterases. Investigations on the relation between chemical structure of organophosphoric esters and the inactivation of acetylcholinesterase (AChE) have revealed that anticholinesterase activity depends to a large extent on the chemical reactivity of the esters. As a rule, the chemical reactivity of the phosphorus atom is the single most important property which determines the anticholinesterase activity of an organophosphoric ester. 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

Ciliv, G., and P.T. Oezand. 1972. Human erythrocyte acetylcholinesterase purification, properties and kinetic behavior. Biochim Biophys Acta 284 136. 

Sihotang, K. 1974. Properties of human erythrocyte acetylcholinesterase. J Biochem 75 939. 

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