Subsystem: Fe-S cluster assembly

This subsystem's description is:

Fe-S cluster assembly

Iron-sulfur (Fe-S) proteins are present in all living organisms and play important roles in electron transport and metalloenzyme catalysis [1]. Although Fe-S clusters can be assembled into proteins in vitro from Fe2+ and S2, it is clear that in vivo, this process mus tbe facilitated by protein factors to avoid accumulation of Fe2+ and S2 to toxic levels. The complex, multi-step process involved in the biosynthesis of Fe-S clusters is only now being clarified, and early work has identified three distinct systems termed NIF (nitrogen fixation), ISC (iron-sulfur cluster), and SUF (sulfur mobilization). NifS-NifU are required for the assembly of Fe-S clusters of the nitrogenase proteins in Azotobacter vinelandii [2]. NifS is a pyridoxal phosphate-dependent cysteine desulfurase that initiates Fe-S cluster formation by eliminating elemental sulfur from cysteine and transferring it to NifU, which serves as a scaffold for the assembly of Fe-S clusters prior to their delivery to apo–Fe-S protein targets. In contrast to the NIF machinery that specifically deals with the maturation of nitrogenase, the ISC proteins are involved in the general biosynthesis pathway for numerous Fe-S proteins [3]. In several bacteria, the genes encoding these Fe-S assembly proteins (IscS, IscU, IscA, Hsc66, Hsc20, and ferredoxin) are organized in a cluster, iscSUA-hscBA-fdx. Mutation of these genes in Escherichia coli decreases the activity of many Fe-S proteins, whereas overexpression of the operon leads to increased production of Fe-S proteins [4].
A third system (SUF) encoded by the sufABCDSE operon represents a minor pathway for the assembly of Fe-S clusters [5]. In an E. coli mutant from which the entire isc operon was deleted, the activity of Fe-S proteins was only 2–10% that in wild-type cells. The residual activity may arise from the contribution of the SUF system, since overexpression of the suf operon restores the growth phenotype and activity of Fe-S proteins in mutant cells lacking the ISC machinery. Disruption of the suf operon does not cause any major defects, whereas the loss of both the ISC and SUF systems leads to synthetic lethality.
Several similarities have been found among the NIF, ISC, and SUF systems. IscS and SufS are structurally similar to NifS, and all three function as a cysteine desulfurase [6]. IscU is homologous to the N-terminal domain of NifU and contains three conserved cysteine residues that are essential for its function as a scaffold for intermediate Fe-S clusters [7]. SufA and IscA are members of the HesB protein family that binds iron and [2Fe-2S] clusters, and mediates iron delivery for assembly of Fe-S clusters in IscU [8]. The ISC machinery contains three additional components, two essential chaperones HscB and HscA, and nonessential [2Fe-2S]ferredoxin Fdx. The biochemical properties of the SUF-specific components are less well understood. SufE interacts with SufS and stimulates its cysteine desulfurase activity [9]. The SufB, SufC and SufD proteins associate in a stable complex, and SufC has been shown to possess ATPase activity in this context [10].
Mutational analysis has demonstrated that the ISC system predominantly functions in the biosynthesis of Fe-S proteins, whereas the SUF system contributes only modestly [11]. The expression of the suf operon is controlled by OxyR and Fur, suggesting a stress response function for the SUF machinery under conditions of oxidative stress (when FeS clusters are damaged) and iron limitation [12].
Recent functional replacement study of E.coli isc-suf double mutant showed that nifSU-like genes cloned from Helicobacter pylori are functionally exchangeable with the isc and suf operons under anaerobic conditions [13]. Thus, at least some NIF-like systems participates in the maturation of a wide variety of Fe-S proteins. However, the NIF system was only found in a limited number of bacterial species, most of which are anaerobes.

Additional Functional Roles:
#IscR: Iron-sulfur cluster regulator is encoded by an ORF located immediately upstream of the isc operon coding for the Escherichia coli Fe-S cluster assembly proteins. IscR belongs to COG1959, which is also contains the nitrite-sensitive repressor NsrR from Nitrosomonas and its orthologs from other proteobacteria (D.R., unpublished observation).
IscR functions as a repressor of the iscRSUA operon. Analysis of IscR by electron paramagnetic resonance showed that the anaerobically isolated protein contains a [2Fe-2S](1+) cluster. The Fe-S cluster appears to be important for IscR function, because repression of iscR expression is significantly reduced in strains containing null mutations of the Fe-S cluster assembly genes iscS or hscA. It suggests that this protein may be part of a novel autoregulatory mechanism that senses the Fe-S cluster assembly status of cells.
#HscA and HscB: Hsc66 and Hsc20 comprise a specialized chaperone system important for the assembly of iron-sulfur clusters in Escherchia coli. Only a single substrate, the Fe/S template protein IscU, has been identified for the Hsc66/Hsc20 system, but the mechanism by which Hsc66 selectively binds IscU is unknown . HscA is similar to the heat shock protein 70 DnaK.
#Fdx: The ferredoxin Fdx could function as an intermediate site for Fe-S cluster assembly
#SufC: is an atypical cytoplasmic ABC-ATPase, which forms a complex with SufB and SufD;
#SufE: forms a complex with SufS and the binding of SufE to SufS is responsible for a 50-fold stimulation of the cysteine desulfurase activity of SufS.

