- In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design
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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.
- Wiktelius, Daniel,Allgardsson, Anders,Bergstr?m, Tomas,Hoster, Norman,Akfur, Christine,Forsgren, Nina,Lejon, Christian,Hedenstr?m, Mattias,Linusson, Anna,Ekstr?m, Fredrik
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supporting information
p. 813 - 819
(2020/12/09)
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- Experimental and quantum chemical evidences for C-H···N hydrogen bonds involving quaternary pyridinium salts and pyridinium ylides
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The rates of equilibrium of eight quaternary pyridinium salts containing activated methylene groups with the corresponding ylides have been measured in DMSO solution containing strong bases (DBU, MTBD and P1-tBu). The effect of the ring substituents on th
- Dega-Szafran,Schroeder,Szafran,Szwajca,L?ska,Lewandowska
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- Preparation of Tetrahydroindolizines from Pyridinuim and Isoquinolinium Ylides
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Carbonyl- and nitrile-stabilised pyridinium and cyclic azonium methylides condense with chalcones to form tetrahydroindolizines and analogous fused pyrrolidines.The stereochemistry is illuminated by 13C and 1H n.m.r. spectroscopy.Several incorrect literature structures are rectified.
- Katritzky, Alan R.,Grzeskowiak, Nicholas E.,Alvarez-Builla, Julio
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p. 1180 - 1185
(2007/10/02)
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