Affinage

ACO1

Cytoplasmic aconitate hydratase · UniProt P21399

Length
889 aa
Mass
98.4 kDa
Annotated
2026-06-09
92 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACO1/IRP1 is a bifunctional cytosolic protein that couples cellular iron status to post-transcriptional gene regulation, switching between a [4Fe-4S]-cluster-bearing cytosolic aconitase and an apo-form that binds iron-responsive elements (IREs) in target mRNAs (PMID:1903202, PMID:17242182). In iron-replete cells the cytosolic iron-sulfur cluster assembly (CIA) machinery inserts a cubane [4Fe-4S] cluster that confers aconitase activity and abolishes RNA binding, whereas iron limitation, oxidative attack, and disruption of cluster assembly drive the apo, IRE-binding state (PMID:17242182, PMID:28768766, PMID:34039609). When bound to a cap-proximal IRE, IRP1 permits eIF4F assembly but blocks bridging to the 43S ribosomal subunit, repressing translation initiation downstream of cap recognition; binding to other IREs stabilizes target mRNAs such as transferrin receptor mRNA (PMID:9774976, PMID:12052872). IRP1 activity is tuned by multiple inputs: extracellular H2O2 and nitric oxide activate IRE binding while inactivating aconitase, tyrosine nitration follows cluster loss, ATP/ADP binding induces a conformational change that suppresses IRE binding, and phosphorylation at Ser-711 inhibits both activities while Ser-138 phosphorylation supports iron rescue under CIA stress (PMID:9092514, PMID:8639920, PMID:15258160, PMID:20569198, PMID:28768766). Apo-IRP1 that cannot form a cluster is degraded by FBXL5-directed ubiquitin-proteasomal turnover, providing a synergistic second layer of control (PMID:17242182, PMID:28768766). Physiologically, IRP1 is the dominant translational regulator of HIF-2α mRNA—owing to a bulge uridine in the HIF-2α IRE that impairs IRP2 binding—and its loss de-represses HIF-2α to elevate renal EPO, causing polycythemia and systemic iron-handling defects, establishing IRP1 as a master regulator of erythropoiesis and iron homeostasis (PMID:23395174, PMID:23777768, PMID:39316647). IRP1 also binds a novel IRE in Bcl-xL mRNA to link iron sensing to FUNDC1-dependent mitophagy and regulates systemic energy homeostasis, with deficiency rewiring hepatocyte and muscle metabolism toward glycolysis (PMID:32795936, PMID:41493805). Frataxin and MUSTN1 are characterized physical partners modulating IRP1 cluster status and its mRNA-binding output (PMID:20053667, PMID:41547500).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1991 Medium

    Establishing that the IRE-binding regulatory protein is structurally an aconitase family member set up the central hypothesis that one protein interconverts between enzyme and RNA-binding regulator.

    Evidence Computational sequence homology analysis comparing IRE-BP with aconitase and isopropylmalate isomerase

    PMID:1903202

    Open questions at the time
    • Homology alone did not demonstrate the iron-dependent functional switch
    • No structural basis for the dual function established
  2. 1995 High

    Defining iron regulation of IRP1 as post-translational and dissecting cysteine-dependent RNA-binding inactivation distinguished IRP1's regulatory logic from the synthesis-dependent IRP2 and tied RNA binding to free sulfhydryl/cluster status.

    Evidence In vitro RNA-binding inhibition with NEM/diamide, translation-inhibitor experiments, and recombinant IRP1/IRP2 translation-repression comparisons

    PMID:7544791 PMID:7890603

    Open questions at the time
    • Did not resolve the cluster-assembly machinery responsible in vivo
    • Cysteine residues mediating the effect not individually mapped here
  3. 1998 High

    Resolving the precise translation step blocked by IRP1 showed it acts after cap recognition by preventing eIF4F-43S bridging, defining the molecular mechanism of IRE-mediated translational repression.

