Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators
- Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, and the Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208, United States
- Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
- Departments of Chemistry and Molecular Biosciences and the Proteomics Center of Excellence, Northwestern University, Evanston, Illinois 60208, United States
- X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, Lemont, Illinois 60439, United States
Low levels of gamma-aminobutyric acid (GABA), one of two major neurotransmitters that regulate brain neuronal activity, are associated with many neurological disorders, such as epilepsy, Parkinsons disease, Alzheimers disease, Huntingtons 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 bloodbrain barrier and inhibit the activity of gamma-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 pi-pi interaction with Phe-189, and a weak nonbonded (SO)-O-...=C interaction with Glu-270, thereby inactivating the enzyme.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- National Institutes of Health (NIH)
- DOE Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1391869
- Journal Information:
- Journal of the American Chemical Society, Vol. 137, Issue 13; ISSN 0002-7863
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
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