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Chemical Compound Review

CPD-7     iron; sulfanide

Synonyms: CHEBI:33722, CHEBI:33723, CHEBI:33724, CHEBI:33725, CHEBI:49883, ...
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Disease relevance of [Fe4S4](2+)

  • The crystal structure of photosystem I from the thermophilic cyanobacterium Synechococcus elongatus described here provides a picture at atomic detail of 12 protein subunits and 127 cofactors comprising 96 chlorophylls, 2 phylloquinones, 3 Fe4S4 clusters, 22 carotenoids, 4 lipids, a putative Ca2+ ion and 201 water molecules [1].
  • The topics include a description of the electron transfer cofactors, the mode of binding of the cofactors to protein-bound ligands, and a description of intraprotein contacts that ultimately allow photosystem I to be assembled (in cyanobacteria) from 96 chlorophylls, 22 carotenoids, 2 phylloquinones, 3 [4Fe-4S] clusters, and 12 polypeptides [2].
  • T. maritima ferredoxin expressed in E. coli is a heat-stable, monomeric protein, the spectroscopic properties of which show that its 4Fe-4S cluster is correctly assembled within the mesophilic host, and that it remains stable during purification under aerobic conditions [3].
  • [3Fe-4S] to [4Fe-4S] cluster conversion in Desulfovibrio fructosovorans [NiFe] hydrogenase by site-directed mutagenesis [4].
  • The [4Fe-4S] cluster of Azotobacter vinelandii ferredoxin I receives three of its four ligands from a Cys-Xaa-Xaa-Cys-Xaa-Xaa-Cys sequence at positions 39-45 while the fourth ligand, Cys20, is provided by a distal portion of the sequence [5].

High impact information on [Fe4S4](2+)

  • Crystal structure of formate dehydrogenase H: catalysis involving Mo, molybdopterin, selenocysteine, and an Fe4S4 cluster [6].
  • An oxygen-sensitive [4Fe-4S] cluster in each subunit is proposed to regulate protein turnover in vivo and is distant from the catalytic site [7].
  • Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III [8].
  • The results show that removal of a labile iron atom from the [4Fe-4S] cluster, by a cytotoxic activated macrophage-mediated mechanism, is causally related to aconitase inhibition [9].
  • Iron regulatory protein 1 (IRP1) is regulated through the assembly/disassembly of a [4Fe-4S] cluster, which interconverts IRP1 with cytosolic aconitase [10].

Chemical compound and disease context of [Fe4S4](2+)


Biological context of [Fe4S4](2+)

  • A recent structure of the Moorella thermoacetica enzyme revealed that the ACS active site contains a [4Fe-4S] cluster bridged to a binuclear Cu-Ni site [15].
  • Our findings suggest that stability of the Fe-S cluster of IRP1 can be regulated by phosphorylation and reveal a mechanism whereby the balance between the IRE binding and [4Fe-4S] forms of IRP1 can be modulated independently of cellular iron status [16].
  • Alternative proposals have suggested that superoxide may accelerate oxidative DNA damage by leaching iron from storage proteins or enzymic [4Fe-4S] clusters [17].
  • The presence of the [4Fe-4S] cluster increases dimerization of FNR which is correlated with an increase in site-specific DNA binding of FNR, a property expected of transcription factors of the FNR/CRP family [18].
  • Amino acid sequence of the [4Fe-4S] ferredoxin isolated from Desulfovibrio desulfuricans Norway [19].

