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.

Specialized metabolic convergence in the gut microbiomes of cycad-feeding insects tolerant to β-methylamino-L-alanine (BMAA)

“…An interesting possibility is that siderophore-producing bacteria could provide protective benefits for cycadivorous insects by mediating chemical interactions between metal ions and BMAA inside the gut lumen. BMAA is also capable of chelating iron and other metals (Glover et al, 2012), and the formation of BMAA-metal ion complexes has been proposed as one possible cause of neurotoxicity in humans (Diaz-Parga et al, 2018, 2021; Nunn et al, 1989). The chelation of divalent metal ions alters the equilibrium between BMAA and its corresponding carbamate adducts, which are required for binding to glutamate receptors and exerting neurotoxic effects (Diaz-Parga et al, 2021).…”

Gut Symptoms, Gut Dysbiosis and Gut-Derived Toxins in ALS

“…HCSA in the circulation could enter the CNS and activate synaptic receptors including NMDAR and mGluR and cause excitotoxicity in some patients with ALS. BMAA is a small molecule that has the structure of an amino acid [110,111]; it is highly reactive and can exist in free and protein-bound forms [112]. It is the best-known toxin in ALS [113].…”

Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

“…3 H-BMAA was retained in NMcontaining neurons of frogs, and 3 H-BMAA bound to Sepia melanin and interacted with synthesis of melanin in vitro [124]. When bicarbonate ions are present (bicarbonate is a major physiological buffer in our bodies), carbamate adducts form with L-BMAA that can chelate divalent metals such as iron, manganese and zinc [126], which could implicate that L-BMAA-carbamate may interfere with NM's metal-chelating ability [75]. However, being hydrophilic, L-BMAA can likely not reach already incapsulated NM residing inside double membranes.…”