    Evidence In vitro translation initiation factor assembly assay, gel retardation, and sucrose gradient analysis on ferritin IRE

    PMID:9774976

    Open questions at the time
    • Mechanism shown for cap-proximal IREs; 3'-UTR mRNA-stabilization mechanism not addressed
    • Bridging factor identity not pinned down
  4. 2001 High

    Demonstrating that oxidative stimuli (H2O2, NO, superoxide-driven nitration) selectively activate IRP1 but not IRP2 across cells, macrophages, and intact liver established IRP1 as a redox sensor and argued against simple direct cluster oxidation as the sole activation route.

    Evidence Cellular and intercellular NO/H2O2 systems, rat-liver perfusion with isoform-specific probes, anti-nitrotyrosine IP/Western, aconitase and EMSA assays

    PMID:11297549 PMID:15258160 PMID:8639920 PMID:9092514 PMID:9545264

    Open questions at the time
    • The signaling intermediate linking extracellular H2O2 to cluster loss not identified
    • Quantitative contribution of nitration vs. cluster disassembly in vivo unclear
  5. 2005 High

    Identifying Ser-711 phosphorylation as inhibitory to both aconitase and IRE-binding activities added a covalent, signal-driven regulatory layer beyond iron and redox control.

    Evidence Site-directed mutagenesis (S711E phosphomimetic), recombinant protein aconitase assays, EMSA, and mammalian cell expression

    PMID:15636585

    Open questions at the time
    • The kinase phosphorylating Ser-711 in vivo not identified
    • Physiological stimulus driving phosphorylation not defined
  6. 2007 High

    Showing that apo-IRP1 unable to form a [4Fe-4S] cluster is targeted for iron-dependent ubiquitin-proteasomal degradation, requiring the cysteine desulfurase Nfs1, established degradation as a regulatory fate complementary to the cluster switch.

    Evidence Inducible IRP1(C437S) expression, pulse-chase, proteasome inhibitors, ubiquitination assay, and Nfs1 siRNA

    PMID:17242182

    Open questions at the time
    • The E3 ligase was not identified in this study
    • Relative weighting of cluster switch vs. degradation in normal physiology unresolved
  7. 2010 High

    Defining frataxin as a direct, cluster-dependent IRP1 partner and ATP/ADP binding as a conformational suppressor of IRE binding revealed additional protein and nucleotide inputs governing the enzyme/regulator equilibrium.

    Evidence Co-IP and functional rescue in FRDA cells; radiolabeled ATP/ADP binding, CD spectroscopy, and ATPase assays with C437S mutant

    PMID:20053667 PMID:20569198

    Open questions at the time
    • Structural basis of ATP/ADP-induced conformational change not solved
    • In vivo relevance of IRP1 ATPase activity unclear
  8. 2013 High

    In vivo genetics established IRP1 as the dominant translational regulator of HIF-2α, with loss causing polycythemia, elevated EPO, and disrupted systemic iron handling—placing IRP1 at the apex of erythropoietic and iron-homeostatic control.

    Evidence Irp1-/- and Irp2-/- mice with ribosome profiling, serum EPO measurement, hematological analysis, and tissue gene expression

    PMID:23395174 PMID:23777768

    Open questions at the time
    • Did not yet explain the molecular basis of IRP1 vs IRP2 selectivity for the HIF-2α IRE
    • Age/condition dependence of dominance over PHD/VHL control only partly mapped
  9. 2017 High

    Integrating CIA-mediated cluster insertion as the primary RNA-binding off-switch with FBXL5-driven degradation as a synergistic, feedback-coupled secondary mechanism, and adding Ser-138 phosphorylation, unified the control logic of IRP1.

    Evidence siRNA of CIA components, inducible IRP1(3C>3S), polyubiquitination and phosphorylation analysis, viability and aconitase assays

    PMID:28768766

    Open questions at the time
    • Kinase for Ser-138 not identified
    • Quantitative kinetics of cluster insertion vs. degradation in vivo unresolved
  10. 2021 High

    Genetic dissection at physiological O2 showed ISC occupancy competitively governs IRP1 binding, that IRP2 acts redundantly and independently of IRP1/FBXL5, and that double deletion abolishes the iron-starvation response, defining the division of labor between the two IRPs.

