Skip to main content

Advertisement

SpringerLink
Log in

Glutathione: a key component of the cytoplasmic labile iron pool

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The cytoplasmic labile iron pool supplies iron to the mitochondrion for heme and iron sulfur cluster synthesis and to many cytoplasmic enzymes, thereby controlling numerous metabolic reactions. Surprisingly the chemical nature of this pool has never been convincingly characterised. Here we provide evidence for iron(II)glutathione being the dominant component of this pool. We report for the first time the affinity constant for the glutathione–iron(II) interaction and use this value to study the cytoplasmic speciation of iron(II). The formation of this complex is a major determinant of the electrode potential of the cytoplasmic ferrous iron pool, a means of selecting between iron(II) and manganese(II) and it provides a substrate for glutaredoxin/iron clusters at the dimer interface of glutaredoxins involved in the synthesis of Fe–S cluster proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Scheme 1
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Albert A (1952) Quantitative studies of the avidity of naturally occurring substances for trace metals. 2. Amino-acids having three ionizing groups. J Chem Soc 50:690–697

    CAS  Google Scholar 

  • Alderighi L, Gans P, Ienco A, Sabatini A, Vacca A (1999) Hyperquad simulation and speciation (HySS): a utility program for the investigation of equilibria involving soluble and partially soluble species. Coord Chem Rev 184:311–318

    Article  CAS  Google Scholar 

  • Ba LA, Doering M, Burkholz T, Jacob C (2009) Metal trafficking: from maintaining the metal homeostasis to future drug design. Metallomics 1:292–311

    Article  PubMed  CAS  Google Scholar 

  • Breuer W, Epsztejn S, Cabantchik ZI (1995) Iron acquired from transferrin by K562 cells is delivered into a cytoplasmic pool of chelatable iron(II). J Biol Chem 270:24209–24215

    Article  PubMed  CAS  Google Scholar 

  • Camaschella C, Campanella A, DeFalco L, Boschetto L, Merlini R, Silvestri L, Levi S, Iolascon A (2007) The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood 110:1353–1358

    Article  PubMed  CAS  Google Scholar 

  • Crichton R (2009) Iron metabolism, 3rd edn. Wiley, Chichester

    Book  Google Scholar 

  • Devireddy LR, Hart DO, Goetz DH, Green MRA (2010) Mammalian siderophore synthesised by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:1006–1017

    Article  PubMed  CAS  Google Scholar 

  • Dickinson DA, Forman HJ (2002) Cellular glutathione and thiols metabolism. Biochem Pharmacol 64:1019–1026

    Article  PubMed  CAS  Google Scholar 

  • Egyed A, Saltman P (1984) Iron is maintained as Fe(II) under aerobic conditions in erythroid cells. Biol Trace Element Res 6:357–364

    Article  CAS  Google Scholar 

  • Eisenstein RS, Blemings KP (1998) Iron regulatory proteins, iron responsive elements and iron homeostasis. J Nutrit 128:2295–2298

    PubMed  CAS  Google Scholar 

  • Fuhr J, Rabenstein D (1973) Nuclear magnetic resonance studies of the solution chemistry of metal complexes. IX Binding of cadmium, zinc, lead, and mercury by glutathione. J Am Chem Soc 95:6944–6948

    Article  PubMed  CAS  Google Scholar 

  • Furne J, Saeed A, Levitt MD (2008) Whole tissue hydrogen sulphide concentrations are orders of magnitude lower than presently accepted levels. Am J Physiol 295:R1479–R1485

    CAS  Google Scholar 

  • Hamed MY, Silver J, Wilson MT (1983) Studies of the reactions of ferric iron with glutathione and some related thiols. Inorg Chim Acta 78:1–11

    Article  CAS  Google Scholar 

  • Han Y, Qin J, Chang X, Yang Z, Du J (2006) Hydrogen sulfide and carbon monoxide are in synergy with each other in the pathogenesis of recurrent febrile seizures. Cell Mol Neurobiol 26:101–107

    Article  PubMed  Google Scholar 

  • Harris DC, Aisen P (1973) Facilitation of Fe(II) autoxidation by Fe(III) complexing agents. Biochim Biophys Acta 329:156–158

    Article  PubMed  CAS  Google Scholar 

  • Helm L, Merbach AE (2005) Inorganic and bioin-organic solvent exchange mechanisms. Chem Rev 105:1922–1959

