Naslov
Structure-activity relationship in interaction of cholinesterases with bisdimethylcarbamates

Autori
Bosak, Anita ; Gazić, Ivana ; Vinković, Vladimir ; Šinko, Goran ; Štimac, Adela ; Kovarik, Zrinka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
11th International Meeting on Cholinesterases, Kazan, Rusija, Book of Abstracts / Lushchekina, S. - : Kazan State University, 2012

Skup
11th International Meeting on Cholinesterases

Mjesto i datum
Kazan, Ruska Federacija, 04.06.2012. - 09.06.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
bisdimethylcarbamates; butyrylcholinesterase; selectivity; stereoselectivity

Sažetak
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

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Javno zdravstvo i zdravstvena zaštita

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