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Transition metal dysregulation is associated with a host of pathologies, many of which are therapeutically targeted using chelators and ionophores. Chelators and ionophores are used as therapeutic metal-binding compounds which impart biological effects by sequestering or trafficking endogenous metal ions in an effort to restore homeostasis. Many current therapies take inspiration or derive directly from small molecules and peptides found in plants. This review focuses on plant-derived small molecule and peptide chelators and ionophores that can affect metabolic disease states. Understanding the coordination chemistry, bioavailability, and bioactivity of such molecules provides the tools to further research applications of plant-based chelators and ionophores. 

Copper is essential in a host of biological processes, and disruption of its homeostasis is associated with diseases including neurodegeneration and metabolic disorders. Extracellular copper shifts in its speciation between healthy and disease states, and identifying molecular components involved in these perturbations could widen the panel of biomarkers for copper status. While there have been exciting advances in approaches for studying the extracellular proteome with mass spectrometry–based methods, the typical workflows disrupt metal–protein interactions due to the lability of these bonds either during sample preparation or in gas-phase environments. We sought to develop and apply a workflow to enrich for and identify protein populations with copper-binding propensities in extracellular fluids using an immobilized metal affinity chromatography (IMAC) resin. The strategy was optimized using human serum to allow for maximum quantity and diversity of protein enrichment. Protein populations could be differentiated based on protein load on the resin, likely on account of differences in abundance and affinity. The enrichment workflow was applied to plasma samples from patients with Wilson’s disease and protein IDs and differential abundancies relative to healthy subjects were compared to those yielded from a traditional proteomic workflow. While the IMAC workflow preserved differential abundance and protein ID information from the traditional workflow, it identified several additional proteins being differentially abundant including those involved in lipid metabolism, immune system, and antioxidant pathways. Our results suggest the potential for this IMAC workflow to identify new proteins as potential biomarkers in copper-associated disease states.