Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization

Maio, Nunziata; Zhang, Deliang; Ghosh, Manik C.; Jain, Anshika; SantaMaria, Anna M.; Rouault, Tracey A.

doi:10.1053/j.seminhematol.2021.06.001

Cited by 26 publications

(26 citation statements)

References 167 publications

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“…One way to drug these intrinsically disordered proteins (IDPs) is to inhibit their translation by targeting the encoding mRNA. Iron-responsive elements (IREs) are small stem-loop structures present in 5′-or 3′UTRs [197][198][199] that bind to iron regulatory proteins (IRPs) 200,201 . IRP binding to IREs in the 5′UTR prevents ribosome docking and blocks RNA translation whereas binding to the 3′UTR stabilizes the transcript and upregulates translation 202 .…”

Section: Discovery Of An Antifungal That Targets a Group II Intronmentioning

confidence: 99%

Targeting RNA structures with small molecules

Childs‐Disney

Yang

Gibaut

et al. 2022

Nat Rev Drug Discov

197

219

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RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing — by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.

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Section: Discovery Of An Antifungal That Targets a Group II Intronmentioning

confidence: 99%

Targeting RNA structures with small molecules

Childs‐Disney

Yang

Gibaut

et al. 2022

Nat Rev Drug Discov

197

219

View full text Add to dashboard Cite

show abstract

“…Fe-S clusters are also indispensable for heme biosynthesis (discussed in depth in ref. [19]). Heme consists of the protoporphyrin IX ring complexed with ferrous iron and it is necessary for the function of [4Fe-4S] clusters have the capability to delocalize electrons between iron sites (as depicted by the tan cloud-like frames, which illustrate that the iron-associated electrons are highly delocalized between neighboring iron atoms).…”

Section: Biological Roles Of Fe-s Proteinsmentioning

confidence: 99%

“…Fe‐S clusters are also indispensable for heme biosynthesis (discussed in depth in ref. [19]). Heme consists of the protoporphyrin IX ring complexed with ferrous iron and it is necessary for the function of several proteins, including hemoglobin and myoglobin, cytochromes of the electron transport chain, catalase, and nitric oxide synthase.…”

Section: Biological Roles Of Fe‐s Proteinsmentioning

confidence: 99%

Mammalian iron sulfur cluster biogenesis: From assembly to delivery to recipient proteins with a focus on novel targets of the chaperone and co‐chaperone proteins

Maio

Rouault

2022

IUBMB Life

Self Cite

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“…Due to iron’s critical role in cell metabolism, maintaining its balance is essential for most organisms ( Maio et al, 2022 ). Low-intracellular iron concentration inhibits the activity of Fe-dependent enzymes, while high iron accumulation stimulates reactive oxygen species (ROS) formation and disrupts other metal-trafficking pathways ( Vachon et al, 2012 ; Chen et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Schizosaccharomyces pombe Grx4, Fep1, and Php4: In silico analysis and expression response to different iron concentrations

et al. 2022

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Due to iron’s essential role in cellular metabolism, most organisms must maintain their homeostasis. In this regard, the fission yeast Schizosaccharomyces pombe (sp) uses two transcription factors to regulate intracellular iron levels: spFep1 under iron-rich conditions and spPhp4 under iron-deficient conditions, which are controlled by spGrx4. However, bioinformatics analysis to understand the role of the spGrx4/spFep1/spPhp4 axis in maintaining iron homeostasis in S. pombe is still lacking. Our study aimed to perform bioinformatics analysis on S. pombe proteins and their sequence homologs in Aspergillus flavus (af), Saccharomyces cerevisiae (sc), and Homo sapiens (hs) to understand the role of spGrx4, spFep1, and spPhp4 in maintaining iron homeostasis. The three genes’ expression patterns were also examined at various iron concentrations. A multiple sequence alignment analysis of spGrx4 and its sequence homologs revealed a conserved cysteine residue in each PF00085 domain. Blast results showed that hsGLRX3 is most similar to spGrx4. In addition, spFep1 is most closely related in sequence to scDal80, whereas scHap4 is most similar to spFep1. We also found two highly conserved motifs in spFep1 and its sequence homologs that are significant for iron transport systems because they contain residues involved in iron homeostasis. The scHap4 is most similar to spPhp4. Using STRING to analyze protein-protein interactions, we found that spGrx4 interacts strongly with spPhp4 and spFep1. Furthermore, spGrx4, spPhp4, and spFep1 interact with spPhp2, spPhp3, and spPhp5, indicating that the three proteins play cooperative roles in iron homeostasis. At the highest level of Fe, spgrx4 had the highest expression, followed by spfep1, while spphp4 had the lowest expression; a contrast occurred at the lowest level of Fe, where spgrx4 expression remained constant. Our findings support the notion that organisms develop diverse strategies to maintain iron homeostasis.

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Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization

Cited by 26 publications

References 167 publications

Targeting RNA structures with small molecules

Targeting RNA structures with small molecules

Mammalian iron sulfur cluster biogenesis: From assembly to delivery to recipient proteins with a focus on novel targets of the chaperone and co‐chaperone proteins

Schizosaccharomyces pombe Grx4, Fep1, and Php4: In silico analysis and expression response to different iron concentrations

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