Design and mechanism of tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators

Journal of the American Chemical Society
Hoang V LeRichard B Silverman

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.

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Citations

Oct 5, 2016·Journal of the American Chemical Society·Alexander S MikherdovVadim Yu Kukushkin
May 12, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Erika Tovar-GudiñoMario Fernández-Zertuche
Nov 18, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Josué Rodríguez-LozadaMario Fernández-Zertuche
Jun 20, 2020·Protein Science : a Publication of the Protein Society·Daniel S CatlinDali Liu
Feb 20, 2020·Mini Reviews in Medicinal Chemistry·Juan F MoralesAlan Talevi

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