Can acetylcholinesterase mutations help create more efficient reactivators for organophosphorus compounds poisoning treatment? (CROSBI ID 614672)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | domaća recenzija
Podaci o odgovornosti
Katalinić, Maja ; Šinko, Goran ; Nachon, Florian ; Dias, José ; Maček, Nikolina ; Kovarik, Zrinka
engleski
Can acetylcholinesterase mutations help create more efficient reactivators for organophosphorus compounds poisoning treatment?
Ever since its discovery at the turn of the 20th century, acetylcholinesterase (AChE) has been a focus of investigation in biochemistry, biomedicine and toxicology, owing to its irreplaceable role in neurotransmission. Organophosphorus compounds (OPs) were synthesized to modulate AChE activity as a way of efficient pest control and became a great problem due to intentional or unintentional human poisonings. The development of more effective treatment for OP poisoning still presents a challenge for researchers in this field. In the 1950s, pyridinium based oximes such as 2-PAM and HI-6 were developed as reactivators of OP-inhibited AChE and introduced into medical practice. However, they were synthesized before any knowledge about the AChE active site structure was gained, and are therefore not as efficient in OP-inhibited AChE reactivation as one would expect. Today, since we possess knowledge about the fine architecture of AChE and computational techniques, a more rational approach in oxime design should be made a priority. Nevertheless, there is still too little experimentally obtained kinetic data on interactions of OP-AChE w.t./mutants with oximes to complete a high-quality structure-activity relationship scheme. Only with such data can AChE mutations help create more efficient reactivators for OP poisoning treatment. To meet the requirements for a step forward in the synthesis of more efficient oximes, we bring a full-scope interactions kinetic profile for a set of five AChE mutants with structurally related pyridinium oximes. Results indicated residues at the choline binding site (Y337, F338) and the acyl pocket (F295) as ones influencing the placement of oximes into the right position for reactivation, while the amino acids at the peripheral site (Y124, W286) dictated the binding affinity for bispyridinum oximes and presented a limitation to their reactivation efficiency. Results also indicated that the aromatic aspects of oximes are favourable for the formation of required interactions but the two aromatic rings in the oximes were shown to be a disadvantage. On the other hand, several mutants showed favourable characteristics that could enable the development of pseudo-catalytic scavengers for OP detoxification. By means of computational modelling we suggested possible oxime orientations/interactions within the phosphylated AChE active site. We can generally assert that we have obtained a clearer concept as to where we can focus the design of oximes in the future. Acknowledgment: This work was supported in part by the Croatian-French bilateral grant (PIs: M. Katalinić, F. Nachon).
pyridinium oximes; Y337; F338; F295; Y124; W286
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Podaci o prilogu
101-x.
2014.
objavljeno
Podaci o matičnoj publikaciji
Book of Abstracts of the Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014
Katalinić, M. ; Kovarik, Z.
Zagreb: The Croatian Society of Biochemistry and Molecular Biology
978-953-95551-5-1
Podaci o skupu
The Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014
poster
24.09.2014-27.09.2014
Zadar, Hrvatska