Anatomical context of [Fe4S4](2+)


Associations of [Fe4S4](2+) with other chemical compounds

  • It is then applied to blue Cu proteins, the Cu(A) site, hydrogen bonding in Fe-S clusters, and the delocalization behavior in [2Fe-2S] vs [4Fe-4S] clusters [25].
  • The [3Fe-4S] to [4Fe-4S] cluster conversion resulted in a lowering of approximately 300 mV of the midpoint potential of the modified cluster, whereas no significant alteration of the spectroscopic and redox properties of the two native [4Fe-4S] clusters and the NiFe center occurred [4].
  • Here we report the site-directed mutation of Cys-20, which is a ligand of the [4Fe-4S] cluster in the native protein, to alanine and the characterization of the protein product by x-ray crystallographic and spectroscopic methods [26].
  • Mössbauer and EPR studies of activated aconitase: development of a localized valence state at a subsite of the [4Fe-4S] cluster on binding of citrate [27].
  • Maturation requires insertion of a [4Fe-4S] cluster and processing of the pro-peptide to expose an NH2-terminal active site cysteine residue [28].

Gene context of [Fe4S4](2+)

  • S. cerevisiae NTG1 does not have the [4Fe-4S] cluster DNA binding domain characteristic of the other members of this family [29].
  • Along these lines, we show here that a highly purified preparation of recombinant human IRP1 bearing a phosphomimetic S138E substitution (IRP1(S138E)) lacks aconitase activity, which is a hallmark of [4Fe-4S] cluster integrity [30].
  • Iron regulates IRP-1 activity by converting it from an RNA-binding apoprotein into a [4Fe-4S] cluster protein exhibiting aconitase activity [31].
  • In photosystem I (PSI) of oxygenic photosynthetic organisms the psaC polypeptide, encoded by the psaC gene, provides the ligands for two [4Fe-4S] clusters, FA and FB [32].
  • The rdxB gene product is predicted to encode a membrane protein which can bind two [4Fe-4S] clusters [33].

Analytical, diagnostic and therapeutic context of [Fe4S4](2+)

  • The cluster is bound entirely within the carboxyl-terminal loop with a ligation pattern (Cys-X6-Cys-X2-Cys-X5-Cys) distinct from all other known [4Fe-4S] proteins [8].
  • However, it does not give rise to observable paramagnetic magnetic circular dichroism in the visible-near UV spectral region and is therefore neither an oxidized HIPIP [4Fe-4S] cluster nor an oxidized [3Fe-3S] cluster [34].
  • The Fe(CN)3-(6) oxidation of the crystallographically characterized [[3Fe-3S], [4Fe-4S]] ferredoxin I of Azotobacter vinelandii has been studied using absorption, circular dichroism, magnetic circular dichroism, and EPR spectroscopies [34].
  • Even though they are able to bind iron in the (4Fe-4S) form, as shown by Mössbauer spectroscopy, the corresponding Cys to Ala mutants are catalytically inactive [35].
  • Reductive optical/EPR titrations of trimethylamine dehydrogenase with sodium dithionite have been performed, indicating that the equilibrium distribution of reducing equivalents between the covalently bound FMN and 4Fe/4S centers in partially reduced trimethylamine dehydrogenase is pH-dependent [36].


