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In Situ Assembly of...
In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design
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Wiktelius, Daniel (author)
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Allgardsson, Anders (author)
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Bergström, Tomas (author)
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- Hoster, Norman (author)
- Umeå universitet,Kemiska institutionen
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Akfur, Christine (author)
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Forsgren, Nina (author)
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Lejon, Christian (author)
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- Hedenström, Mattias, 1976- (author)
- Umeå universitet,Kemiska institutionen
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- Linusson, Anna, 1970- (author)
- Umeå universitet,Kemiska institutionen
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Ekstrom, Fredrik (author)
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(creator_code:org_t)
- 2020-11-20
- 2021
- English.
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In: Angewandte Chemie International Edition. - : Wiley-VCH Verlagsgesellschaft. - 1433-7851 .- 1521-3773. ; 60:2, s. 813-819
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- The potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T-cells, and B-cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A-dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target-catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Keyword
- choline acetyltransferase
- coenzyme A
- drug discovery
- hydrothiolation
- in situ assembly
Publication and Content Type
- ref (subject category)
- art (subject category)
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Wiktelius, Danie ...
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Allgardsson, And ...
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Bergström, Tomas
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Hoster, Norman
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Akfur, Christine
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Forsgren, Nina
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show more...
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Lejon, Christian
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Hedenström, Matt ...
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Linusson, Anna, ...
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Ekstrom, Fredrik
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
- Articles in the publication
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Angewandte Chemi ...
- By the university
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Umeå University