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, succinate – coenzyme Q reductase and nitrogenase.^[1] Iron–sulfur clusters are best known for their role in the oxidation-reduction reactions of electron transport in mitochondria and chloroplasts. 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, forming dinitrosyl iron complexes. In most Fe–S proteins, the terminal ligands on Fe are thiolate, but exceptions exist.^[2]

The prevalence of these proteins on the metabolic pathways of most organisms leads some scientists to theorize that iron–sulfur compounds had a significant role in the origin of life in the iron–sulfur world theory.

Structural motifs

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

Structure-Function Principles

To serve their various biological roles, iron-sulfur proteins effect rapid electron transfers and span the whole range of physiological redox potentials from -600 mV to +460 mV.

Iron-sulfur proteins are involved in various biological electron transport processes, such as photosynthesis and cellular respiration, which require rapid electron transfer to sustain the energy or biochemical needs of the organism.

Fe³⁺-SR bonds have unusually high covalency which is expected. When comparing the covalency of Fe³⁺ with the covalency of Fe²⁺, Fe³⁺ has almost double the covalency of Fe²⁺ (20% to 38.4%).^[3] Fe³⁺ is also much more stabilized than Fe²⁺. Hard ions like Fe³⁺ normally have low covalency because of the energy mismatch of the metal Lowest Unoccupied Molecular Orbital with the ligand Highest Occupied Molecular Orbital.

There is HO-H—S-Cys H-bonding from external H₂O’s positioned by the protein close to the active site and this H-bonding decreases the lone pair electron donation from the Cys-S donor to the Fe^3+/2+. Using lyophilization to remove these external H₂O’s results in increased Fe-S covalency, which means that the H₂O’s are decreasing the covalency because HOH-S Hydrogen-bonding pulls the sulfur electrons. Since covalency stabilizes Fe³⁺ more than Fe²⁺, therefore Fe³⁺ is more destabilized by the HOH-S hydrogen-bonding.

The Fe³⁺ 3d orbital energies follow the “inverted” bonding scheme which fortuitously has the Fe³⁺ d-orbitals closely matched in energy with the sulfur 3p orbitals which gives high covalency in the resulting bonding molecular orbital.^[4] This high covalency lowers the inner sphere reorganization energy^[4] and ultimately contributes to a rapid electron transfer.

2Fe–2S clusters

 

2Fe–2S clusters

The simplest polymetallic system, the [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, (Fe^III)₂ and Fe^IIIFe^II. CDGSH iron sulfur domain is also associated with 2Fe-2S clusters.

 

Rieske 2Fe-2S Cluster Oxidation States of Fe³⁺ and Fe²⁺

4Fe–4S clusters

A common motif features a four iron ions and four sulfide ions placed at the vertices of a cubane-type cluster. The Fe centers are typically further coordinated 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:

 

4Fe-4S clusters serve as electron-relays in proteins.

In HiPIP, the cluster shuttles between [2Fe³⁺, 2Fe²⁺] (Fe₄S₄²⁺) and [3Fe³⁺, Fe²⁺] (Fe₄S₄³⁺). The potentials for this redox couple range from 0.4 to 0.1 V. In the bacterial ferredoxins, 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 modifies the basicity of the cysteinyl thiolate ligands.^{[citation needed]} A further redox couple, which is still more reducing than the bacterial ferredoxins is implicated in the nitrogenase.

Some 4Fe–4S clusters bind substrates and are thus classified as enzyme cofactors. 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 citrate to isocitrate. In radical SAM enzymes, the cluster binds and reduces S-adenosylmethionine to generate a radical, which is involved in many biosyntheses.^[5]

 

4Fe-4S Oxidation States of Fe³⁺, Fe^2.5+, and Fe²⁺.

The second cubane shown here with mixed valence pairs (2 Fe3+ and 2 Fe2+), has a greater stability from covalent communication and strong covalent delocalization of the “extra” electron from the reduced Fe2+ that results in full ferromagnetic coupling.

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 monoxide dehydrogenase and the [FeFe]-hydrogenase also feature unusual Fe–S clusters. A special 6 cysteine-coordinated [Fe₄S₃] cluster was found in oxygen-tolerant membrane-bound [NiFe] hydrogenases.^[6][7]

 

Structure of the FeMoco cluster in nitrogenase. The cluster is linked to the protein by the amino acid residues cysteine and histidine.

 

Ranges of reduction potentials, E^o (mV), covered by the different classes of iron-sulfur proteins, heme proteins, and copper proteins. (HiPIP = High potential iron-sulfur proteins, Rdx = rubredoxins, Fdx = ferredoxins, Cyt = cytochromes.)

Biosynthesis

See also: Iron-sulfur cluster biosynthesis protein family

The biosynthesis of the Fe–S clusters has been well studied.^[8][9][10] 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 have been identified so far, namely nif, suf, and isc systems, which were first identified in bacteria. The nif system is responsible for the clusters in the enzyme nitrogenase. The suf and isc systems are more general.

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 (2) transfer of the preformed cluster to the recipient proteins. The first step of this process occurs in the cytoplasm of prokaryotic organisms or in the mitochondria of eukaryotic 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 prokaryotic systems.

