title: Design and mechanism of tetrahydrothiophene-based γ-aminobutyric acid aminotransferase inactivators.
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.
authors.affiliation: †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.
authors.forename: Hoang V
authors.initials: HV
authors.lastname: Le
authors.affiliation: †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.
authors.forename: Dustin D
authors.initials: DD
authors.lastname: Hawker
authors.affiliation: ‡Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: §Departments of Chemistry and Molecular Biosciences and the Proteomics Center of Excellence, Northwestern University, Evanston, Illinois 60208, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: Doud
authors.affiliation: †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.
authors.forename: Julia
authors.initials: J
authors.lastname: Widom
authors.affiliation: ∥X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, Lemont, Illinois 60439, United States.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Sanishvili
authors.affiliation: ‡Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States.
authors.forename: Dali
authors.initials: D
authors.lastname: Liu
authors.affiliation: §Departments of Chemistry and Molecular Biosciences and the Proteomics Center of Excellence, Northwestern University, Evanston, Illinois 60208, United States.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher
authors.affiliation: †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.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013876:Thiophenes; D005680:gamma-Aminobutyric Acid; C121030:tetrahydrothiophene; D000612:4-Aminobutyrate Transaminase