1. Beinert, H., Holm, R.H., and Münck, E. (1997) Iron-sulfur clusters: nature’s modular, multipurpose structures. Science 277, 653–659.
2. Frazzon, J. and Dean, D.R. (2003) Formation of iron-sulfur clusters in bacteria: an emerging field in bioinorganic chemistry. Curr. Opin. Chem. Biol. 7, 166–173.
3. Zheng, L., Cash, V.L., Flint, D.H., and Dean, D.R. (1998) Assembly of iron-sulfur clusters: identification of an iscSUA-hscBA-fdx gene cluster from Azotobacter vinelandii. J. Biol. Chem. 273, 13264–13272.
4. Tokumoto, U. and Takahashi, Y. (2001) Genetic analysis of the isc operon in Escherichia coli involved in the biogenesis of cellular iron-sulfur proteins. J. Biochem. 130, 63–71.
5. Takahashi, Y. and Tokumoto, U. (2002) A third bacterial system for the assembly of iron-sulfur clusters with homologs in archaea and plastids. J. Biol. Chem. 277, 28380–28383.
6. Mihara, H. and Esaki, N. (2002) Bacterial cysteine desulfurases: their function and mechanisms. Appl. Microbiol. Biotechnol. 60, 12–23.
7. Urbina, H.D., Silberg, J.J., Hoff, K.G., and Vickery, L.E. (2001) Transfer of sulfur from IscS to IscU during Fe/S cluster assembly. J. Biol. Chem. 276, 44521–44526.
8. Krebs, C., Agar, J.N., Smith, A.D., Frazzon, J., Dean, D.R., Huynh, B.H., and Johnson, M.K. (2001) IscA, an alternate scaffold for Fe-S cluster biosynthesis. Biochemistry 40, 14069–14080.
9. Outten, F.W., Wood, M.J., Muñoz, F.M., and Storz, G. (2003) The SufE protein and the SufBCD complex enhance SufS cysteine desulfurase activity as part of a sulfur transfer pathway for Fe-S cluster assembly in Escherichia coli. J. Biol. Chem. 278, 45713–45719.
10. Rangachari, K., Davis, C.T., Eccleston, J.F., Hirst, E.M., Saldanha, J.W., Strath, M., and Wilson, R.J. (2002) SufC hydrolyzes ATP and interacts with SufB from Thermotoga maritima. FEBS Lett. 514, 225–228.
11. Zheng, M., Wang, X., Templeton, L.J., Smulski, D.R., LaRossa, R.A., and Storz, G. (2001) DNA microarray-mediated transcriptional profiling of the Escherichia coli response to hydrogen peroxide. J. Bacteriol. 183, 4562–4570.
12. McHugh, J.P., Rodríguez-Quinoñes, F., Abdul-Tehrani, H., Svistunenko, D.A., Poole, R.K., Cooper, C.E., and Andrews, S.C. (2003) Global iron-dependent gene regulation in Escherichia coli. A new mechanism for iron homeostasis. J. Biol. Chem. 278, 29478–29486
13. Tokumoto U, Kitamura S, Fukuyama K, Takahashi Y. (2004) Interchangeability and distinct properties of bacterial Fe-S cluster assembly systems: functional replacement of the isc and suf operons in Escherichia coli with the nifSU-like operon from Helicobacter pylori. J Biochem (Tokyo) 136: 199-209.

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Literature ReferencesIron-sulfur clusters: nature's modular, multipurpose structures. Beinert H Science (New York, N.Y.) 1997 Aug 19235882
Methanosarcina acetivorans contains a functional ISC system for iron-sulfur cluster biogenesis. Deere TM BMC microbiology 2020 Oct 2333096982
The SufBCD protein complex is the scaffold for iron-sulfur cluster assembly in Thermus thermophiles HB8. Tian T Biochemical and biophysical research communications 2014 Jan 1024333431
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