Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts

Abstract

Beta-N-methylamino-L-alanine (BMAA) has been demonstrated to contribute to the onset of the ALS/Parkinsonism-dementia complex (ALS/PDC) and is implicated in the progression of other neurodegenerative diseases. While the role of BMAA in these diseases is still debated, one of the suggested mechanisms involves the activation of excitatory glutamate receptors. In particular, the excitatory effects of BMAA are shown to be dependent on the presence of bicarbonate ions, which in turn forms carbamate adducts in physiological conditions. The formation of carbamate adducts from BMAA and bicarbonate is similar to the formation of carbamate adducts from non-proteinogenic amino acids. Structural, chemical, and biological information related to non-proteinogenic amino acids provide insight into the formation of and possible neurological action of BMAA. This article reviews the carbamate formation of BMAA in the presence of bicarbonate ions, with a particular focus on how the chemical equilibrium of BMAA carbamate adducts may affect the molecular mechanism of its function. Highlights of nuclear magnetic resonance (NMR)-based studies on the equilibrium process between free BMAA and its adducts are presented. The role of divalent metals on the equilibrium process is also explored. The formation and the equilibrium process of carbamate adducts of BMAA may answer questions on their neuroactive potency and provide strong motivation for further investigations into other toxic mechanisms.

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Acknowledgements

JG and VVK thank Dr. Paul Cox at the Institute of Ethnomedicine for organizing the 2016 BMAA symposium where part of the work was presented. PD acknowledges the support by the Bridges to Doctorate Program (R25 GM115293). The authors thank David Zimmerman for part of the work related to NMR studies of carbamate formation. The authors thank C. Cortney for critical reading of the manuscript.

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Correspondence to Joy J. Goto or V.V. Krishnan.

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Diaz-parga, P., Goto, J.J. & Krishnan, V. Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts. Neurotox Res 33, 76–86 (2018). https://doi.org/10.1007/s12640-017-9801-2

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Keywords

  • β-N-methylamino-L-alanine (BMAA)
  • Carbamate
  • NMR
  • Chemical equilibrium