    Article  Google Scholar 

  • Hentze MW, Kuhn LC (1996) Molecular control of vertebrate iron metabolism: in RNA-based regulatory circuits operated by iron, nitric oxide and oxidative stress. Proc Natl Acad Sci USA 93:8175–8182

    Article  PubMed  CAS  Google Scholar 

  • Hider RC, Kong XL (2010) Chemistry, biology of siderophores. Nat Prod Rep 27:637–657

    Article  PubMed  CAS  Google Scholar 

  • Jacobs A (1977) Low molecular weight intracellular iron transport compounds. Blood 50:433–439

    PubMed  CAS  Google Scholar 

  • Kondo T, Dale GL, Beutler E (1995) Thiol transport from human red blood cells. Methods Enzymol 252:72–82

    Article  PubMed  CAS  Google Scholar 

  • Kong XL, Zhou T, Neubert H, Liu Z, Hider RC (2009) 3-Hydroxy-2-(5-hydroxypentyl)-4H-chromen-4-one: a bidentate or tridentate iron(III) ligand? J Med Chem 49:3028–3130

    Article  Google Scholar 

  • Kovaleva EG, Lipscomb JD (2008) Versatility of biological non-heme Fe(II) centres in oxygen activation reactions. Nat Chem Biol 4:186–193

    Article  PubMed  CAS  Google Scholar 

  • Li H, Mapolelo DT, Dingra NN, Naik SG, Lees NS, Hoffman BM, Riggs-Gelasco PJ, Huynh BH, Johnson MK, Outten CE (2009) The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe–2S] cluster with cysteinyl and histidyl ligation. Biochemistry 48:9569–9581

    Article  PubMed  CAS  Google Scholar 

  • Lillig CH, Berndt C, Holmgren A (2008) Glutaredoxin systems. Biochim Biophys Acta 1780:1304–1317

    Article  PubMed  CAS  Google Scholar 

  • Loenarz C, Schofield CJ (2008) Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol 4:152–156

    Article  PubMed  CAS  Google Scholar 

  • Luther GW, Rickard DT, Theberge S, Olroyd A (1996) Determination of metal sulphide stability constants of Mn2+, Fe2+, Co2+, Ni2+, Ci2+, and Zn2+ by voltammetric methods. Environ Sci Technol 30:671–679

    Article  CAS  Google Scholar 

  • Marschner H (1993) Mineral nutrition of higher plants, 2nd edn. Academic Press, London

    Google Scholar 

  • Martell A, Hancock R (1996) Metal complexes in aqueous solutions. Plenum Press, New York

    Google Scholar 

  • Martin HB, Edsall JT (1959) The association of divalent cations with glutathione. J Am Chem Soc 81:4044

    Article  CAS  Google Scholar 

  • Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263:17205–17208

    PubMed  CAS  Google Scholar 

  • Mesecke N, Mittler S, Eckers E, Herrmann JM, Deponte M (2008) Two novel monothiol glutaredoxins from Saccharomyces cerevisiae provide further insight into iron–sulfur cluster binding, oligomerization, and enzymatic activity of glutaredoxins. Biochemistry 47:1452–1463

    Article  PubMed  CAS  Google Scholar 

  • Miller JPG, Perkins DJ (1969) Model experiments for the study of iron transfer from transferrin to ferritin. Eur J Biochem 10:146–151

    Article  PubMed  CAS  Google Scholar 

  • Morley CGD, Bezkorovainy A (1983) Identification of the iron chelate in hepatocyte cytosol. IRCS Med Sci 11:1106–1107

    CAS  Google Scholar 

  • O’Halloran TV (1993) Transition metals in control of gene expression. Science 261:715–724

    Article  PubMed  Google Scholar 

  • Ozer A, Bruick RK (2007) Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one? Nat Chem Biol 3:144–153

    Article  PubMed  CAS  Google Scholar 

  • Petrat F, de Groot H, Sustmann R, Raven U (2002) The chelatable iron pool in living cells: a methodically defined quantity. Biol Chem 383:489–502

    Article  PubMed  CAS  Google Scholar 

  • Qi W, Cowan JA (2011) Mechanism of glutaredoxin-ISU [2Fe–2S] cluster exchange. Chem Commun 47(17):4989–4991

    Article  CAS  Google Scholar 

  • Rouhier N, Couturier J, Johnson MK, Jacquot JP (2009) Glutaredoxins: roles in iron homeostasis. Trends Biochem Sci 35:43–52