    Evidence ISC synthesis inhibition, IRP1/IRP2/FBXL5 siRNA, IRE-binding and ferroptosis assays at tissue-level O2

    PMID:34039609

    Open questions at the time
    • Tissue-specific apportioning of IRP1 vs IRP2 function in vivo not fully resolved
    • How O2 tension is sensed mechanistically not detailed
  11. 2025 High

    Pinpointing a bulge uridine in the HIF-2α IRE that impairs IRP2 binding provided the structural explanation for IRP1's selective control of HIF-2α and the opposite EPO phenotypes of IRP1 vs IRP2 loss.

    Evidence Affinity measurements with both IRPs, mutagenesis of the HIF-2α IRE bulge uridine, and Irp1-/- vs Irp2-/- mouse EPO/HIF-2α analysis

    PMID:39316647

    Open questions at the time
    • Co-structure of IRP1 with the HIF-2α IRE not reported
    • Whether other IREs use similar bulge-based discrimination not generalized
  12. 2026 High

    Expanding IRP1's physiological reach, deficiency was shown to rewire hepatic and muscle metabolism toward glycolysis and alter systemic glucose/insulin handling, and MUSTN1 was identified as a partner enhancing IRP1-TFRC mRNA binding in ferroptosis control.

    Evidence Irp1-/- mice with Seahorse flux, proteomics, metabolomics; Co-IP and TFRC 3'-UTR binding assays for MUSTN1

    PMID:41493805 PMID:41547500

    Open questions at the time
    • Direct mRNA targets driving the metabolic phenotype not fully enumerated
    • MUSTN1 interaction is a single-lab Co-IP without structural detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IRP1's nuclear translocation, identified as cell-specific and iron-dependent, contributes mechanistically to gene regulation remains unresolved.
  • No nuclear function or nuclear target identified
  • Import/export machinery for IRP1 unknown
  • Significance restricted to specific cell types not generalized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0016853 isomerase activity 4 GO:0045182 translation regulator activity 4 GO:0140299 molecular sensor activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1430728 Metabolism 1 R-HSA-9612973 Autophagy 1
Partners
FBXL5FXNIRP2MUSTN1NFS1

