L-α-Aminoadipic Acid

Ki value of 209 μM

L-α-Aminoadipic Acid is a glutamine synthetase inhibitor.

Glutamine synthetase is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine.

In vitro: Previous study found that DL- and L-alpha-aminoadipic acid (alpha-AA) were specific gliotoxins in vitro. HPLC analysis of cultures incubated with D- or L-alpha-AA and DL-[14C]-alpha-AA autoradiograms conducted in the presence of D- or L-alpha-AA suggested a stereospecificity of astroglial L-alpha-AA uptake. Both the uptake of alpha-AA by astrocytes and alpha-AA-induced gliotoxicity were sodium dependent [1]. Another study found that the L-isomer of alpha aminoadipate was able to competitively inhibit the transport protein, whereas the D-isomer of alpha aminoadipate was ineffective. Moreover, it was found that L-alpha aminoadipate was a competitive inhibitor of both glutamine synthetase, and gamma-glutamylcysteine synthetase. In constrast, the D-isomer of alpha aminoadipate was a far weaker inhibitor of either enzyme [2].

In vivo: Animal study showed that L-a-aminoadipic acid could lower the levels of endogenous extracellular kynurenic acid in the hippocampus in a dose-dependent fashion), though the effect of L-a-aminoadipic acid seemed to be less pronounced than its reduction of de novo produced kynurenic acid [3].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Huck, S. ,Grass, F., and Hrtnagl, H. The glutamate analogue α-aminoadipic acid is taken up by astrocytes before exerting its gliotoxic effect in vitro. Journal of Neuroscience 4(10), 2650-2657 (1984).
[2] McBean GJ.  Inhibition of the glutamate transporter and glial enzymes in rat striatum by the gliotoxin, alpha aminoadipate. Br J Pharmacol. 1994 Oct;113(2):536-40.
[3] Wu HQ, Ungerstedt U, Schwarcz R. L-alpha-aminoadipic acid as a regulator of kynurenic acid production in the hippocampus: a microdialysis study in freely moving rats. Eur J Pharmacol. 1995 Jul 25;281(1):55-61.