    Article  PubMed  Google Scholar 

  • Savage JC, Gould DH (1990) Determination of sulfide in brain tissue and rumen fluid by ion-interaction, reverse-phase, high performance, liquid chromatography. J Chromatogr 526:540–545

    Article  PubMed  CAS  Google Scholar 

  • Sharma AK, Pallesen LJ, Spang RJ, Walden WE (2010) Cytosolic iron–sulfur cluster assembly (CIA) system: factors, mechanism, and relevance to cellular iron regulation. J Biol Chem 285:26745–26751

    Article  PubMed  CAS  Google Scholar 

  • Sipos K, Lange H, Fekete Z, Ullmann P, Lill R, Kispal G (2002) Maturation of cytosolic iron–sulfur proteins requires glutathione. J Biol Chem 30:26944–26949

    Article  Google Scholar 

  • Soboll S, Gründel S, Harris J, Kolb-Bachofen V, Ketterer B, Sies H (1995) The content of glutathione and glutathione S-transferases and the glutathione peroxidase activity in rat liver nuclei determined by a non-aqueous technique of cell fractionation. Biochem J 311:889–894

    PubMed  CAS  Google Scholar 

  • Timberlake CF (1964) Iron-malate and iron-citrate complexes. J Chem Soc 5078–5085

  • Tong WH, Chen S, Lloyd SG, Edmondson DE, Huynh B-H, Stubbe J (1996) Mechanism of assembly of the diferric cluster-tyrosyl radical cofactor of Escherichia coli ribonucleotide reductase from the diferrous form of the R2 subunit. J Am Chem Soc 118:2107–2108

    Article  CAS  Google Scholar 

  • Veiga N, Torres J, Mansell D, Freeman S, Domínguez S, Barker CJ, Díaz A, Kremer C (2009) “Chelatable iron pool”: inositol 1,2,3-trisphosphate fulfils the conditions required to be a safe cellular iron ligand. J Biol Inorg Chem 14:51–59

    Article  PubMed  CAS  Google Scholar 

  • Vivancos PD, Wolff T, Markovic J, Pallardó FV, Foyer CH (2010) A nuclear glutathione cycle within the cell cycle. Biochem J 431:169–178

    Article  Google Scholar 

  • Waldron KJ, Rutherford JC, Ford D, Robinson NJ (2009) Metalloproteins and metal sensing. Nature 460:823–830

    Article  PubMed  CAS  Google Scholar 

  • Weaver J, Pollack S (1989) Low-Mr iron isolated from guinea pig reticulocytes as AMP-Fe and ATP-Fe complexes. Biochem J 261:787–792

    PubMed  CAS  Google Scholar 

  • Wells WW, Yang Y, Deits TL, Gan ZR (1993) Thioltransferases. Adv Enzymol Relat Areas Mol Biol 66:149–201

    PubMed  CAS  Google Scholar 

  • Whitfield NL, Kreimier EL, Verdial FC, Skovgaard N, Olson KR (2008) Reappraisal of H2S/sulfide concentration in vertebrate blood and its potential significance in ischemic pre conditioning and vascular signalling. Am J Physiol 294:R1930–R1937

    CAS  Google Scholar 

  • Williams RJP (1982) Free manganese(II) and iron(II) cations can act as intracellular cell controls. FEBS Lett 140:3–10

    Article  PubMed  CAS  Google Scholar 

  • Ye H, Jeong SY, Ghosh MC, Kovtunovych G, Silvestri L, Ortillo D, Uchida N, Tisdale J, Camaschella C, Rouault TA (2010) Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120:1749–1761

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Dr Wolfgang Maret (KCL) for many critical discussions and both Prof Willem H. Koppenol and Dr Reinhard Kissner (ETH, Zurich) for assistance with anaerobic titrations.

Author information

Authors and Affiliations

  1. Institute of Pharmaceutical Science, King’s College London, Franklin–Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK

    Robert C. Hider & Xiao L. Kong

Authors
  1. Robert C. Hider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao L. Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert C. Hider.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hider, R.C., Kong, X.L. Glutathione: a key component of the cytoplasmic labile iron pool. Biometals 24, 1179–1187 (2011). https://doi.org/10.1007/s10534-011-9476-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-011-9476-8

Keywords

Search

Navigation