Biological iron-sulfur storage in a thioferrate-protein nanoparticle

Vaccaro, Brian J.; Clarkson, Sonya M.; Holden, James F.; Lee, Dong Woo; Wu, Chang Hao; Poole, Farris L.; Cotelesage, Julien J. H.; Hackett, Mark J.; Mohebbi, Sahel; Sun, Jingchuan; Li, Huilin; Johnson, Michael K.; George, Graham N.; Adams, Michael W. W.

doi:10.1038/ncomms16110

Cited by 23 publications

(39 citation statements)

References 50 publications

(82 reference statements)

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“… b FtnA, ferritin (nonheme dependent); Bfr, bacterioferritin (protoheme dependent); IssA, iron-sulfur storage protein. c The IssA homologs retrieved were further analyzed according to methods described by Vaccaro et al ( 104 ) in order to assess their likely membership in IssA versus NifB and NafY families, as shown in Fig. S2.…”

Section: Resultsmentioning

confidence: 99%

Pathways of Iron and Sulfur Acquisition, Cofactor Assembly, Destination, and Storage in Diverse Archaeal Methanogens and Alkanotrophs

et al. 2021

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Archaeal methanogens, methanotrophs, and alkanotrophs have a high demand for iron (Fe) and sulfur (S); however, little is known of how they acquire, traffic, deploy, and store these elements. Here, we examined the distribution of homologs of proteins mediating key steps in Fe/S metabolism in model microorganisms, including iron(II) sensing/uptake (FeoAB), sulfide extraction from cysteine (SufS), the biosynthesis of iron-sulfur [Fe-S] clusters (SufBCDE), siroheme (Pch2-dehydrogenase), protoheme (AhbABCD), and cytochrome c (CcmCF), and iron-storage/detoxification (Bfr, FtrA, IssA), among 326 publicly available, complete or metagenome-assembled genomes of archaeal methanogens/methanotrophs/alkanotrophs. Results indicate several prevalent but non-universal features including FeoB, SufBC, and the biosynthetic apparatus for the basic tetrapyrrole scaffold as well as its siroheme (and F 430 ) derivatives. However, several early diverging genomes lacked SufS and pathways to synthesize and deploy heme. Genomes encoding complete versus incomplete heme biosynthetic pathways exhibited an equivalent prevalence of [Fe-S]-cluster binding proteins, suggesting an expansion of catalytic capabilities rather than substitution of heme for [Fe-S] in the former group. Several strains with heme binding proteins lacked heme biosynthesis capabilities while other strains with siroheme biosynthesis capability lacked homologs of known siroheme binding proteins, indicating heme auxotrophy and unknown siroheme biochemistry, respectively. While ferritin proteins involved in ferric oxide storage were widespread, those involved in storing Fe as thioferrate were unevenly distributed. Collectively, the results suggest that differences in the mechanisms of Fe and S acquisition, deployment, and storage have accompanied the diversification of methanogens/methanotrophs/alkanotrophs, possibly in response to differential availability of these elements as these organisms evolved. IMPORTANCE Archaeal methanogens, methanotrophs, and alkanotrophs, argued to be among the most ancient forms of life, have a high demand for iron (Fe) and sulfur (S) for co-factor biosynthesis, among other uses. Here, using comparative bioinformatic approaches applied to 326 genomes, we show that major differences in Fe/S acquisition, trafficking, deployment, and storage exist in this group. Variation in these characters was generally congruent with the phylogenetic placement of these genomes, indicating that variation in Fe/S usage and deployment has contributed to the diversification and ecology of these organisms. However, incongruency was observed among the distribution of cofactor biosynthesis pathways and known protein destinations for those co-factors, suggesting auxotrophy or yet to be discovered pathways for cofactor biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Pathways of Iron and Sulfur Acquisition, Cofactor Assembly, Destination, and Storage in Diverse Archaeal Methanogens and Alkanotrophs

et al. 2021

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“…Two roles have been proposed for IssA; that it is involved in Fe storage or that it serves to detoxify insoluble FeS clusters (22,23). To test the role of IssA in Fe storage, WT cells were harvested after growth under +S 0 and -S 0 conditions, and ΔIssA under +S 0 conditions.…”

Section: Growth Experimentsmentioning

confidence: 99%

“…Supporting information-This article contains supporting information (3,6,11,14,(19)(20)(21)(22)(23).…”

