Naslov
Stereoselective inhibition of human, mouse, and horse cholinesterases by bambuterol enantiomers

Autori
Bosak, Anita ; Gazić, Ivana ; Vinković, Vladimir ; Kovarik, Zrinka

Izvornik
Chemico-Biological Interactions (0009-2797) 175 (2008), 1-3; 192-195

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, kratko priopcenje, znanstveni

Ključne riječi
carbamates ; acetylcholinesterase ; butyrylcholinesterase ; catalytic constants ; mutants ; carbamoylation

Sažetak
Bambuterol is a chiral carbamate known as selective inhibitor of butyrylcholinesterase (BChE). In order to relate bambuterol selectivity and stereoselectivity of cholinesterases to the active site residues, we studied the inhibition of recombinant BChE, acetylcholinesterase (AChE) and six AChE mutants, employed to mimic BChE active site residues, by bambuterol enantiomers. Both enantiomers selectively inhibited BChE about 8000 times faster than AChE. The largest inhibition rate increase in comparison to AChE w.t. was observed with the F295L/Y337A mutant, showing that leucine 295 and alanine 337 are crucial residues in BChE for high bambuterol selectivity. All studied enzymes preferred inhibition by the R- over the S-bambuterol. The enlargement of the AChE choline binding site and of the acyl pocket by single or double mutations (Y337A, F295L/Y337A and F297I/Y337A) increased, in comparison to w. t. enzymes, inhibition rate constants of R- bambuterol more than that of S- bambuterol resulting in four times higher stereoselectivity. Peripheral site mutations (Y124Q and Y72N/Y124Q/Y337A) increased inhibition rate by S- more than R-bambuterol and consequently diminished the stereoselectivity.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

Napomena
Proceedings of the IX International Meeting on Cholinesterases Edited by Karl Tsim and Bhupendra Doctor ; Karl Tsim, Bhupendra Doctor (eds.).

POVEZANOST RADA