Synthetic analogues

Synthetic analogues of the naturally occurring Fe–S clusters were first reported by Holm and coworkers.^[11] Treatment of iron salts with a mixture of thiolates and sulfide affords derivatives such as (Et₄N)₂Fe₄S₄(SCH₂Ph)₄].^[12][13]

See also

• Bioinorganic chemistry
• Iron-binding proteins
• Mitosome

References

1. S. J. Lippard, J. M. Berg “Principles of Bioinorganic Chemistry” University Science Books: Mill Valley, CA; 1994. ISBN 0-935702-73-3.
2. Bak, D. W.; Elliott, S. J. (2014). "Alternative FeS cluster ligands: tuning redox potentials and chemistry". Curr. Opin. Chem. Biol. 19: 50–58. doi:10.1016/j.cbpa.2013.12.015. PMID 24463764.
3. Sun, Ning; Dey, Abhishek; Xiao, Zhiguang; Wedd, Anthony G.; Hodgson, Keith O.; Hedman, Britt; Solomon, Edward I. (2010-08-20). "Solvation Effects on S K-Edge XAS Spectra of Fe−S Proteins: Normal and Inverse Effects on WT and Mutant Rubredoxin". Journal of the American Chemical Society. 132 (36): 12639–12647. doi:10.1021/ja102807x. ISSN 0002-7863. PMC 2946794. PMID 20726554.
4. Kennepohl, Pierre; Solomon, Edward I. (2003-01-16). "Electronic Structure Contributions to Electron-Transfer Reactivity in Iron−Sulfur Active Sites: 3. Kinetics of Electron Transfer". Inorganic Chemistry. 42 (3): 696–708. doi:10.1021/ic0203320. ISSN 0020-1669. PMID 12562183.
5. Susan C. Wang; Perry A. Frey (2007). "S-adenosylmethionine as an oxidant: the radical SAM superfamily". Trends in Biochemical Sciences. 32 (3): 101–10. doi:10.1016/j.tibs.2007.01.002. PMID 17291766.
6. Fritsch, J; Scheerer, P; Frielingsdorf, S; Kroschinsky, S; Friedrich, B; Lenz, O; Spahn, CMT (2011-10-16). "The crystal structure of an oxygen-tolerant hydrogenase uncovers a novel iron-sulphur centre". Nature. 479 (7372): 249–252. Bibcode:2011Natur.479..249F. doi:10.1038/nature10505. PMID 22002606. S2CID 4411671.
7. Shomura, Y; Yoon, KS; Nishihara, H; Higuchi, Y (2011-10-16). "Structural basis for a [4Fe-3S] cluster in the oxygen-tolerant membrane-bound [NiFe]-hydrogenase". Nature. 479 (7372): 253–256. Bibcode:2011Natur.479..253S. doi:10.1038/nature10504. PMID 22002607. S2CID 4313414.
8. Johnson D, Dean DR, Smith AD, Johnson MK (2005). "Structure, function and formation of biological iron–sulfur clusters". Annual Review of Biochemistry. 74 (1): 247–281. doi:10.1146/annurev.biochem.74.082803.133518. PMID 15952888.
9. 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.
10. Lill R, Mühlenhoff U (2005). "Iron–sulfur-protein biogenesis in eukaryotes". Trends in Biochemical Sciences. 30 (3): 133–141. doi:10.1016/j.tibs.2005.01.006. PMID 15752985.
11. T. Herskovitz; B. A. Averill; R. H. Holm; J. A. Ibers; W. D. Phillips; 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. Bibcode:1972PNAS...69.2437H. doi:10.1073/pnas.69.9.2437. PMC 426959. PMID 4506765.
12. Holm, R. H.; Lo, W. (2016). "Structural Conversions of Synthetic and Protein-Bound Iron-Sulfur Clusters". Chem. Rev. 116 (22): 13685–13713. doi:10.1021/acs.chemrev.6b00276. PMID 27933770.
13. Lee, S. C.; Lo, W.; Holm, R. H. (2014). "Developments in the Biomimetic Chemistry of Cubane-Type and Higher Nuclearity Iron–Sulfur Clusters". Chemical Reviews. 114 (7): 3579–3600. doi:10.1021/cr4004067. PMC 3982595. PMID 24410527.

• Sticht, Heinrich; Rösch, Paul (1998-09-01). "The structure of iron–sulfur proteins". Progress in Biophysics and Molecular Biology. 70 (2): 95–136. doi:10.1016/S0079-6107(98)00027-3. ISSN 0079-6107. PMID 9785959.

Further reading

• Beinert, H. (2000). "Iron-sulfur proteins: ancient structures, still full of surprises". J. Biol. Inorg. Chem. 5 (1): 2–15. doi:10.1007/s007750050002. PMID 10766431. S2CID 20714007.
• Beinert, H.; Kiley, P.J. (1999). "Fe-S proteins in sensing and regulatory functions". Curr. Opin. Chem. Biol. 3 (2): 152–157. doi:10.1016/S1367-5931(99)80027-1. PMID 10226040.
• Johnson, M.K. (1998). "Iron-sulfur proteins: new roles for old clusters". Curr. Opin. Chem. Biol. 2 (2): 173–181. doi:10.1016/S1367-5931(98)80058-6. PMID 9667933.
• Nomenclature Committee of the International Union of Biochemistry (NC-IUB) (1979). "Nomenclature of iron-sulfur proteins. Recommendations 1978". Eur. J. Biochem. 93 (3): 427–430. doi:10.1111/j.1432-1033.1979.tb12839.x. 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 (2): 259–273. doi:10.1016/S1367-5931(02)00309-5. PMID 12039013.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Spiro, T.G., Ed. (1982). Iron-sulfur proteins. New York: Wiley. ISBN 0-471-07738-0.{{cite book}}: CS1 maint: multiple names: authors list (link)

External links

• Iron-Sulfur+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)