Naslov
Interactions of pyridinium oximes with the peripheral alosteric site limit their efficiency in reactivation of phosphorylated AChE

Autori
Katalinić, Maja ; Maček, Nikolina ; Šinko, Goran ; 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, 04.09.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
oximes; tabun; mutants; reactivation

Sažetak
Oximes antidotal property is attributed to their ability to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus compounds (OPs). Even if there is an ongoing discussion on potential benefits of oxime therapy in OP poisoning, oximes are still the mainstay of the treatment. In the search for more efficient oximes an important step presents understanding of their interactions within active site of inhibited AChE. For this investigation, employment of AChE site-directed mutants has been proven to be very successful. In here presented study we evaluated which amino acid residues structurally limit newly developed bispyridinium oximes in reactivation of nerve agent tabun inhibited AChE. For this purpose we selected five site-directed mutants with mutations at the choline binding site (Y337A, F338A), the acyl pocket (F295L) and the peripheral binding site (Y124Q, W286A). Interactions of oximes were also evaluated using the molecular docking technique. Our results indicated that aromatic residues at the choline binding site and the acyl pocket are important for placing bispyridinium oximes in the right position to the phosphorylated active site serine. Namely, substitution of the aromatic amino acids with aliphatic ones in the choline binding site and the acyl pocket negatively influenced reactivation by bispyridinium oximes. These changes probably opened space for oximes to form stable interactions with other aromatic residues, in example W86, which resulted in increased affinity for these oximes but lower reactivation rates due to positioning of oxime group further from phosphorylated catalytic serine. On the other hand, disruption of the π-π sandwich formed between one of the oxime pyridinium rings and the amino acids of the peripheral site (i.e. Y124Q, W286A), allowed oximes to get into the more favourable position for nucleophilic attack on the phosphylated catalytic serine. In this case, reactivation rates increased 2-5 times compared to w.t. AChE. Therefore, it seems that aromatic amino acids at the AChE peripheral site present limitation in bispyridinium oxime reactivation efficiency.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA