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
, Coenzyme Q - cytochrome c reductase
, Succinate - coenzyme Q reductase
. 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
. Additionally some Fe-S proteins regulate gene expression. Fe-S proteins are vulnerable to attack by biogenic nitric oxide
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.
The simplest polymetallic system, [Fe2
] cluster, is constituted by two iron ions bridged by two sulfide ions and coordinated by four cysteinyl ligands
) 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
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 coordinated by cysteinyl ligands. The [Fe4
] electron-transfer proteins ([Fe4
) 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:
In HiPIP, the cluster shuttles between [2Fe3+, 2Fe2+] (Fe4S42+) and [3Fe3+, Fe2+] (Fe4S43+). The potentiasl for this redox couple range from 0.4 to 0.1 V. In the bacterial Fd's, the pair of oxidation states are [Fe3+, 3Fe2+] (Fe4S4+) and [2Fe3+, 2Fe2+] (Fe4S42+). The potentials for this redox couple range from -0.3 to -0.7 V. The two families of 4Fe-4S clusters share the Fe4S42+ oxidation state. The difference in the redox couples is attributed to the degree of hydrogen bonding, which strongly modified the basicity of the cysteinyl thiolate ligands. A further redox couple, which is still more reducing than the bacterial Fd's is implicated in the nitrogenase.
Some 4Fe-4S clusters bind substrates and are thus classified as enzymes. In aconitase, the Fe-S cluster binds aconitate at the one Fe centre that lacks a thiolate ligand. The cluster does not undergo redox, but serves as a Lewis acid catalyst to convert aconitate to isocitrate. In the radical-SAM enzymes, the cluster binds and reduces S-adenosylmethionine to generate a radical, which is involved in many biosyntheses.
Proteins are also known to contain [Fe3
] centres, which feature one iron less than the more common [Fe4
] cores. Three sulfide ions bridge two iron ions each, while the fourth sulfide bridges three iron ions. Their formal oxidation states may vary from [Fe3
form) to [Fe3
form). In a number of iron-sulfur proteins, the [Fe4
] cluster can be reversibly converted by oxidation and loss of one iron ion to a [Fe3
] cluster. E.g., the inactive form of aconitase
possesses an [Fe3
] and is activated by addition of Fe2+
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
also feature unusual Fe-S clusters.
The biosynthesis of the Fe-S clusters has been well studied.
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 systems, 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
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 possess 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 of the naturally occurring Fe-S clusters were first reported by Holm
and coworkers. Treatment of iron salts with a mixture of thiolates and sulfide affords derivatives such as (Et4N
- Beinert, H. (2000). "Iron-sulfur proteins: ancient structures, still full of surprises". J. Biol. Inorg. Chem. 5 2–15.
- Beinert, H. and Kiley, P.J. (1999). "Fe-S proteins in sensing and regulatory functions". Curr. Opin. Chem. Biol. 3 152–157.
- Johnson, M.K. (1998). "Iron-sulfur proteins: new roles for old clusters". Curr. Opin. Chem. Biol. 2 173–181.
- Nomenclature Committee of the International Union of Biochemistry (NC-IUB) (1979). "Nomenclature of iron-sulfur proteins. Recommendations 1978". Eur. J. Biochem. 93 427–430.
- 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.
- Spiro, T.G., Ed. (1982). Iron-sulfur proteins. New York: Wiley. ISBN 0-471-07738-0.