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Design and Mechanism of Tetrahydrothiophene-Based γ‑Aminobutyric Acid Aminotransferase Inactivators
journal contribution
posted on 2015-04-08, 00:00 authored by Hoang
V. Le, Dustin D. Hawker, Rui Wu, Emma Doud, Julia Widom, Ruslan Sanishvili, Dali Liu, Neil L. Kelleher, Richard B. SilvermanLow 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···OC interaction
with Glu-270, thereby inactivating the enzyme.