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Characterization of a novel butyrylcholinesterase point mutation (p.Ala34Val), "silent" with mivacurium

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dc.contributor.author Delacour H.
dc.contributor.author Lushchekina S.
dc.contributor.author Mabboux I.
dc.contributor.author Ceppa F.
dc.contributor.author Masson P.
dc.contributor.author Schopfer L.
dc.contributor.author Lockridge O.
dc.date.accessioned 2018-09-18T20:02:03Z
dc.date.available 2018-09-18T20:02:03Z
dc.date.issued 2014
dc.identifier.issn 0006-2952
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/135921
dc.description.abstract © 2014 Elsevier Inc. All rights reserved. Butyrylcholinesterase deficiency is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or mivarcurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of mivacurium leading to the discovery of a novel BCHE variant (c.185C>T, p.Ala34Val). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation remote from the active center determines the "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with a heterozygous enzyme of type atypical/silent. Kinetic analysis with succinyldithiocholine (SCdTC) as the substrate showed that Ala34Val BChE was inactive against this substrate. However, with BTC, the mutant enzyme was active, displaying an unexpected activation by excess substrate. Competitive inhibition of BTC by mivacurium gave a K<inf>i</inf> = 1.35 mM consistent with the lack of activity with the related substrate SCdTC, and with the clinical data. Molecular dynamic simulations revealed the mechanism by which mutation Ala34Val determines the silent phenotype: a chain of intramolecular events leads to disruption of the catalytic triad, so that His438 no longer interacts with Ser198, but instead forms hydrogen bonds either with residues Glu197 and Trp82, or peripheral site residue Tyr332. However, at high BTC concentration, initial binding of substrate to the peripheral site triggers restoration of a functional catalytic triad, and activity with BTC.
dc.relation.ispartofseries Biochemical Pharmacology
dc.subject Butyrylcholinesterase deficiency
dc.subject Genetic diagnosis
dc.title Characterization of a novel butyrylcholinesterase point mutation (p.Ala34Val), "silent" with mivacurium
dc.type Article
dc.relation.ispartofseries-issue 3
dc.relation.ispartofseries-volume 92
dc.collection Публикации сотрудников КФУ
dc.relation.startpage 476
dc.source.id SCOPUS00062952-2014-92-3-SID84910642392


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  • Публикации сотрудников КФУ Scopus [20180]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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