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 IRE-BP (IRP1) shares extensive amino acid sequence homology with aconitase and isopropylmalate isomerase, suggesting a structural and functional relationship between this RNA-binding regulatory protein and known isomerases involved in intermediary metabolism. Computational sequence homology analysis Nucleic acids research Medium 1903202
1998 IRP1 bound to the cap-proximal IRE of ferritin mRNA allows assembly of the cap-binding complex eIF4F but prevents bridging interactions between eIF4F and the small (43S) ribosomal subunit, thereby blocking translation initiation at a step downstream of cap recognition. Novel in vitro translation initiation factor assembly assay; gel retardation; sucrose gradient analysis Molecular cell High 9774976
1995 IRP1 RNA-binding activity can be inhibited in vitro by alkylation of free sulfhydryl groups (N-ethylmaleimide) or oxidation with diamide; in vivo iron regulation of IRP1 activity is predominantly a post-translational process, not dependent on de novo protein synthesis (unlike IRP2). In vitro RNA-binding inhibition assays; translation inhibitor experiments; immunoblot analysis The Journal of biological chemistry High 7544791
1995 Purified recombinant IRP2 inhibits ferritin mRNA translation with molar efficacy equal to that of recombinant IRP1; translational repressor function correlates quantitatively with IRE-binding affinity measured by gel retardation; IRP1 (but not IRP2) is inactivated for RNA binding by N-ethylmaleimide alkylation of cysteines. In vitro translation assay with purified recombinant proteins; gel retardation (EMSA) The Journal of biological chemistry High 7890603
1997 IRP1 is activated by extracellular H2O2 even without detectable increases in intracellular H2O2; intracellular H2O2 elevation alone (via catalase inhibition) is not sufficient for IRP1 activation; antimycin A-mediated mitochondrial oxidative stress activates IRP1 with kinetics lagging behind intracellular H2O2 rise, suggesting a direct attack on the 4Fe-4S cluster is an unlikely primary mechanism. Cellular H2O2 generation systems; FACS-based redox probe (DCFH-DA); EMSA for IRP1 activity The Journal of biological chemistry High 9092514
1996 Nitric oxide (NO) increases IRP1 IRE-binding activity and simultaneously decreases IRP1 aconitase activity in rat hepatoma cells; NO has no effect on IRP2 IRE-binding activity in the same cells; the IRP1 activation by NO coincides with translational repression of ferritin synthesis. SNAP-mediated NO generation; cytokine/LPS induction; EMSA; aconitase activity assay; metabolic labeling of ferritin Blood High 8639920
1998 In immunological stimulated (IFN-γ/LPS) murine RAW 264.7 macrophages, IRP1 IRE-binding activity increases 4-fold while IRP2 activity decreases 2-fold; IRP2 decrease is not due to NO production and does not require de novo synthesis; NO released from activated macrophages acts as an intercellular signal to increase IRP1 activity in adjacent cells within 1 hour without requiring de novo protein synthesis, indicating direct action of NO on IRP1. EMSA; macrophage/target cell co-culture system; pharmacological inhibitors The Journal of biological chemistry High 9545264
2001 H2O2 generated extracellularly by glucose/glucose oxidase perfusion of intact rat liver rapidly activates IRP1 IRE-binding activity as assessed by mobility shift assays with IRP1-specific probes; IRP2 does not respond to H2O2 in this intact organ model, demonstrating IRP1-selective regulation by oxidative stress at the organ level. Rat liver perfusion model; EMSA with IRP1- and IRP2-specific probes The Journal of biological chemistry High 11297549
2004 Endogenous IRP1 is nitrated on tyrosine residues in NO-producing macrophages that also generate superoxide; nitration is accompanied by both aconitase inhibition and loss of IRE-binding activity; inclusion of cis-aconitate to stabilize the [4Fe-4S] cluster prevents nitration, indicating that cluster loss and conformational change are prerequisites for tyrosine nitration. Myeloperoxidase inhibitors reduce IRP1 nitration, implicating the nitrite/H2O2/peroxidase pathway. Immunoprecipitation of endogenous IRP1; anti-nitrotyrosine Western blot; aconitase activity assay; EMSA; pharmacological inhibitors The Journal of biological chemistry High 15258160
