ArticleACS chemical biology2015
Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator.Journal of the American Chemical Society · 2026Article
- Synthesis of (2The Journal of organic chemistry · 2024Article
- Design, Synthesis, and Mechanistic Studies of (ACS chemical biology · 2024Article
- Identification of novel C-15 fluoro isosteviol derivatives for GABA-AT inhibition by in silico investigations.Journal of molecular modeling · 2023Article
- Mechanism of action involved in the anxiolytic-like effects of Hibalactone isolated fromJournal of traditional and complementary medicine · 2022Article
- Rational Design, Synthesis, and Mechanism of (3Journal of the American Chemical Society · 2022Article
- (S)-4-Amino-5-phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR.Protein science : a publication of the Protein Society · 2020Article
- QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT.Molecules (Basel, Switzerland) · 2018Article
- Novel-Substituted Heterocyclic GABA Analogues. Enzymatic Activity against the GABA-AT Enzyme fromMolecules (Basel, Switzerland) · 2018Article
- Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions.Chemical reviews · 2018Review
- Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1'-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators.Journal of the American Chemical Society · 2017Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.