Metal dyshomeostasis is frequently observed in AD due to anomalous binding of metals such as iron (Fe), copper (Cu), and zinc (Zn), or impaired regulation of redox-active metals inducing the neuronal damage.
Moreover, Fe(II) and Co II) are relatively low in the Irving Williams stability series, rendering selectivity challenging for recognition over biologically relevant and tight ligand-binding divalent metals, such as Zn II) and Cu II).
Thus the locus of inhibition was determined by identifying non-conserved amino acids between the CaV3.2 and CaV3.1/CaV3.3 channels, specifically looking for residues that are capable of binding with trace metals, such as glutamate, aspartate, cysteine and histidine.
Among natural chelators, histidine and histidine-containing peptides, especially those having the N-terminal XaaYaaHis motif (e.g., albumin), play the major role in biologic binding of transition metals such as Cu II), Ni II), or Co II) (Harford and Sarkar 1995).
At these concentrations AHCs may not exert their effects by critical depletion of the pool of intracellular iron but by binding to other trace metals such as copper (see discussion below).
Nonenzymatic endogenous antioxidants (apart from thiols) include metal-binding proteins which sequester prooxidant metals such as iron and copper [ 12].
However, the low binding capacity of biomass for certain recalcitrant metals such as Ni and failure to effectively remove metals from real industrial effluents due to presence of organic or inorganic ligands limit this approach.
In particular, metallosupramolecular chemistry involves the self-assembly of bifunctional organic ligands such as bipyridyl molecules (which possess two binding sites for metal ions) with ions of metals such as palladium (Pd2+).
Hydrothermal sources release high quantities of organic compounds, enabling the stabilization and preservation of metals such as Fe as organic-binding complexes in the water column44,45.
