umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: Possible implications for the HI-6 antidote substrate specificity
Swedish Defence Research Agency, CBRN, Defence and Security, Umeå.
Swedish Defence Research Agency, CBRN, Defence and Security, Umeå.
Swedish Defence Research Agency, CBRN, Defence and Security, Umeå.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Show others and affiliations
2013 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 85, no 9, 1389-1397 p.Article in journal (Refereed) Published
Abstract [en]

Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300 μM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation.

Place, publisher, year, edition, pages
Elsevier, 2013. Vol. 85, no 9, 1389-1397 p.
Keyword [en]
Crystal structure, Time-resolved fluorescence, Time correlated single photon counting, Fluorescence decay spectroscopy, acetylcholinesterase, tabun, cyclosarin, Russian VX, HI-6, reactivator, oxime, structure activity relationship
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-65835DOI: 10.1016/j.bcp.2013.01.016PubMedID: 23376121OAI: oai:DiVA.org:umu-65835DiVA: diva2:604944
Available from: 2013-02-12 Created: 2013-02-12 Last updated: 2017-12-06Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Linusson, Anna

Search in DiVA

By author/editor
Linusson, Anna
By organisation
Department of Chemistry
In the same journal
Biochemical Pharmacology
Chemical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 205 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf