TY - JOUR
T1 - Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase
AU - Shen, Sida
AU - Doubleday, Peter F.
AU - Weerawarna, Pathum M.
AU - Zhu, Wei
AU - Kelleher, Neil L.
AU - Silverman, Richard B.
N1 - Funding Information:
This research was supported by NIH grants (Grant R01 DA030604 to R.B.S. and Grant P30 DA018310 to N.L.K.) and NSF grant (Grant 2015210477 to P.F.D.). This work made use of the IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF Grant NNCI-1542205), the State of Illinois, and the International Institute for Nanotechnology (IIN).
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/10/8
Y1 - 2020/10/8
N2 - Aminotransferases are pyridoxal 5′-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and an α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident that γ-aminobutyric acid aminotransferase (GABA-AT), which balances the levels of inhibitory and excitatory neurotransmitters, has emerged as a promising therapeutic target for epilepsy and cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established an integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry to facilitate our design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue (6a), 25-times more efficient as an inactivator of GABA-AT compared to the parent compound (1R,3S,4S)-3-amino-4-fluorocyclopentane carboxylic acid (FCP, 4).
AB - Aminotransferases are pyridoxal 5′-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and an α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident that γ-aminobutyric acid aminotransferase (GABA-AT), which balances the levels of inhibitory and excitatory neurotransmitters, has emerged as a promising therapeutic target for epilepsy and cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established an integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry to facilitate our design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue (6a), 25-times more efficient as an inactivator of GABA-AT compared to the parent compound (1R,3S,4S)-3-amino-4-fluorocyclopentane carboxylic acid (FCP, 4).
KW - GABA aminotransferase
KW - cyclopentene
KW - deprotonation
KW - inactivation efficiency
KW - rate constant
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U2 - 10.1021/acsmedchemlett.9b00672
DO - 10.1021/acsmedchemlett.9b00672
M3 - Article
C2 - 33062178
AN - SCOPUS:85080090274
SN - 1948-5875
VL - 11
SP - 1949
EP - 1955
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 10
ER -