Iron–sulfur clusters as inhibitors and catalysts of viral replication

Ebrahimi, Kourosh Honarmand; Ciofi‐Baffoni, Simone; Hagedoorn, Peter‐Leon; Nicolet, Yvain; Brun, Nick E. Le; Hagen, Wilfred R.; Armstrong, Fräser A.

doi:10.1038/s41557-021-00882-0

Cited by 35 publications

(26 citation statements)

References 169 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[52] On the one hand, a high level of iron should be maintained for the synthesis of iron-sulfur clusters and heme, both of which are essential intracellular components and play critical physiological roles, e.g., electron transfer, catalysis, protein stabilization, and oxygen sensor. [53,54] On the other hand, the labile iron pool is well regulated to limit the extensive production of ROS via the Fenton reaction, which is partly realized by the upregulation of antioxidant enzymes such as nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1. [55] In the current work, the data in both cellular and animal models demonstrated the elevation of cardiac iron concentration against that in tumor cells even at the presence of Dox (Figure 6g; Figure S23, Supporting Information).…”

Section: Discussionmentioning

confidence: 99%

Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

Chen

Yan

et al. 2023

Adv Funct Materials

View full text Add to dashboard Cite

The dose‐dependent cardiomyopathy of adriamycin (doxorubicin) limits its long‐term clinical use, which is revealed as a consequence of cardiomyocyte ferroptosis. As a ferrous iron (Fe2+)‐dependent regulated cell death pathway, ferroptosis is induced by the tailored lipid peroxides in the cell membranes. Herein, iron‐chelating polymer micelles are reported for concurrent doxorubicin delivery and cardiotoxicity reduction. The amphiphilic polymer consists of methoxy poly (ethylene glycol)‐co‐poly (glutamic acid) copolymer as the backbone and deferiprone analog as the side chain. The chiral polymer adopted the α‐helix conformation to enable prolonged retention in the cell membranes, resulting in efficient iron chelation, ferroptosis inhibition, and cardiotoxicity reduction. The co‐encapsulation of doxorubicin and coenzyme Q10 (CoQ10) in micelles further alleviates the cardiotoxicity because the reduced CoQ10 can act as a radical trapping agent to constrain lipid peroxidation and cardiomyocyte ferroptosis. The reduction of cardiotoxicity is accompanied by enhanced anticancer efficacy in an in vivo murine breast cancer model. The chiral iron‐chelating polymer micelles can be a promising platform for enhanced doxorubicin delivery and reduced cardiac adverse effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

Chen

Yan

et al. 2023

Adv Funct Materials

View full text Add to dashboard Cite

show abstract

“…Thus, the enzyme is rendered inactive after a single turnover in the absence of a system that can regenerate the auxiliary cluster either by repairing it or by fully replacing it. Fe–S clusters are essential in all domains of life and are involved in various cellular processes, including respiration, ribosome assembly, DNA repair, and the biosynthesis of key metabolites. − Due to the complexity of ISC assembly, trafficking, and repair mechanisms in vivo, these processes are yet to be fully understood. Understanding these mechanisms in humans is vital because Fe–S clusters and their incorporation into proteins that require them are critical to many serious diseases. ,,,− While recent in vitro attempts to characterize Fe–S cluster assembly and trafficking have been reported, the determination of which late-acting carriers mediate LIAS auxiliary cluster regeneration during catalytic turnover remains unresolved.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1

