TY - JOUR
T1 - Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid
AU - Lee, Hyunbeom
AU - Le, Hoang V.
AU - Wu, Rui
AU - Doud, Emma
AU - Sanishvili, Ruslan
AU - Kellie, John F.
AU - Compton, Philip D
AU - Pachaiyappan, Boobalan
AU - Liu, Dali
AU - Kelleher, Neil L
AU - Silverman, Richard B
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/9/18
Y1 - 2015/9/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84942049010&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942049010&partnerID=8YFLogxK
U2 - 10.1021/acschembio.5b00212
DO - 10.1021/acschembio.5b00212
M3 - Article
C2 - 26110556
AN - SCOPUS:84942049010
SN - 1554-8929
VL - 10
SP - 2087
EP - 2098
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 9
ER -