2005 Ser-711 is a phosphorylation site on IRP1 in HEK-293 cells treated with PMA; the S711E phosphomimetic mutant displays negligible IRE-binding and aconitase activities when expressed in mammalian cells, and impairs the first step of the aconitase reaction (citrate→cis-aconitate) more severely than the second step; sequence conservation of Ser-711 across all species is noted. Site-directed mutagenesis; recombinant protein purification; aconitase activity assay; EMSA; mammalian cell expression The Biochemical journal High 15636585
2007 IRP1 assembles a cubane [4Fe-4S] iron-sulfur cluster (ISC) in iron-replete cells, converting it to cytosolic aconitase and inhibiting RNA binding; apo-IRP1 (unable to form ISC, e.g., C437S mutant) is degraded by the ubiquitin-proteasome pathway in an iron-dependent manner requiring ongoing transcription and translation; siRNA knockdown of the cysteine desulfurase Nfs1 (ISC assembly) sensitizes endogenous IRP1 for iron-dependent proteasomal degradation. Tetracycline-inducible expression of IRP1(C437S) mutant; pulse-chase half-life assay; proteasome inhibitors (MG132, lactacystin); ubiquitination assay; siRNA knockdown of Nfs1 Molecular and cellular biology High 17242182
2010 Extramitochondrial (mature) frataxin directly interacts with cytosolic aconitase/IRP1; this interaction is ISC-dependent; cytosolic aconitase defect and consequent IRP1 activation observed in Friedreich Ataxia cells are reversed by extramitochondrial frataxin action. Co-immunoprecipitation; frataxin knockdown/overexpression; aconitase activity assay; IRP1 IRE-binding assay in FRDA cells Human molecular genetics High 20053667
2010 IRP1 binds ATP and ADP (approximately 2 molecules per protein, with positive co-operativity); ATP/ADP binding induces a conformational change (altered electrophoretic mobility, shifted CD spectrum) that suppresses IRE-binding activity; IRP1 has ATPase activity; the C437S mutant lacking aconitase activity shows only one ATP-binding site and lacks co-operativity, with increased IRE-binding and lower ATPase activity. Radiolabeled [α-32P]ATP/ADP binding assays; agarose gel electrophoresis; CD spectroscopy; ATPase activity assay; C437S mutant analysis The Biochemical journal High 20569198
2002 Expression of constitutively active IRP1(C437S) in H1299 and MCF7 cells stabilizes transferrin receptor mRNA and inhibits ferritin mRNA translation via IRE binding; at high cell density, ferritin mRNA translation escapes IRP1(C437S)-mediated repression through a mechanism involving impaired global protein synthesis (increased underphosphorylated 4E-BP1) without altering ferritin mRNA levels or IRE position. Tetracycline-inducible IRP1(C437S) expression; Northern blot; metabolic labeling; polysome analysis; 4E-BP1 phosphorylation status Molecular and cellular biology High 12052872
2004 Native PAGE blotting reveals that in most cell types the iron-bound aconitase form of IRP1 is by far the predominant form; cellular iron manipulation causes a shift primarily between free (aconitase) and RNA-bound IRP1 rather than changes in total IRP1 levels; standard EMSA tends to under-evaluate total IRP1 and over-evaluate actual RNA-binding activity. Non-denaturing PAGE; specific antibody blotting; biochemical fractionation; cell treatments with iron salts, chelators, H2O2 Biochemistry Medium 14705945
2013 IRP1 (but not IRP2) is the principal regulator of HIF-2α mRNA translation in vivo; IRP1-null mice display polycythemia due to de-repression of HIF-2α mRNA translation specifically in kidneys, leading to increased renal EPO and elevated serum EPO; IRP1 deficiency also enhances expression of iron transport genes (DCytb, Dmt1, ferroportin) and other HIF-2α targets in duodenum. Irp1-/- and Irp2-/- mouse models; polysome/ribosome profiling; quantitative mRNA analysis; serum EPO measurement; tissue-specific gene expression Cell metabolism High 23395174
2013 IRP1 deficiency (but not IRP2 deficiency) in mice causes HIF-2α accumulation, elevated EPO, reticulocytosis, polycythemia, suppressed hepatic hepcidin, hyperferremia, and iron depletion in splenic macrophages due to unrestricted ferroportin expression; this demonstrates that translational control of HIF-2α by IRP1 dominates over PHD/VHL-mediated protein stability regulation in young mice. Irp1-/- and Irp2-/- mouse models; Western blot; qPCR; hematological analysis; serum EPO Blood High 23777768
2017 IRP1 RNA-binding inactivation by iron primarily involves [4Fe-4S] cluster insertion by the cytosolic iron-sulfur cluster assembly (CIA) system; FBXL5-mediated proteasomal degradation provides a secondary, synergistic mechanism; suppression of FBXL5 combined with impaired CIA (IRP1(3C>3S) mutant or knockdown of NUBP2/FAM96A) reduces cell viability rescued by iron supplementation; IRP1 phosphorylation at Ser-138 is increased when CIA is inhibited and is required for iron rescue; IRP1 expression induces FBXL5 protein level, forming a negative feedback loop. siRNA knockdown; inducible mutant IRP1 expression; polyubiquitination assay; phosphorylation analysis; aconitase activity assay; cell viability assay The Journal of biological chemistry High 28768766
