Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase

Sida Shen, Peter F. Doubleday, Pathum M. Weerawarna, Wei Zhu, Neil L. Kelleher, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Aminotransferases are pyridoxal 5′-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and an α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident that γ-aminobutyric acid aminotransferase (GABA-AT), which balances the levels of inhibitory and excitatory neurotransmitters, has emerged as a promising therapeutic target for epilepsy and cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established an integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry to facilitate our design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue (6a), 25-times more efficient as an inactivator of GABA-AT compared to the parent compound (1R,3S,4S)-3-amino-4-fluorocyclopentane carboxylic acid (FCP, 4).

Original languageEnglish (US)
JournalACS Medicinal Chemistry Letters
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • GABA aminotransferase
  • cyclopentene
  • deprotonation
  • inactivation efficiency
  • rate constant

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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