Glutathione Complexed Fe–S Centers

Abstract

Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is a major thiol-containing peptide with cellular levels of up to 10 mM.1 Several recent reports have demonstrated glutaredoxins (Grx) to form [Fe2S2] cluster-bridged dimers, where glutathione provides two exogenous thiol ligands, and have implicated such species in cellular iron sulfur cluster biosynthesis. We report the finding that glutathione alone can coordinate and stabilize an [Fe2S2] cluster under physiological conditions, with optical, redox, Mössbauer and NMR characteristics that are consistent with a [Fe2S2](GS)4 composition. The Fe-S assembly protein ISU catalyzes formation of [Fe2S2](GS)4 from iron and sulfide ions in the presence of glutathione, and the [Fe2S2] core undergoes reversible exchange between apo ISU and free glutathione.

Iron–Sulfur Cluster Binding by Mitochondrial Monothiol Glutaredoxin-1 ofTrypanosoma brucei: Molecular Basis of Iron–Sulfur Cluster Coordination and Relevance for Parasite Infectivity

“…Recently, GSH has been proposed to be the major chelating agent of the labile iron pool (34) and to be absolutely indispensable for intracellular iron homeostasis and cytosolic ISC maturation (45). Thus, our finding that a stable T(SH) 2 -ISC complex can be formed in vitro poses a new biological role for T(SH) 2 in the iron-sulfur metabolism of trypanosomatids, either as a ligand of ISC proteins or as an intracellular ISC carrier, as recently proposed for GSH (65). As shown here, under in vitro conditions, T(SH) 2 was capable to fulfill very efficiently these functions: it acted as a thiol ligand of holoTb1-C-Grx1 and holo-Tb2-C-Grx1, and as a carrier for the assembly of the ISC-T(SH) 2 complex into Tb2-C-Grx1, but not Tb1-C-Grx1.…”

“…It displayed the typical UV-visible spectra of ISCs bound to proteins or the recently reported [2Fe-2S]-(GSH) 4 complex ( Fig. 4C) (65). The CD spectrum (Fig.…”

The Diabetes Drug Target MitoNEET Governs a Novel Trafficking Pathway to Rebuild an Fe-S Cluster into Cytosolic Aconitase/Iron Regulatory Protein 1

“…Interestingly, it has been proposed recently that GSH, a member of the export pathway (10) 4 ] 2Ϫ , which may deliver Fe-S to target proteins, in particular ABCb7 (54,55). Such a small and stable nonprotein-bound GSH⅐Fe-S complex that can probably exit mitochondria through MTP proteins (56), therefore, constitutes a plausible candidate for Fe-S delivery to mNT.…”

The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron–sulfur proteins

“…Interestingly, Cowan has recently provided evidence for a tetra-GSH-coordinated [2Fe-2S] cluster (defined as (GS) 4 −[2Fe-2S]) that was claimed to be fairly stable, even in aqueous, oxygenated solutions (Qi et al, 2012). Hence, it was reasonable to propose that this compound may be a possible substrate of Atm1.…”