2017 IRP1 binding to ferritin IRE-RNA and ACO2 IRE-RNA is enthalpy-driven and entropy-favorable; temperature increases IRP1 binding 3-4 fold; Mn2+ (50 µM) increases binding affinity 6-12 fold with altered thermodynamic contributions; different IRE-RNAs (FRT vs. ACO2) show distinct activation energies and thermodynamic profiles for IRP1 binding, demonstrating that conserved sequence differences among IRE-mRNAs selectively influence IRP1 interaction. Isothermal titration calorimetry; stopped-flow kinetics; fluorescence spectroscopy Scientific reports Medium 28819260
2019 The pseudotriloop conformation of the IRE apical loop (C1-G5 pairing) is required for IRP1 (and IRP2) binding; G5-to-A mutation reduces IRP1/2 binding while compensatory C1-to-U mutation restores and even enhances IRP1 binding; deletion of bulged U6 does not significantly affect IRP1 binding but C substitution enhances it; IRP1 shows stronger binding than IRP2 to certain IRE variants (e.g., FTL C1U-G5A); HIF-2α (EPAS1) IRE shows slightly weaker binding than FTL IRE to IRPs. Yeast three-hybrid (Y3H) system; site-directed mutagenesis of IRE variants Gene Medium 31200088
2020 IRP1 is required for iron-starvation-induced FUNDC1-dependent mitophagy; IRP1 binds to a newly characterized IRE in the 5' UTR of Bcl-xL mRNA and suppresses its translation; reduced Bcl-xL releases PGAM5 phosphatase activity, promoting FUNDC1 dephosphorylation and mitophagy activation, coupling ISC biogenesis with selective mitophagy. IRP1 knockdown; IRE identification in Bcl-xL 5' UTR; luciferase reporter assay; FUNDC1 dephosphorylation assay; mitophagy flux analysis Redox biology Medium 32795936
2022 Human IRP1 translocates to the nucleus in a cell-specific and iron-dependent manner: nuclear IRP1 is detected in iron-replete human Huh7 and HepG2 hepatoma cells and human liver sections but not in HeLa cells, mouse embryonic fibroblasts, or primary mouse hepatocytes; pharmacological iron chelation abolishes nuclear IRP1. Western blotting of subcellular fractions; immunofluorescence; immunohistochemistry; Irp1-/- mouse controls; iron chelation (deferoxamine) International journal of molecular sciences Medium 36142654
2025 IRP1 binds the HIF-2α IRE with higher affinity than IRP2; this differential binding arises from a bulge uridine in the upper stem of the HIF-2α IRE that specifically impairs IRP2 binding; IRP2 deficiency reduces HIF-2α and EPO expression, compromising stress erythropoiesis, in contrast to IRP1 deficiency which elevates EPO via de-repressed HIF-2α mRNA translation. IRP1 and IRP2 binding affinity measurements; mutagenesis of HIF-2α IRE bulge uridine; Irp1-/- and Irp2-/- mouse models; EPO and HIF-2α expression analysis Blood High 39316647
2021 ISC synthesis suppression activates IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level at tissue-level O2 concentrations; deletion of both IRP1 and IRP2 abolishes the iron-starvation response, confirming redundancy; IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. ISC synthesis inhibition; siRNA knockdown of IRP1, IRP2, FBXL5; IRE-binding assays; cell viability/ferroptosis assays at physiological O2 Science advances High 34039609
2026 MUSTN1 directly binds to ACO1 (IRP1), enhancing its interaction with the 3' UTR of TFRC mRNA, thereby promoting TFRC expression and inhibiting SLC39A14, which ultimately alleviates iron accumulation and lipid peroxidation; this identifies ACO1 as a binding partner of MUSTN1 in the context of ferroptosis regulation in skeletal muscle satellite cells. Co-immunoprecipitation; functional overexpression and knockdown experiments; TFRC 3'-UTR binding assay International journal of biological macromolecules Medium 41547500
2026 IRP1 deficiency in mice causes fasting hypoglycemia and protection against high-fat diet-induced hyperglycemia and hepatic steatosis; Irp1-/- hepatocytes and myotubes show impaired mitochondrial respiratory capacity with a shift from oxidative phosphorylation to glycolytic ATP production; this metabolic rewiring is associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle, identifying IRP1 as a regulator of systemic energy homeostasis. Irp1-/- mouse model; high-fat diet challenge; Seahorse flux analysis; proteomics; metabolomics JCI insight High 41493805

