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On the Differential Roles of Mg²⁺, Zn²⁺, and Cu²⁺ in the Equilibrium of β-N-Methyl-Amino-L-Alanine (BMAA) and its Carbamates.

ABSTRACT: β-N-methyl-amino-L-alanine (BMAA) in the presence of bicarbonate (HCO₃^-) 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 (Mg²⁺, Zn²⁺, and Cu²⁺) 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 Zn²⁺ and Cu²⁺, 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 Cu²⁺ is more drastic than with the Zn²⁺, under the same stoichiometric ratios of BMAA and the individual divalent ions. However, the presence of Mg²⁺ 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 Cu²⁺ using UV-Vis spectroscopy. Our results demonstrate that BMAA differentially interacts with divalent metal ions (Mg²⁺ < Zn²⁺ < Cu²⁺), 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.

SUBMITTER: Diaz-Parga P

PROVIDER: S-EPMC7367705 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:It was well documented that macro/trace elements were associated with the neurodevelopment. We aimed to investigate the relationship between copper (Cu)/zinc (Zn)/iron/calcium (Ca)/magnesium (Mg) levels and cerebral palsy (CP) by performing a meta-analysis. We searched the PubMed, Embase, Cochrane and Chinese WanFang databases from January 1985 to June 2022 to yield studies that met our predefined criteria. Standard mean differences (SMDs) of Cu/Zn/Iron/Ca/Mg levels between CP cases and healthy controls were calculated using the fixed-effects model or the random-effects model, in the presence of heterogeneity. 95% confidence intervals (CI) were also computed. Sensitivity analysis was performed by omitting each study in turn. A total of 19 studies were involved in our investigation. CP cases showed markedly lower Cu, Zn, iron and Ca levels than those in controls among overall populations (SMD = - 2.156, 95% CI - 3.013 to - 1.299, P < 10-4; SMD = - 2.223, 95% CI - 2.966 to - 1.480, P < 10-4; SMD = - 1.092, 95% CI - 1.513 to - 0.672, P < 10-4; SMD = - 0.757, 95% CI - 1.475 to - 0.040, P = 0.038) and Asians (SMD = - 2.893, 95% CI - 3.977 to - 1.809, P < 10-4; SMD = - 2.559, 95% CI - 3.436 to - 1.683, P < 10-4; SMD = - 1.336, 95% CI - 1.807 to - 0.865, P < 10-4; SMD = - 1.000, 95% CI - 1.950 to - 0.051, P = 0.039). CP cases showed markedly lower Zn level than that in controls among Caucasians (SMD = - 0.462, 95% CI - 0.650 to - 0.274, P < 10-4). No significant differences of Cu, iron and Ca levels between CP cases and controls among Caucasians (SMD = - 0.188, 95% CI - 0.412 to 0.037, P = 0.101; SMD = - 0.004, 95% CI - 0.190 to 0.182, P = 0.968; SMD = 0.070, 95% CI - 0.116 to 0.257, P = 0.459) were observed. No marked difference of Mg level between CP cases and controls was noted among overall populations (SMD = - 0.139, 95% CI - 0.504 to 0.226, P = 0.455), Asians (SMD = - 0.131, 95% CI - 0.663 to 0.401, P = 0.629), and Caucasians (SMD = - 0.074, 95% CI - 0.361 to 0.213, P = 0.614). Sensitivity analysis did not change the overall results significantly for Cu, Zn, iron and Mg. CP cases demonstrated significantly lower levels of Cu/Zn/iron/Ca than those in healthy controls, particularly in Asians. Decreasing trend of Cu/Zn/iron/Ca levels merit attention, particularly in the population with high susceptibility to CP. Frequent monitoring and early intervention may be needed.

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On the Differential Roles of Mg²⁺, Zn²⁺, and Cu²⁺ in the Equilibrium of β-N-Methyl-Amino-L-Alanine (BMAA) and its Carbamates.

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On the Differential Roles of Mg2+, Zn2+, and Cu2+ in the Equilibrium of β-N-Methyl-Amino-L-Alanine (BMAA) and its Carbamates.

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OmicsDI is part of the ELIXIR infrastructure

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On the Differential Roles of Mg²⁺, Zn²⁺, and Cu²⁺ in the Equilibrium of β-N-Methyl-Amino-L-Alanine (BMAA) and its Carbamates.