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

Abstract

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.

Authors:
 [1];  [1];  [2];  [3];  [1];  [4];  [2];  [3];  [1]
  1. 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
  2. Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, Illinois 60660, United States
  3. Departments of Chemistry and Molecular Biosciences and the Proteomics Center of Excellence, Northwestern University, Evanston, Illinois 60208, United States
  4. X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, Lemont, Illinois 60439, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1391869
DOE Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of the American Chemical Society; Journal Volume: 137; Journal Issue: 13
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Le, Hoang V., Hawker, Dustin D., Wu, Rui, Doud, Emma, Widom, Julia, Sanishvili, Ruslan, Liu, Dali, Kelleher, Neil L., and Silverman, Richard B. Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators. United States: N. p., 2015. Web. doi:10.1021/jacs.5b01155.
Le, Hoang V., Hawker, Dustin D., Wu, Rui, Doud, Emma, Widom, Julia, Sanishvili, Ruslan, Liu, Dali, Kelleher, Neil L., & Silverman, Richard B. Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators. United States. doi:10.1021/jacs.5b01155.
Le, Hoang V., Hawker, Dustin D., Wu, Rui, Doud, Emma, Widom, Julia, Sanishvili, Ruslan, Liu, Dali, Kelleher, Neil L., and Silverman, Richard B. Wed . "Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators". United States. doi:10.1021/jacs.5b01155.
@article{osti_1391869,
title = {Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators},
author = {Le, Hoang V. and Hawker, Dustin D. and Wu, Rui and Doud, Emma and Widom, Julia and Sanishvili, Ruslan and Liu, Dali and Kelleher, Neil L. and Silverman, Richard B.},
abstractNote = {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.},
doi = {10.1021/jacs.5b01155},
journal = {Journal of the American Chemical Society},
number = 13,
volume = 137,
place = {United States},
year = {Wed Mar 25 00:00:00 EDT 2015},
month = {Wed Mar 25 00:00:00 EDT 2015}
}