Benzoyl cholinesterase

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],... 

Acylcholine acylhydrolase Pseudochoiinesterase, benzoyl.. cholineesterase II (scrum cholinesterase). - ChL (SChE)... 

The physiological levels of cocaine can reach a maximum of about 0.3 micromolar (M) in serum immediately after cocaine administration (Jeffcoat et al. 1989). These levels are much less than the Km of the liver benzoyl esterase (0.7 mM). Hence, the enzyme will obey first-order kinetics, where activity equals k at/KM, called the catalytic efficiency, times the cocaine concentration. The catal5Tic efficiency of the liver benzoyl esterase, 11 min mM", is similar to human serum cholinesterase, 7 min mM ", another enzyme that catalyzes the hydrolysis of the benzoyl group of cocaine. The content and kinetic properties of serum cholinesterase and liver benzoyl esterase need to be evaluated to determine which enz5mie has the greater capacity for hydrolysis of cocaine in human. 

The hydrolysis of esters and amides (including peptides) is important in medicinal chemistry (see Chapters 36 and 38). Here, two drugs are presented to illustrate these two chemical classes. (-)-Cocaine (5) has two ester groups whose hydrolysis (Figure 32.7a) is a route of detoxification, which accounts for as much as 90% of the dose in humans. Three human enzymes are now known to be involved in the hydrolysis of cocaine. One is the liver carboxylesterase hCE-1 which catalyzes the hydrolysis of the methyl ester group. As for the benzoyl ester goup, it is hydrolyzed by the liver carboxylesterase hCE-2 and serum cholinesterase. 

Differences between the species toward the thiocholine substrates have been reported. Table 11.1 illustrates some observed differences with three species. For plasma pseudocholinesterase measurements, dog, rabbit, and man show higher substrate specificity for butyryl substrates, whereas rat, mouse, and hamster show higher specihcity for propionyl substrates all the species show less specihcity toward benzoyl substrates. Female rats have higher values compared to males with all three substrates, and the cholinesterase levels in platelets are higher in rats compared to the very low levels in human platelets. 

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