  1. Three-dimensional structure of cyanobacterial photosystem I at 2.5 A resolution. Jordan, P., Fromme, P., Witt, H.T., Klukas, O., Saenger, W., Krauss, N. Nature (2001) [Pubmed]
  2. The binding of cofactors to photosystem I analyzed by spectroscopic and mutagenic methods. Golbeck, J.H. Annual review of biophysics and biomolecular structure. (2003) [Pubmed]
  3. Sequence, assembly and evolution of a primordial ferredoxin from Thermotoga maritima. Darimont, B., Sterner, R. EMBO J. (1994) [Pubmed]
  4. [3Fe-4S] to [4Fe-4S] cluster conversion in Desulfovibrio fructosovorans [NiFe] hydrogenase by site-directed mutagenesis. Rousset, M., Montet, Y., Guigliarelli, B., Forget, N., Asso, M., Bertrand, P., Fontecilla-Camps, J.C., Hatchikian, E.C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  5. Site-directed mutagenesis of Azotobacter vinelandii ferredoxin I: cysteine ligation of the [4Fe-4S] cluster with protein rearrangement is preferred over serine ligation. Shen, B., Jollie, D.R., Diller, T.C., Stout, C.D., Stephens, P.J., Burgess, B.K. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  6. Crystal structure of formate dehydrogenase H: catalysis involving Mo, molybdopterin, selenocysteine, and an Fe4S4 cluster. Boyington, J.C., Gladyshev, V.N., Khangulov, S.V., Stadtman, T.C., Sun, P.D. Science (1997) [Pubmed]
  7. Structure of the allosteric regulatory enzyme of purine biosynthesis. Smith, J.L., Zaluzec, E.J., Wery, J.P., Niu, L., Switzer, R.L., Zalkin, H., Satow, Y. Science (1994) [Pubmed]
  8. Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III. Kuo, C.F., McRee, D.E., Fisher, C.L., O'Handley, S.F., Cunningham, R.P., Tainer, J.A. Science (1992) [Pubmed]
  9. Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. Drapier, J.C., Hibbs, J.B. J. Clin. Invest. (1986) [Pubmed]
  10. A novel eukaryotic factor for cytosolic Fe-S cluster assembly. Roy, A., Solodovnikova, N., Nicholson, T., Antholine, W., Walden, W.E. EMBO J. (2003) [Pubmed]
  11. Iron-sulfur cluster disassembly in the FNR protein of Escherichia coli by O2: [4Fe-4S] to [2Fe-2S] conversion with loss of biological activity. Khoroshilova, N., Popescu, C., Münck, E., Beinert, H., Kiley, P.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  12. A new [2Fe-2S] ferredoxin from Rhodobacter capsulatus. Coexpression with a 2[4Fe-4S] ferredoxin in Escherichia coli. Grabau, C., Schatt, E., Jouanneau, Y., Vignais, P.M. J. Biol. Chem. (1991) [Pubmed]
  13. NapF is a cytoplasmic iron-sulfur protein required for Fe-S cluster assembly in the periplasmic nitrate reductase. Olmo-Mira, M.F., Gavira, M., Richardson, D.J., Castillo, F., Moreno-Vivián, C., Roldán, M.D. J. Biol. Chem. (2004) [Pubmed]
  14. The heme and Fe4S4 cluster in the crystallographic structure of Escherichia coli sulfite reductase. McRee, D.E., Richardson, D.C., Richardson, J.S., Siegel, L.M. J. Biol. Chem. (1986) [Pubmed]
  15. Functional copper at the acetyl-CoA synthase active site. Seravalli, J., Gu, W., Tam, A., Strauss, E., Begley, T.P., Cramer, S.P., Ragsdale, S.W. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. Novel role of phosphorylation in Fe-S cluster stability revealed by phosphomimetic mutations at Ser-138 of iron regulatory protein 1. Brown, N.M., Anderson, S.A., Steffen, D.W., Carpenter, T.B., Kennedy, M.C., Walden, W.E., Eisenstein, R.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  17. Superoxide accelerates DNA damage by elevating free-iron levels. Keyer, K., Imlay, J.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  18. Oxygen sensing by the global regulator, FNR: the role of the iron-sulfur cluster. Kiley, P.J., Beinert, H. FEMS Microbiol. Rev. (1998) [Pubmed]
  19. Amino acid sequence of the [4Fe-4S] ferredoxin isolated from Desulfovibrio desulfuricans Norway. Bruschi, M.H., Guerlesquin, F.A., Bovier-Lapierre, G.E., Bonicel, J.J., Couchoud, P.M. J. Biol. Chem. (1985) [Pubmed]