Warui¹,

Sil

Lee

et al. 2022

ACS Bio Med Chem Au

View full text Add to dashboard Cite

Lipoyl synthase (LS) catalyzes the last step in the biosynthesis of the lipoyl cofactor, which is the attachment of sulfur atoms at C6 and C8 of an n-octanoyllysyl side chain of a lipoyl carrier protein (LCP). The protein is a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes, which use SAM as a precursor to a 5′-deoxyadenosyl 5′-radical (5′-dA·). The role of the 5′-dA· in the LS reaction is to abstract hydrogen atoms from C6 and C8 of the octanoyl moiety of the substrate to initiate subsequent sulfur attachment. All radical SAM enzymes have at least one [4Fe–4S] cluster that is used in the reductive cleavage of SAM to generate the 5′-dA·; however, LSs contain an additional auxiliary [4Fe–4S] cluster from which sulfur atoms are extracted during turnover, leading to degradation of the cluster. Therefore, these enzymes catalyze only 1 turnover in the absence of a system that restores the auxiliary cluster. In Escherichia coli, the auxiliary cluster of LS can be regenerated by the iron–sulfur (Fe–S) cluster carrier protein NfuA as fast as catalysis takes place, and less efficiently by IscU. NFU1 is the human ortholog of E. coli NfuA and has been shown to interact directly with human LS (i.e., LIAS) in yeast two-hybrid analyses. Herein, we show that NFU1 and LIAS form a tight complex in vitro and that NFU1 can efficiently restore the auxiliary cluster of LIAS during turnover. We also show that BOLA3, previously identified as being critical in the biosynthesis of the lipoyl cofactor in humans and Saccharomyces cerevisiae, has no direct effect on Fe–S cluster transfer from NFU1 or GLRX5 to LIAS. Further, we show that ISCA1 and ISCA2 can enhance LIAS turnover, but only slightly.

show abstract

“…Iron-sulfur (Fe-S) clusters are inorganic cofactors of proteins made of iron and sulfide and are essential for life . Fe-S cluster-containing proteins are involved in many biological functions including redox and nonredox catalysis, sensing, gene expression, and regulation. − The most common Fe-S structural arrangements found in proteins are [2Fe-2S], cubane [4Fe-4S], and, to a lesser extent, cubane [3Fe-4S] clusters . Unusual Fe-S cluster architectures are also encountered in proteins for specific biological purposes .…”

mentioning

confidence: 99%

Evidence for [2Fe-2S]²⁺ and Linear [3Fe-4S]¹⁺ Clusters in a Unique Family of Glycine/Cysteine-Rich Fe-S Proteins from Megavirinae Giant Viruses

et al. 2023

View full text Add to dashboard Cite

We have discovered a protein with an amino acid composition exceptionally rich in glycine and cysteine residues in the giant virus mimivirus. This small 6 kDa protein is among the most abundant proteins in the icosahedral 0.75 μm viral particles; it has no predicted function but is probably essential for infection. The aerobically purified red-brownish protein overproduced in Escherichia coli contained both iron and inorganic sulfide. UV/vis, EPR, and Mossbauer studies revealed that the viral protein, coined GciS, accommodated two distinct Fe-S clusters: a diamagnetic S = 0 [2Fe-2S] 2+ cluster and a paramagnetic S = 5/2 linear [3Fe-4S] 1+ cluster, a geometry rarely stabilized in native proteins. Orthologs of mimivirus GciS were identified within all clades of Megavirinae, a Mimiviridae subfamily infecting Acanthamoeba, including the distantly related tupanviruses, and displayed the same spectroscopic features. Thus, these glycine/cysteine-rich proteins form a new family of viral Fe-S proteins sharing unique Fe-S cluster binding properties.

show abstract

Iron–sulfur clusters as inhibitors and catalysts of viral replication

Cited by 35 publications

References 169 publications

Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1

Evidence for [2Fe-2S]²⁺ and Linear [3Fe-4S]¹⁺ Clusters in a Unique Family of Glycine/Cysteine-Rich Fe-S Proteins from Megavirinae Giant Viruses

Contact Info

Product

Resources

About

Iron–sulfur clusters as inhibitors and catalysts of viral replication

Cited by 35 publications

References 169 publications

Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

Chiral Polymer Micelles Alleviate Adriamycin Cardiotoxicity via Iron Chelation and Ferroptosis Inhibition

In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1

Evidence for [2Fe-2S]2+ and Linear [3Fe-4S]1+ Clusters in a Unique Family of Glycine/Cysteine-Rich Fe-S Proteins from Megavirinae Giant Viruses

Contact Info

Product

Resources

About

Evidence for [2Fe-2S]²⁺ and Linear [3Fe-4S]¹⁺ Clusters in a Unique Family of Glycine/Cysteine-Rich Fe-S Proteins from Megavirinae Giant Viruses