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 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, 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.
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, (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 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:
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. 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.[3]
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.[4][5]
Structure of the FeMoco cluster in nitrogenase. The
cluster is linked to the protein by the amino acid
cluster is linked to the protein by the amino acid
residues cysteine and histidine.
Biosynthesis
The biosynthesis of the Fe–S clusters has
been well studied.[6][7][8] 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.[9] Treatment of
iron salts with a mixture of thiolates and
sulfide affords derivatives such as
(Et4N)2Fe4S4(SCH2Ph)4].[10][11]
See also
Bioinorganic chemistry
Iron-binding proteins
Notes
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 .
3. 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 .
4. 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.
doi:10.1038/nature10505 .
PMID 22002606 .
5. 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.
doi:10.1038/nature10504 .
PMID 22002607 .
6. 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.74.082803.1
33518 . PMID 15952888 .
7. 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.
8. 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 .
9. 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.
doi:10.1073/pnas.69.9.2437 .
PMC 426959 . PMID 4506765 .
10. Holm, R. H.; Lo, W. (2016). "Structural
Conversions of Synthetic and Protein-
Bound Iron-Sulfur Clusters". Chem. Rev.
116: 13685–13713.
doi:10.1021/acs.chemrev.6b00276 .
11. 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: 3579–3600.
doi:10.1021/cr4004067 . PMC 3982595 .
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 .
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 .
Spiro, T.G., Ed. (1982). Iron-sulfur
proteins. New York: Wiley. ISBN 0-471-
07738-0.
External links
Iron-Sulfur+Proteins at the US National
Library of Medicine Medical Subject
Headings (MeSH)
Examples of iron-sulfur clusters
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