Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Apr;16(1-2):45-53.
doi: 10.1016/j.cbpa.2012.03.004. Epub 2012 Apr 4.

Iron sulfur cluster proteins and microbial regulation: implications for understanding tuberculosis

Vikram Saini  1 , Aisha Farhana, Joel N Glasgow, Adrie J C Steyn
Affiliations
Review

Iron sulfur cluster proteins and microbial regulation: implications for understanding tuberculosis

Vikram Saini et al. Curr Opin Chem Biol. 2012 Apr.

Abstract

All pathogenic and nonpathogenic microbes are continuously exposed to environmental or endogenous reactive oxygen and nitrogen species, which can critically effect survival and disease. Iron-sulfur [Fe-S] cluster containing prosthetic groups provide the microbial cell with a unique capacity to sense and transcriptionally respond to diatomic gases (e.g. NO and O2) and redox-cycling agents. Recent advances in our understanding of the mechanisms for how the FNR and SoxR [Fe-S] cluster proteins respond to NO and O2 have provided new insights into the biochemical mechanism of action of the Mycobacterium tuberculosis (Mtb) family of WhiB [Fe-S] cluster proteins. These insights have provided the basis for establishing a unifying paradigm for the Mtb WhiB family of proteins. Mtb is the etiological agent for tuberculosis (TB), a disease that affects nearly one-third of the world's population.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Schematic representation of the mechanism of action of E. coli FNR, E. coli SoxR and Mtb WhiB3. (a) FNR exists in its apo form under aerobic conditions, wherein prolonged exposure to O2 inactivates FNR. With decreased O2 concentration, IscS transfers an [2Fe–2S]2+ cluster to the monomeric apo-FNR, leading to the formation of the [4Fe–4S]2+ FNR dimer in a stepwise process. The dimer is capable of binding DNA to activate or repress target gene expression. Conversion of the Fe–S cluster and monomerization can lead to the loss of binding, wherein [4Fe–4S]2+ is converted to [4Fe–4S]3+ upon oxidation, with the release of superoxide (O2•–) and hydrogen peroxide (H2O2). O2•– can cause loss of the FNR Fe–S cluster and provides an additional mechanism of regulation of FNR DNA binding. Besides O2, the active dimeric FNR [4Fe–4S]2+ is also responsive to NO to form a DNIC–FNR complex, which leads to its monomerization and dissociation from DNA. (b) SoxR exists as a homodimer in a [2Fe–2S]1+ state in its inactive form, which is capable of sensing and responding to oxidative stress, intracellular NADPH, redox-active and superoxide-generating compounds and NO. Upon exposure to such stresses, oxidation of SoxR [2Fe–2S]1+ leads to the formation of [2Fe–2S]2+, which induces DNA binding and transcription of target genes as well as its downstream signaling protein, SoxS. Besides this emerging model, the classical SoxR regulation demonstrates SoxR binding to SoxS in a complex leading to structural changes in SoxS that allow its binding to target DNA. This modulates the transcription of genes of the SoxRS regulon such as superoxide dismutase, xenobiotic efflux pumps and carbon metabolism enzymes. In addition to external stimuli, the intracellular redox environment also affects SoxR binding to DNA. (c) Mtb WhiB3 is a Fe–S cluster protein present exclusively in members of Actinobacteria and harbors a [4Fe–4S] cluster, which upon exposure to O2 generate [3Fe–4S], [2Fe–2S], and eventually apo, oxidized WhiB3. The WhiB3 [4Fe–4S] cluster can also react with NO to generate a stable DNIC complex. The DNA binding properties of WhiB3 are distinct from that of FNR and SoxR as oxidized apo-WhiB3 binds DNA exceptionally strongly compared to WhiB3 [4Fe–4S]2+ or [4Fe–4S]1+, and FNR and SoxR. Whether WhiB3 exists as a monomer or dimer in its active or inactive form is the subject of further investigation. Vertical color triangles represent gradients of O2 or NO.
Figure 2
Figure 2
Microarray-based expression profiles of Mtb Fe–S cluster and Fe–S cluster assembly genes. Using bioinformatics-based amino acid pattern searches and manual curation of the literature, we identified 50 genes encoding putative Mtb Fe–S cluster proteins. Expression profiles of these 50 genes, and genes encoding the Fe–S cluster assembly machinery (Rv1460-Rv1466, Rv3025c) were extracted from independent Mtb expression studies [–48] and a representative expression heat-map was generated. The heat-map represents differential expression profiles of these genes under diverse stress conditions such as aerated and non-aerated starvation, hypoxia, macrophage infection and exposure to NO and H2O2. The data suggest that most genes exposed to H2O2 and NO are weakly to highly upregulated compared to starvation and hypoxic conditions. The expression profiles under hypoxic conditions, macrophage infection and starvation conditions are similar to some degree. Intriguingly, the Fe–S cluster assembly genes are downregulated during hypoxia, but are highly upregulated within macrophages, and upon exposure to H2O2 and NO. The dramatic upregulation of Fe–S cluster assembly genes is probably to compensate for the loss of Fe–S clusters due to oxidative stress. Note that aconitase, a bifunctional enzyme involved in iron homeostasis during oxidative stress [49], is the most highly upregulated gene, followed by several of the Fe–S cluster assembly genes. Color scale represents fold changes in mRNA levels in wt Mtb compared to wt Mtb grown under the ‘control’ conditions. Gray boxes; value not available, Rrf — ribosome recycling factor.
Figure 3
Figure 3
Functional classification of Mtb Fe–S cluster proteins. Using Tuberculist and the COG databases, 50 putative Fe–S cluster containing proteins were analyzed. Approximately 70% of these proteins belong to intermediary metabolism and respiration followed by regulatory functions for ~15% of these proteins. Over 40% of Fe–S proteins in Mtb participate in energy production and conversion. This is followed by transcription regulation (mainly the WhiB family) and amino acid transport and metabolism for ~15% and 10% of Fe–S proteins, respectively.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Py B, Moreau PL, Barras F. Fe–S clusters, fragile sentinels of the cell. Curr Opin Microbiol. 2011;14:218–223. - PubMed
    1. Xu XM, Moller SG. Iron sulfur clusters: biogenesis, molecular mechanisms, and their functional significance. Antioxid Redox Signal. 2011;15:271–307. - PubMed
    1. Wollers S, Layer G, Garcia-Serres R, Signor L, Clemancey M, Latour JM, Fontecave M, Ollagnier deChoudens S. Iron–Sulfur (Fe–S) cluster assembly: the SufBCD complex is a new type of Fe–S scaffold with a flavin redox cofactor. J Biol Chem. 2010;285:23331–23341. - PMC - PubMed
    1. Ayala-Castro C, Saini A, Outten FW. Fe–S cluster assembly pathways in bacteria. Microbiol Mol Biol Rev. 2008;72:110–125. - PMC - PubMed
    1. Liu Y, Sieprawska-Lupa M, Whitman WB, White RH. Cysteine is not the sulfur source for iron-sulfur cluster and methionine biosynthesis in the methanogenic archaeon Methanococcus maripaludis. J Biol Chem. 2010;285:31923–31929. [This is the first demonstration that sulfide can be used as a source of sulfur during Fe–S cluster biosynthesis. Usually organisms that stay in sulfide-rich habitats, mostly those belonging to archaea, use sulfide rather than cysteine to make Fe–S clusters.] - PMC - PubMed

Publication types

MeSH terms