Metal trafficking: from maintaining the metal homeostasis to future drug design

Abstract

The diverse proteins and enzymes involved in metal trafficking between and inside human cells form numerous transport networks which are highly specific for each essential metal ion and apoprotein. Individual players include voltage-gated ion channels, import and export proteins, intracellular metal-ion sensors, storage proteins and chaperones. In the case of calcium, iron and copper, some of the most apparent trafficking avenues are now well established in eukaryotes, while others are just emerging (e.g. for zinc, manganese and molybdenum). Chemistry provides an important contribution to many issues surrounding these transport pathways, from metal binding-constants and ion specificity to metal-ion exchange kinetics. Ultimately, a better understanding of these processes opens up opportunities for metal-ion-related therapy, which goes beyond traditional chelate-based metal ion detoxification.

Glutathione: a key component of the cytoplasmic labile iron pool

“…6), in a fashion similar to that of the reduction of methemoglobin. Iron(II) binding by GSH offers a means by which the cytoplasm can distinguish iron(II) and manganese(II), both of which are present at similar levels (Ba et al 2009). The affinity of manganese(II) for GSH is markedly lower than that of iron(II); the log K 1 values being respectively 2.7 (Martin and Edsall 1959) and 5.1 (This study).…”

“…Metal trafficking, both within and between cells, is currently being investigated in some depth (O'Halloran 1993;Ba et al 2009;Waldron et al 2009), iron movement and transport being particularly well characterised in bacteria (Hider and Kong 2010), plants (Marschner 1993) and animals (Crichton 2009). However the nature of the cytoplasmic iron pool remains uncharacterised.…”

Separative techniques for metalloproteomics require balance between separation and perturbation

“…All these proteins play a crucial role in biological systems, so the binding of an unexpected metal can have dramatic consequences. While invivo metal misincorporation in an enzyme site appears to occur rarely [2], the transport of undesirable metals seems to be reported more often [3,4].…”

“…It has been pointed out that selectivity cannot be explained only by binding constants and coordination geometries but is also achieved by the fine control of metal availability [12]. Mechanisms used by cells to regulate metal concentrations have been discussed by several authors [3,[13][14][15][16][17]. The free-metal concentration is adapted through the action of both metal transporters and storage proteins.…”

The Metal-Thiolate Clusters of Plant Metallothioneins

“…Cd II again for Zn II . [13] Additional effects observed for some MT forms include neuronal growth inhibitory activity, [14] resistance development against platinum anticancer drugs, [15] as well as antioxida tive properties and relevance in reactive oxygen species (ROS) scavenging. [16] The latter can be understood in light of the rel ative oxidation sensitivity of the thiol(ate) groups in MTs.…”