  20. Active photosynthesis in cyanobacterial mutants with directed modifications in the ligands for two iron-sulfur clusters on the PsaC protein of photosystem I. Mannan, R.M., He, W.Z., Metzger, S.U., Whitmarsh, J., Malkin, R., Pakrasi, H.B. EMBO J. (1996) [Pubmed]
  21. ACCUMULATION OF PHOTOSYSTEM ONE1, a member of a novel gene family, is required for accumulation of [4Fe-4S] cluster-containing chloroplast complexes and antenna proteins. Amann, K., Lezhneva, L., Wanner, G., Herrmann, R.G., Meurer, J. Plant Cell (2004) [Pubmed]
  22. Strains of synechocystis sp. PCC 6803 with altered PsaC. I. Mutations incorporated in the cysteine ligands of the two [4Fe-4S] clusters FA and FB of photosystem I. Yu, J., Vassiliev, I.R., Jung, Y.S., Golbeck, J.H., McIntosh, L. J. Biol. Chem. (1997) [Pubmed]
  23. The role of iron in the activation-inactivation of aconitase. Kennedy, M.C., Emptage, M.H., Dreyer, J.L., Beinert, H. J. Biol. Chem. (1983) [Pubmed]
  24. The role of manganese superoxide dismutase in health and disease. Robinson, B.H. J. Inherit. Metab. Dis. (1998) [Pubmed]
  25. Ligand K-edge X-ray absorption spectroscopy: a direct probe of ligand-metal covalency. Glaser, T., Hedman, B., Hodgson, K.O., Solomon, E.I. Acc. Chem. Res. (2000) [Pubmed]
  26. Site-directed mutagenesis of Azotobacter vinelandii ferredoxin I: [Fe-S] cluster-driven protein rearrangement. Martín, A.E., Burgess, B.K., Stout, C.D., Cash, V.L., Dean, D.R., Jensen, G.M., Stephens, P.J. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  27. Mössbauer and EPR studies of activated aconitase: development of a localized valence state at a subsite of the [4Fe-4S] cluster on binding of citrate. Emptage, M.H., Kent, T.A., Kennedy, M.C., Beinert, H., Münck, E. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  28. Mutational analysis of the glutamine phosphoribosylpyrophosphate amidotransferase pro-peptide. Souciet, J.L., Hermodson, M.A., Zalkin, H. J. Biol. Chem. (1988) [Pubmed]
  29. Base excision of oxidative purine and pyrimidine DNA damage in Saccharomyces cerevisiae by a DNA glycosylase with sequence similarity to endonuclease III from Escherichia coli. Eide, L., Bjørås, M., Pirovano, M., Alseth, I., Berdal, K.G., Seeberg, E. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  30. A phosphomimetic mutation at Ser-138 renders iron regulatory protein 1 sensitive to iron-dependent degradation. Fillebeen, C., Chahine, D., Caltagirone, A., Segal, P., Pantopoulos, K. Mol. Cell. Biol. (2003) [Pubmed]
  31. Cytosolic aconitase and ferritin are regulated by iron in Caenorhabditis elegans. Gourley, B.L., Parker, S.B., Jones, B.J., Zumbrennen, K.B., Leibold, E.A. J. Biol. Chem. (2003) [Pubmed]
  32. Absence of PsaC subunit allows assembly of photosystem I core but prevents the binding of PsaD and PsaE in Synechocystis sp. PCC6803. Yu, J., Smart, L.B., Jung, Y.S., Golbeck, J., McIntosh, L. Plant Mol. Biol. (1995) [Pubmed]
  33. Evidence for the role of redox carriers in photosynthesis gene expression and carotenoid biosynthesis in Rhodobacter sphaeroides 2.4.1. O'Gara, J.P., Kaplan, S. J. Bacteriol. (1997) [Pubmed]
  34. Spectroscopic studies of ferricyanide oxidation of Azotobacter vinelandii ferredoxin I. Morgan, T.V., Stephens, P.J., Devlin, F., Stout, C.D., Melis, K.A., Burgess, B.K. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  35. The activating component of the anaerobic ribonucleotide reductase from Escherichia coli. An iron-sulfur center with only three cysteines. Tamarit, J., Gerez, C., Meier, C., Mulliez, E., Trautwein, A., Fontecave, M. J. Biol. Chem. (2000) [Pubmed]
  36. Intramolecular electron transfer in trimethylamine dehydrogenase from bacterium W3A1. Rohlfs, R.J., Hille, R. J. Biol. Chem. (1991) [Pubmed]
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