10.1021/acschembio.5b00212.s001
Hyunbeom Lee
Hyunbeom
Lee
Hoang
V. Le
Hoang
V.
Le
Rui Wu
Rui
Wu
Emma Doud
Emma
Doud
Ruslan Sanishvili
Ruslan
Sanishvili
John F. Kellie
John F.
Kellie
Phillip
D. Compton
Phillip
D.
Compton
Boobalan Pachaiyappan
Boobalan
Pachaiyappan
Dali Liu
Dali
Liu
Neil L. Kelleher
Neil L.
Kelleher
Richard B. Silverman
Richard B.
Silverman
Mechanism of Inactivation of GABA Aminotransferase
by (<i>E</i>)- and (<i>Z</i>)‑(1<i>S</i>,3<i>S</i>)‑3-Amino-4-fluoromethylenyl-1-cyclopentanoic
Acid
American Chemical Society
2015
CPP
metabolite formyl group
acid
GABA
vigabatrin
inactivation
future inactivator design
inactivating
Arg 445
2015-09-18 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Mechanism_of_Inactivation_of_GABA_Aminotransferase_by_i_E_i_and_i_Z_i_1_i_S_i_3_i_S_i_3_Amino_4_fluoromethylenyl_1_cyclopentanoic_Acid/2129971
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 (1<i>S</i>,3<i>S</i>)-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 (<i>E</i>)- and (<i>Z</i>)-(1<i>S</i>,3<i>S</i>)-3-amino-4-fluoromethylenyl-1-cyclopentanoic
acid (<b>1</b> and <b>2</b>, 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 <b>1</b> and <b>2</b>. 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.