cb5b00212_si_001.pdf (4.9 MB)
Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)‑(1S,3S)‑3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid
journal contribution
posted on 2015-09-18, 00:00 authored by Hyunbeom Lee, Hoang
V. Le, Rui Wu, Emma Doud, Ruslan Sanishvili, John F. Kellie, Phillip
D. Compton, Boobalan Pachaiyappan, Dali Liu, Neil L. Kelleher, Richard B. SilvermanWhen
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.