J. Biol. Chem., Vol. 265, Issue 18, 10193-10195, Jun, 1990
Neuroactive carbamate adducts of beta-N-methylamino-L-alanine and ethylenediamine. Detection and quantitation under physiological conditions by 13C NMR
TG Myers and SD Nelson
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
beta-N-Methylamino-L-alanine (BMAA) reacts with dissolved carbon dioxide to
form two carbamate compounds at physiological pH, temperature and
bicarbonate concentration. The reversible reactions of BMAA with dissolved
carbon dioxide were monitored by 13C NMR. At 37 degrees C and pH 7.4, the
fraction of BMAA existing as the alpha-N- carboxy adduct is 0.22 while the
fraction of BMAA existing as the beta- N-carboxy adduct is 0.09. Although
both adducts could be implicated in the bicarbonate-dependent neurotoxicity
of BMAA (Weiss, J. H., and Choi, D. W. (1988) Science 241, 973-975; Mroz,
E. A., Weiss, J. W., and Choi, D. W. (1989) Science 243, 1613), the
beta-N-carboxy adduct shares structural characteristics with the
appropriate endogenous ligand, glutamic acid. Analogously, the GABA-mimetic
properties of ethylenediamine have been attributed to a carbamate adduct,
ethylenediamine monocarbamate (Kerr, D. I. B., and Ong, J. (1987) Br. J.
Pharmacol. 90, 763-769). Using the same method, we were able to detect
directly and quantify the formation of this carbamate under physiological
conditions. Information on the carbamate equilibria of these compounds is
essential in order to address questions of their neuroactive potency.
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