The Role of GSH in Intracellular Iron Trafficking

Abstract

Evidence is reviewed for the role of glutathione in providing a ligand for the cytosolic iron pool. The possibility of histidine and carnosine forming ternary complexes with iron(II)glutathione is discussed and the physiological significance of these interactions considered. The role of carnosine in muscle, brain, and kidney physiology is far from established and evidence is presented that the iron(II)-binding capability of carnosine relates to this role.

Keywords: carnosine; cytosol; glutathione; histidine; labile iron.

Figure 1

Speciation plots of iron(II) (1 μM) with glutathione: (a) glutathione [GSH] = 2 mM and (b) [GSH] = 10 mM. Fe⁺⁺ is ferrous iron.

Scheme 1

Schematic structure of the aqueous, cysteine, and glutathione complexes with iron(II). (1) Hexaaquo·iron(II); (2) iron(II)cysteine complex; (3) iron(II)glutathione.

Figure 2

Speciation plot of iron(II) in the presence of cytosolic levels of glutathione and citrate. [Fe²⁺]_total = 1 μM, [Cit]_total = 100 μM, and [GSH] = 2 mM. Fe⁺⁺ is ferrous iron.

Figure 3

The buffering of cytoplasmic iron(II) by GSH. Although there is predicted to be a slow rate of autoxidation of Fe^II·GS, the resulting Fe^III·GS will be rapidly reduced back to Fe^II·GS by the presence of the large excess of GSH.

Figure 4

Variation of [Fe(H₂O)₆²⁺] (1) with [Fe²⁺]_total in the presence of 8 mM GSH at pH 7.0.

Figure 5

Speciation plots for histidine with Fe(II) in the presence and absence of glutathione (GSH): (A) histidine (300 μM), Fe²⁺ (1 μM); (B) histidine (300 μM), Fe²⁺ (1 μM), GSH (2 mM); and (C) histidine (300 μM), Fe²⁺ (1 μM), GSH (2 mM) with the formation of the ternary complex assumed to be possible. LogK Fe⁽II)-GSH = 5.1; logK Fe(II)-histidine = 5.85; logK Fe(II)-GSH-histidine = 10.95.

Scheme 2

Ternary complexes of iron(II).

Scheme 3

Cytosolic histidine containing dipeptides.

Scheme 4

Linked equilibria which leads to the formation of GS·Fe^II·carnosine

Figure 6

Speciation plots of carnosine with Fe(II) in the presence and absence of glutathione (GSH): (A) carnosine (10 mM), Fe²⁺ (1 μM); (B) carnosine (10 mM), Fe²⁺ (1 μM), GSH (2 mM); and (C) carnosine (10 mM), Fe²⁺ (1 μM), GSH (2 mM) with the formation of the ternary complex assumed to be possible. LogK Fe(II)-GSH = 5.1; LogK Fe(II)-carnosine = 4.5; LogK Fe(II)-GSH-carnosine = 9.6.