Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators

Hoang V. Le, Dustin D. Hawker, Rui Wu, Emma Doud, Julia Widom, Ruslan Sanishvili, Dali Liu, Neil L Kelleher, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Low levels of γ-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cocaine addiction. One of the main methods to raise the GABA level in human brain is to use small molecules that cross the blood-brain barrier and inhibit the activity of γ-aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA. We have designed a series of conformationally restricted tetrahydrothiophene-based GABA analogues with a properly positioned leaving group that could facilitate a ring-opening mechanism, leading to inactivation of GABA-AT. One compound in the series is 8 times more efficient an inactivator of GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. Our mechanistic studies show that the compound inactivates GABA-AT by a new mechanism. The metabolite resulting from inactivation does not covalently bind to amino acid residues of GABA-AT but stays in the active site via H-bonding interactions with Arg-192, a π-π interaction with Phe-189, and a weak nonbonded S...⋯O=C interaction with Glu-270, thereby inactivating the enzyme. (Figure Presented).

Original languageEnglish (US)
Pages (from-to)4525-4533
Number of pages9
JournalJournal of the American Chemical Society
Volume137
Issue number13
DOIs
StatePublished - Mar 17 2015

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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