Structure-activity relationship in interaction of cholinesterases with bisdimethylcarbamates (CROSBI ID 587913)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Bosak, Anita ; Gazić, Ivana ; Vinković, Vladimir ; Šinko, Goran ; Štimac, Adela ; Kovarik, Zrinka
engleski
Structure-activity relationship in interaction of cholinesterases with bisdimethylcarbamates
Here we report our study on interactions of cholinesterases with metacarb [N-(2-(3, 5-bis(dimethylcarbamoyloxy)phenyl)-2-hydroxyethyl)propan-2-aminium chloride] and isocarb [N-(2-(3, 4-bis(dimethylcarbamoyloxy)phenyl)-2-hydroxyethyl)propan-2-aminium chloride]. They are structurally similar to bambuterol, the highly selective butyrylcholinesterase (BChE ; EC 3.1.1.8) inhibitor that inhibits mouse BChE about 86001 times faster than mouse BChE, and usual human BChE about 200002 times faster than human acetylcholinesterase (AChE ; 3.1.1.7). The aim of this study was to define inhibition potency of metacarb and isocarb towards mouse cholinesterases and relate it to the active site residues by studying the time course of inhibition of BChE w.t., AChE w.t. and six selected single and multiple site-directed AChE mutants. Mutations in AChE were introduced at structurally equivalent positions to BChE which were earlier found to be responsible for bambuterol selectivity2. Metacarb and isocarb were very potent BChE inhibitors with overall inhibition rates constants of 106 dm3mol-1min-1, but their inhibition selectivity was not as high as that of bambuterol. Metacarb inhibited BChE only 280 times and isocarb only 36 times faster than AChE. This decrease in selectivity comparing to bambuterol is for metacarb probably related to the difference in size of alcohol part of ester, while lower selectivity of isocarb is attributed to difference in disposition of carbamate groups on the benzene ring. Mutations of AChE active site accelerates carbamylation rate, especially in the case of F295L/Y337A and Y124Q showing that BChE selectivity toward metacarb and isocarb is governed mainly by L295 from the acyl pocket and Q124 from the peripheral site. [1] Kovarik Z. et al. Biochim. Biophys. Acta, 1999, 1422, 261-271. [2] Gazić I. et al. Anal. Bioanal. Chem., 2006, 385, 1513-1519. Acknowledgement: Ministry of Science, Education and Sports of the Republic of Croatia
bisdimethylcarbamates; butyrylcholinesterase; selectivity; stereoselectivity
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Podaci o prilogu
147-x.
2012.
objavljeno
Podaci o matičnoj publikaciji
11th International Meeting on Cholinesterases, Kazan, Rusija, Book of Abstracts
Lushchekina, S.
Kazan State University
Podaci o skupu
11th International Meeting on Cholinesterases
poster
04.09.2012-04.09.2012
Kazan, Ruska Federacija