Carboxylesterases structure

Makhaeva, G.F., Yankovskaya, V.L., Kovaleva, N. V., Fetisov, V.I., Malygin, V. V., andKhaskin, B.A., 0,0-Dialkyl-S-brommethylthiolphosphates - inhibitors of mammalians cholin- and carboxylesterases Structure-activity relationships. Russian J. Bioorganic. Chem., 25(1), 1-5, 1999. 

Satoh T, Hosokawa M (2006) Structure, function and regulation of carboxylesterases. Chem Biol Interact 162 195-211... 

Carboxylesterases are well-represented in insects and are sometimes important in the development of resistance to insecticides. Thus, a well-characterized carboxylesterase E4 is responsible for resistance to organophosphorus insecticides in the aphid (Myzuspersicae) [107]. In the California Culex mosquito, the esterase B1 is 500-fold more abundant in organophosphate-resistant than in susceptible insects. The increase of esterase levels is the result of gene amplification, i.e., the resistant animals have an increased number of copies of the structural esterase gene [108],... 

Series of homologous esters have been investigated to try to establish structure-metabolism relationships, however partial and limited the latter may be. This aspect will be discussed again in the context of prodrugs (Chapt. 8). Here, we mention a few representative studies in which model substrates were used. Table 7.2 documents the substrate specificity of a rabbit liver carboxylesterase (ES-1A) toward homologous series of methyl, 4-nitrophenyl, a-naphthyl, /1-naphthyl, and 4-methylumbelliferyl esters [41]. In... 

In comprehensive studies, the hydrolysis of some 30 naphthyl esters by human, rat, and mouse liver carboxylesterases was investigated [43], A general trend that was apparent was that the rate of hydrolysis of a- and /3-naphthyl carbonates (7.21, R = alkyl or arylalkyl) catalyzed by human microsomes or rat hydrolases showed a tendency to decrease with increasing lipophilic-ity (range ca. 2 to 5). A similar trend was not seen with naphthyl aryl carbonates nor with a-naphthyl carboxylates. These results tell us that, even with purified enzymes and large series of substrates, it is very difficult indeed to discern sound structure-hydrolysis relationships due to the complexity of the structural and enzymatic factors involved. 

T. L. Huang, T. Shiotsuki, T. Uematsu, B. Borhan, Q. X. Li, B. D. Hammock, Structure-Activity Relationships for Substrates and Inhibitors of Mammalian Liver Microsomal Carboxylesterases , Pharm. Res. 1996,13, 1495- 1500. 

Whole cell catalysts do not need immobiUzation, especially when mycelial micro-organisms are involved, since their morphological structure allows for easy filtration and re-utihzation. Carboxylesterases bound to the mycelia of molds have been advantageously employed as biocatalysts in water and/or organic solvents the first report of the use of fungal myceha in organic solvent dates back to 1978... 

Hosokawa, M., Satoh, T. (2006). Structure, function, and regulation of carboxylesterases. In Toxicology of Organophosphate and Carbamate Compounds (R.C. Gupta, ed.), pp. 219-31. Academic Press/Elsevier, Amsterdam. 

Maxwell, D.M., Brecht, K., Saxena, A., Feaster, S., Doctor, B.P. (1998). Comparison of cholinesterases and carboxylesterase as bioscavengers for organophosphorus compounds. In Structure and Function of Cholinesterases and Related Proteins (B.P. Doctor et ah, eds), pp. 387-92. Plenum Press, New York. 

Maxwell, D.M., Wolfe, A. D., Ashani, Y., Doctor, B.P. (1991). Cholinesterases and carboxylesterases as scavengers for organophosphorus agents. In Cholinesterases Structure, Function, Mechanism, Genetics and Cell Biology (J. Massou-lie, F. Bacon, E. Barnard, A. Chatonnet, B.P. Doctor, D.M. Quinn, eds), pp. 206-9. American Chemical Society, Washington. 

In contrast to the structurally related topotecan, irinotecan is a prodrug, which has to be converted to its active form, SN-38 (4,30). Cleavage of the side-chain, a bulky piperidino moiety, at the CIO position is rapidly catalysed by carboxylesterases after intravenous administration. SN-38 (7-ethyl-lO-hydroxy-camptothecin) is 1000 times more potent than the parent compound. There is an equilibrium between the active lactone and the inactive carboxylated forms in a pH- and protein-dependent manner for both irinotecan and SN-38 (31,32). 

Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, et al. Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea Synthesis, quantitative structure-activity relationship analysis, and biological activity. Mol Pharmacol 2004 65 1336—43. 

Based on the above discussion, trifluoromethyl ketones should inhibit proteases such as chymotrypsin (32), and serine esterases, such as acetylcholinesterase (33,24)> carboxylesterases (10), JHE and other esterases with varying selectivity. In a series of some juvenoid-like trifluoromethyl ketones and compounds of the structure A, l,l,l-trifluoro-2-tetradecanone (TFT) was found to be highly active and selective against JHE (I50 lxlO 7M) as compared to a-naphthyl acetate esterase (o-NaE) or trypsin (4iJ>). 

Sanishvili, R., A. F. Yakunin, R. A. Laskowski, T. Skarina, E. Evdokimova, A. Doherty-Kirby, G. A. Lajoie, et al. 2003. Integrating structure, bioinformatics, and enzymology to discover function BioH, a new carboxylesterase from Escherichia coli. J Biol Chem 278 26039-45. 

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