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Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol


Bosak, Anita; Gazić, Ivana; Vinković, Vladimir; Kovarik, Zrinka
Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol // Archives of biochemistry and biophysics, 471 (2008), 1; 72-76 doi:10.1016/j.abb.2007.12.007 (međunarodna recenzija, članak, znanstveni)


Naslov
Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol

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

Izvornik
Archives of biochemistry and biophysics (0003-9861) 471 (2008), 1; 72-76

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, 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 mouse 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



POVEZANOST RADA


Projekt / tema
022-0222148-2889 - Interakcije organofosfata, karbamata i određenih liganada s esterazama (Zrinka Kovarik, )
098-0982904-2910 - Kiralni organski materijali – sintetska, strukturna i funkcionalna istraživanja (Vladimir Vinković, )

Ustanove
Institut za medicinska istraživanja i medicinu rada, Zagreb,
Institut "Ruđer Bošković", Zagreb

Citiraj ovu publikaciju

Bosak, Anita; Gazić, Ivana; Vinković, Vladimir; Kovarik, Zrinka
Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol // Archives of biochemistry and biophysics, 471 (2008), 1; 72-76 doi:10.1016/j.abb.2007.12.007 (međunarodna recenzija, članak, znanstveni)
Bosak, A., Gazić, I., Vinković, V. & Kovarik, Z. (2008) Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol. Archives of biochemistry and biophysics, 471 (1), 72-76 doi:10.1016/j.abb.2007.12.007.
@article{article, year = {2008}, pages = {72-76}, DOI = {10.1016/j.abb.2007.12.007}, keywords = {carbamates, acetylcholinesterase, butyrylcholinesterase, catalytic constants, mutants, carbamoylation}, journal = {Archives of biochemistry and biophysics}, doi = {10.1016/j.abb.2007.12.007}, volume = {471}, number = {1}, issn = {0003-9861}, title = {Amino acid residues involved in stereoselective inhibition of cholinesterases with bambuterol}, keyword = {carbamates, acetylcholinesterase, butyrylcholinesterase, catalytic constants, mutants, carbamoylation} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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