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Iron-sulfur protein

Iron-sulfur proteins are proteins characterized by the presence of iron-sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron-sulfur clusters are found in a variety of metalloproteins, such as the ferredoxins, as well as NADH dehydrogenase, hydrogenases, Coenzyme Q - cytochrome c reductase, and nitrogenase.[1] Iron-sulfur clusters are best known for their role in the oxidation-reduction reactions of mitochondrial electron transport. Both Complex I and Complex II of oxidative phosphorylation have multiple Fe-S clusters. They have many other functions including catalysis as illustrated by aconitase, generation of radicals as illustrated by SAM-dependent enzymes, and as sulfur donors in the biosynthesis of lipoic acid and biotin. Additionally some Fe-S proteins regulate gene expression. Fe-S proteins are vulnerable to attack by biogenic nitric oxide.


Structural motifs

In almost all Fe-S proteins, the Fe centers is tetrahedral and the thiolato sulfur centers, from cysteinyl residues, are terminal ligands. The sulfide groups are either two- or three-coordinated. Three distinct kinds Fe-S clusters with these features are most common.

2Fe-2S clusters

The simplest polymetallic system, [Fe2S2] cluster, is constituted by two iron ions bridged by two sulfide ions and coordinated by four cysteinyl ligands (in Fe2S2 ferredoxins) or by two cysteines and two histidines (in Rieske proteins). The oxidized proteins contain two Fe3+ ions, whereas the reduced proteins contain one Fe3+ and one Fe2+ ion. These species exist in two oxidation states, (FeIII)2 and FeIIIFeII.

4Fe-4S clusters

A common motif features a four iron ions and four sulfide ions placed at the vertices of a cubane-type structure. The Fe centers are typically further oordinated by cysteinyl ligands. The [Fe4S4] electron-transfer proteins ([Fe4S4] ferredoxins) may be further subdivided into low-potential (bacterial-type) and high-potential (HiPIP) ferredoxins. Low- and high-potential ferredoxins are related by the following redox scheme:

The formal oxidation numbers of the iron ions can be [2Fe3+, 2Fe2+] or [1Fe3+, 3Fe2+] in low-potential ferredoxins. The oxidation numbers of the iron ions in high-potential ferredoxins can be [3Fe3+, 1Fe2+] or [2Fe3+, 2Fe2+].

The unique member of the 4Fe-4S clusters is aconitase, wherein the Fe-S cluster is the active site of a protein. Substrate binding and turnover occurs at one Fe centre that lacks terminal coordination to thiolate.

3Fe-4S clusters

Proteins are also known to contain [Fe3S4] centres, which feature one iron less than the more common [Fe4S4] cores. Three sulfide ions bridge two iron ions each, while the fourth sulfide bridges three iron ions. Their formal oxidation states may vary from [Fe3S4]+ (all-Fe3+ form) to [Fe3S4]2- (all-Fe2+ form). In a number of iron-sulfur proteins, the [Fe4S4] cluster can be reversibly converted by oxidation and loss of one iron ion to a [Fe3S4] cluster. E.g., the inactive form of aconitase possesses an [Fe3S4] and is activated by addition of Fe2+ and reductant.

Other Fe-S clusters

More complex polymetallic systems are common. Examples include both the 8Fe and the 7Fe clusters in nitrogenase. Carbon monooxide dehydrogenase and the [[FeFe]-hydrogenase also feature unusual Fe-S clusters.


The biosynthesis of the Fe-S clusters has been well studied.[2][3][4] The biogenesis of iron sulfur clusters has been studied most extensively in the bacteria E. coli and A. vinelandii and yeast S. cerevisiae. At least three different biosynthetic systems so far identified, namely nif, suf, and isc sytems, which were first identified in bacteria. The nif system is responsible the clusters in the enzyme nitrogenase. The suf and isc systems are more general with the isc-related proteins being the only present in the animal kingdom. The yeast isc system is the best described. Several proteins constitute the biosynthetic machinery via the isc pathway. The process occurs in two major steps: 1)the Fe/S cluster is assembled on a scaffold protein followed by transfer of the preformed cluster to the recipient proteins. The first step of this process occurs in the cytoplasm of procaryotic organisms or in the mitochondria of eucaryotic organisms. In the higher organisms the clusters are therefore transported out of the mitochondrion to be incorporated into the extramitochondrial enzymes. These organisms also posess a set of proteins involved in the Fe/S clusters transport and incorporation processes that are not homologous to proteins found in procaryotic systems.

Synthetic analogues

Synthetic analogues of the naturally occurring Fe-S clusters were first reported by Holm and coworkers.[5] Treatment of iron salts with a mixture of thiolates and sulfide affords derivatives such as (Et4N)2Fe4S4(SCH2Ph)4].


  1. ^ S. J. Lippard, J. M. Berg “Principles of Bioinorganic Chemistry” University Science Books: Mill Valley, CA; 1994. ISBN 0-935702-73-3.
  2. ^ Johnson D, Dean DR, Smith AD, Johnson MK (2005). "Structure, function and formation of biological iron–sulfur clusters". Annual Review of Biochemistry 74: 247-281. doi:10.1146/annurev.biochem.74.082803.133518.
  3. ^ Johnson, M.K. and Smith, A.D. (2005) Iron–sulfur proteins in: Encyclopedia of Inorganic Chemistry (King, R.B., Ed.), 2nd edn, John Wiley & Sons, Chichester.
  4. ^ Lill R, Mühlenho U (2005). "Iron–sulfur-protein biogenesis in eukaryotes". Trends in Biochemical Sciences 30: 133–141. doi:10.1016/j.tibs.2005.01.006.
  5. ^ T. Herskovitz, B. A. Averill, R. H. Holm, J. A. Ibers, W. D. Phillips and J. F. Weiher (1972). "Structure and Properties of a Synthetic Analogue of Bacterial Iron-Sulfur Proteins". Proceedings of the National Academy of Sciences 69 (9): 2437-2441. doi:10.1073/pnas.69.9.2437.

Further reading

  • Beinert, H. (2000). "Iron-sulfur proteins: ancient structures, still full of surprises". J. Biol. Inorg. Chem. 5: 2–15. PMID 10766431.
  • Beinert, H. and Kiley, P.J. (1999). "Fe-S proteins in sensing and regulatory functions". Curr. Opin. Chem. Biol. 3: 152–157. PMID 10226040.
  • Johnson, M.K. (1998). "Iron-sulfur proteins: new roles for old clusters". Curr. Opin. Chem. Biol. 2: 173–181. PMID 9667933.
  • Nomenclature Committee of the International Union of Biochemistry (NC-IUB) (1979). "Nomenclature of iron-sulfur proteins. Recommendations 1978". Eur. J. Biochem. 93: 427–430. PMID 421685.
  • Noodleman, L., Lovell, T., Liu, T., Himo, F. and Torres, R.A. (2002). "Insights into properties and energetics of iron-sulfur proteins from simple clusters to nitrogenase". Curr. Opin. Chem. Biol. 6: 259–273. PMID 12039013.
  • Spiro, T.G., Ed. (1982). Iron-sulfur proteins. New York: Wiley. ISBN 0-471-07738-0. 

See also

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Iron-sulfur_protein". A list of authors is available in Wikipedia.
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