Open AccessOn the Differential Roles of Mg2+, Zn2+, and Cu2+ in the Equilibrium of β-N-Methyl-Amino-L-Alanine (BMAA) and its Carbamates
Author(s) -
Pedro Diaz-parga,
Joy J. Goto,
V. V. Krishnan
Publication year - 2020
Publication title -
neurotoxicity research/neurotoxicity resarch
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.923
H-Index - 73
eISSN - 1476-3524
pISSN - 1029-8428
DOI - 10.1007/s12640-019-00157-0
Subject(s) - chemistry , divalent , nuclear magnetic resonance spectroscopy , carbamate , metal ions in aqueous solution , circular dichroism , molecule , adduct , stereochemistry , metal , inorganic chemistry , crystallography , organic chemistry
β-N-methyl-amino-L-alanine (BMAA) in the presence of bicarbonate (HCO 3 - ) undergoes structural modifications generating two carbamate species, α-carbamate and β-carbamate forms of BMAA. The chemical structure of BMAA and BMAA-carbamate adducts strongly suggest they may interact with divalent metal ions. The ability of BMAA to cross the blood-brain barrier and possibly interact with divalent metal ions may augment the neurotoxicity of these molecules. To understand the effects of divalent metal ions (Mg 2+ , Zn 2+ , and Cu 2+ ) on the overall dynamic equilibrium between BMAA and its carbamate adducts, a systematic study using nuclear magnetic resonance (NMR) is presented. The chemical equilibria between BMAA, its carbamate adducts, and each of the divalent ions were studied using two-dimensional chemical exchange spectroscopy (EXSY). The NMR results demonstrate that BMAA preferentially interacts with Zn 2+ and Cu 2+ , causing an overall reduction in the production of carbamate species by altering the dynamic equilibria. The NMR-based spectral changes due to the BMAA interaction with Cu 2+ is more drastic than with the Zn 2+ , under the same stoichiometric ratios of BMAA and the individual divalent ions. However, the presence of Mg 2+ does not significantly alter the dynamic equilibria between BMAA and its carbamate adducts. The NMR-based results are further validated using circular dichroism (CD) spectroscopy, observing the n ➔ π interaction in the complex formation of BMAA and the divalent metal ions, with additional verification of the interaction with Cu 2+ using UV-Vis spectroscopy. Our results demonstrate that BMAA differentially interacts with divalent metal ions (Mg 2+ < Zn 2+ < Cu 2+ ), and thus alters the rate of formation of carbamate products. The equilibria between BMAA, the bicarbonate ions, and the divalent metal ions may alter the total population of a specific form of BMAA-ion complex at physiological conditions and, therefore, add a level of complexity of the mechanisms by which BMAA acts as a neurotoxin.