Section: Data Availabilitymentioning

confidence: 99%

“…The exact function of the IssA protein is unknown but its expression increases dramatically when cells are grown in +S 0 media, but only when iron is present (>7.4 μM) (22). Vaccaro et al (23) suggested that IssA stores iron as thioferrates in which Fe III and S 2− ions form anionic chains of edge-sharing FeS 4 tetrahedra that are charge-neutralized by cations such as Na + or K + . Using TEM, they detected iron-dense particles 20 to 300 nm in diameter in +S 0 P. furiosus cells (23) 57 Fe-enriched WT and ΔIssA whole P. furiosus cells grown on the disaccharide maltose in the presence (+S 0 ) and absence (-S 0 ) of elemental sulfur.…”

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confidence: 99%

“…Vaccaro et al (23) suggested that IssA stores iron as thioferrates in which Fe III and S 2− ions form anionic chains of edge-sharing FeS 4 tetrahedra that are charge-neutralized by cations such as Na + or K + . Using TEM, they detected iron-dense particles 20 to 300 nm in diameter in +S 0 P. furiosus cells (23) 57 Fe-enriched WT and ΔIssA whole P. furiosus cells grown on the disaccharide maltose in the presence (+S 0 ) and absence (-S 0 ) of elemental sulfur. All 57 Fe ions in a sample are detectable by MB spectroscopy, with intensities that are roughly invariant per iron in the sample, regardless of the type of iron center.…”

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The Pyrococcus furiosus ironome is dominated by [Fe4S4]2+ clusters or thioferrate-like iron depending on the availability of elemental sulfur

Vali

Haja

Brand

et al. 2021

Journal of Biological Chemistry

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Pyrococcus furiosus is a hyperthermophilic anaerobic archaeon whose metabolism depends on whether elemental sulfur is (+S 0 ) or is not (-S 0 ) included in growth medium. Under +S 0 conditions, expression of respiratory hydrogenase declines while respiratory membrane-bound sulfane reductase and the putative iron-storage protein IssA increase. Our objective was to investigate the iron content of WT and ΔIssA cells under these growth conditions using Mössbauer spectroscopy. WT-S 0 cells contained 1 mM Fe, with 85% present as two spectroscopically distinct forms of S = 0 [Fe 4 S 4 ] 2+ clusters; the remainder was mainly high-spin Fe II . WT+S 0 cells contained 5 to 9 mM Fe, with 75 to 90% present as magnetically ordered thioferrate-like (TFL) iron nanoparticles. TFL iron was similar to chemically defined thioferrates; both consisted of Fe III ions coordinated by an S 4 environment, and both exhibited strong coupling between particles causing high applied fields to have little spectral effect. At high temperatures with magnetic hyperfine interactions abolished, TFL iron exhibited two doublets overlapping those of [Fe 4 S 4 ] 2+ clusters in -S 0 cells. This coincidence arose because of similar coordination environments of TFL iron and cluster iron. The TFL structure was more heterogeneous in the presence of IssA. Presented data suggest that IssA may coordinate insoluble iron sulfides as TFL iron, formed as a byproduct of anaerobic sulfur respiration under high iron conditions, which thereby reduces its toxicity to the cell. This was the first Mössbauer characterization of the ironome of an archaeon, and it illustrates differences relative to the iron content of better-studied bacteria such as Escherichia coli.

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Hijacking Endogenous Iron and GSH Via a Polyvalent Ferroptosis Agonist to Enhance Tumor Immunotherapy

Li,

Lei,

Yao

et al. 2023

Adv Funct Materials

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The clinical application of ferroptosis, characterized by iron‐dependent lipid peroxidation, is limited because of the serious side effects of using toxic‐dose iron. Herein, a polyvalent ferroptosis agonist‐a hypoxia responsive polymer bearing 18‐crown‐6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural “iron pools” of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer‐chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH2) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti‐tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8+ T‐cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer‐hijacking endogenous iron and GSH may offer new therapeutic opportunities.

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Biological iron-sulfur storage in a thioferrate-protein nanoparticle

Cited by 23 publications

References 50 publications

Pathways of Iron and Sulfur Acquisition, Cofactor Assembly, Destination, and Storage in Diverse Archaeal Methanogens and Alkanotrophs

Pathways of Iron and Sulfur Acquisition, Cofactor Assembly, Destination, and Storage in Diverse Archaeal Methanogens and Alkanotrophs

The Pyrococcus furiosus ironome is dominated by [Fe4S4]2+ clusters or thioferrate-like iron depending on the availability of elemental sulfur

Hijacking Endogenous Iron and GSH Via a Polyvalent Ferroptosis Agonist to Enhance Tumor Immunotherapy

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