Abstract
When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design.
Original language | English (US) |
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Pages (from-to) | 2087-2098 |
Number of pages | 12 |
Journal | ACS chemical biology |
Volume | 10 |
Issue number | 9 |
DOIs | |
State | Published - Sep 18 2015 |
ASJC Scopus subject areas
- Molecular Medicine
- Biochemistry
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Dive into the research topics of 'Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid'. Together they form a unique fingerprint.Datasets
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Pig Brain GABA-AT inactivated by (E)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic acid
Lee, H. (Contributor), Le, H. V. (Contributor), Wu, R. (Contributor), Doud, E. (Contributor), Sanishvili, R. (Contributor), Kellie, J. F. (Contributor), Compton, P. D. (Contributor), Pachaiyappan, B. (Contributor), Liu, D. (Contributor), Kelleher, N. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Jul 8 2015
DOI: 10.2210/pdb4ZSW/pdb, https://www.wwpdb.org/pdb?id=pdb_00004zsw
Dataset
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Pig Brain GABA-AT inactivated by (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic acid.
Lee, H. (Contributor), Le, H. V. (Contributor), Wu, R. (Contributor), Doud, E. (Contributor), Sanishvili, R. (Contributor), Kellie, J. F. (Contributor), Compton, P. D. (Contributor), Pachaiyappan, B. (Contributor), Liu, D. (Contributor), Kelleher, N. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Jul 8 2015
DOI: 10.2210/pdb4ZSY/pdb, https://www.wwpdb.org/pdb?id=pdb_00004zsy
Dataset