Gabaculine is a naturally occurring, conformationally constrained analog of GABA and an irreversible inhibitor of GABA transaminase (GABA-T; Ki = 2.9 μM). [1] It irreversibly inhibits D-amino acid transaminase, L-alanine transaminase, and L-aspartate transaminase with Ki values of 0.1, 1, and 55 mM, respectively.[2] Gabaculine also irreversibly inhibits ornithine aminotransferase in vitro and in mouse brain and liver homogenates, where ornithine aminotransferase activity is suppressed for over 24 hours when administered at a dose of 50 mg/kg. [3] Gabaculine increases latency to convulsion in the 3-mercaptopropionic acid-induced and minimal electroshock-induced seizure models (ED50s = 135 and 200 mg/kg, respectively) and inhibits 3-mercaptopropionic acid-induced increases in glutamic acid decarboxylase (GAD) activity and GABA-T activity in mice (ED50s =135 mg/kg), however, the doses fall above the LD50 value of 62 mg/kg. [4] Gabaculine (135 mg/kg, i.p.) elevates concentrations of GABA in mouse brain by over 500% and knocks out GABA-T activity to below detection limits.
Reference:
[1]. Rando, R.R. Mechanism of the irreversible inhibition of γ-aminobutyric acid--ketoglutaric acid transaminase by the neurotoxin gabaculine. Biochem J. 16(21), 4604-4610 (1977).
[2]. Soper, T.S., and Manning, J.M. Inactivation of pyridoxal phosphate enzymes by gabaculine. Correlation with enzymic exchange of β-protons. J. Biol. Chem. 257(23), 13930-13936 (1982).
[3]. Jung, M.J., and Seiler, N. Enzyme-activated irreversible inhibitors of L-ornithine:2-oxoacid aminotransferase. Demonstration of mechanistic features of the inhibition of ornithine aminotransferase by 4-aminohex-5-ynoic acid and gabaculine and correlation with in vivo activity. J. Biol. Chem. 253(20), 7431-7439 (1978).
[4]. Löscher, W. 3-Mercaptopropionic acid: convulsant properties, effects on enzymes of the γ-aminobutyrate system in mouse brain and antagonism by certain anticonvulsant drugs, aminooxyacetic acid and gabaculine. Biochem. Pharmacol. 28(8), 1397-1407 (1979).