7amd
From Proteopedia
In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design
Structural highlights
DiseaseCLAT_HUMAN Defects in CHAT are the cause of congenital myasthenic syndrome with episodic apnea (CMSEA) [MIM:254210; formerly known as familial infantile myasthenia gravis 2 (FIMG2). CMSEA is an autosomal recessive congenital myasthenic syndrome. Patients have myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement.[1] [2] FunctionCLAT_HUMAN Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Publication Abstract from PubMedThe potential drug target choline acetyltransferase (ChAT) catalyzes 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. In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design.,Wiktelius D, Allgardsson A, Bergstrom T, Hoster N, Akfur C, Forsgren N, Lejon C, Hedenstrom M, Linusson A, Ekstrom F Angew Chem Int Ed Engl. 2020 Oct 20. doi: 10.1002/anie.202011989. PMID:33079431[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Akfur C | Allgardsson A | Bergstrom T | Ekstrom FJ | Forsgren N | Hedenstrom M | Hoster N | Lejon C | Linusson A | Wiktelius D