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F. Molecular cell 215 9774976
2013 The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell metabolism 181 23395174
2021 Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5. Science advances 158 34039609
1991 Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase. Nucleic acids research 157 1903202
1997 Differences in the regulation of iron regulatory protein-1 (IRP-1) by extra- and intracellular oxidative stress. The Journal of biological chemistry 138 9092514
2013 IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation. Blood 115 23777768
1990 Molecular cloning of the yeast mitochondrial aconitase gene (ACO1) and evidence of a synergistic regulation of expression by glucose plus glutamate. Molecular and cellular biology 101 1972545
1995 Differential modulation of the RNA-binding proteins IRP-1 and IRP-2 in response to iron. IRP-2 inactivation requires translation of another protein. The Journal of biological chemistry 88 7544791
2001 A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. Blood cells, molecules & diseases 83 11783942
1995 Translational repressor activity is equivalent and is quantitatively predicted by in vitro RNA binding for two iron-responsive element-binding proteins, IRP1 and IRP2. The Journal of biological chemistry 79 7890603
2006 Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes. Toxicology and applied pharmacology 78 16386771
2001 IRP1 activation by extracellular oxidative stress in the perfused rat liver. The Journal of biological chemistry 68 11297549
1996 Differential regulation of IRP1 and IRP2 by nitric oxide in rat hepatoma cells. Blood 64 8639920
2007 Iron-dependent degradation of apo-IRP1 by the ubiquitin-proteasome pathway. Molecular and cellular biology 63 17242182
2007 The iron-responsive element (IRE)/iron-regulatory protein 1 (IRP1)-cytosolic aconitase iron-regulatory switch does not operate in plants. The Biochemical journal 63 17437406
1998 Converse modulation of IRP1 and IRP2 by immunological stimuli in murine RAW 264.7 macrophages. The Journal of biological chemistry 61 9545264
2022 Trabectedin induces ferroptosis via regulation of HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells. Chemico-biological interactions 60 36396105
2010 Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin. Human molecular genetics 56 20053667
2002 Conditional derepression of ferritin synthesis in cells expressing a constitutive IRP1 mutant. Molecular and cellular biology 48 12052872
1998 Iron-regulatory protein-1 (IRP-1) is highly conserved in two invertebrate species--characterization of IRP-1 homologues in Drosophila melanogaster and Caenorhabditis elegans. European journal of biochemistry 47 9660175
2004 Targeted mutagenesis of the murine IRP1 and IRP2 genes reveals context-dependent RNA processing differences in vivo. RNA (New York, N.Y.) 44 15208438
2005 Generation of conditional alleles of the murine Iron Regulatory Protein (IRP)-1 and -2 genes. Genesis (New York, N.Y. : 2000) 42 16283625
1997 Characterization of lipoprotein IRP1 from Corynebacterium diphtheriae, which is regulated by the diphtheria toxin repressor (DtxR) and iron. Infection and immunity 41 9393842
2004 Endogenous nitration of iron regulatory protein-1 (IRP-1) in nitric oxide-producing murine macrophages: further insight into the mechanism of nitration in vivo and its impact on IRP-1 functions. The Journal of biological chemistry 37 15258160
2017 A synergistic role of IRP1 and FBXL5 proteins in coordinating iron metabolism during cell proliferation. The Journal of biological chemistry 34 28768766
2002 Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells. Journal of cellular physiology 34 11807826
1999 An atypical iron-responsive element (IRE) within crayfish ferritin mRNA and an iron regulatory protein 1 (IRP1)-like protein from crayfish hepatopancreas. Insect biochemistry and molecular biology 34 10070739
2010 ACO1, a gene for aminocyclopropane-1-carboxylate oxidase: effects on internode elongation at the heading stage in rice. Plant, cell & environment 29 20040065
2022 SnRK2 subfamily I protein kinases regulate ethylene biosynthesis by phosphorylating HB transcription factors to induce ACO1 expression in apple. The New phytologist 28 35182082
2008 Characterization of transcriptional profiles of MA-ACS1 and MA-ACO1 genes in response to ethylene, auxin, wounding, cold and different photoperiods during ripening in banana fruit. Journal of plant physiology 28 18554749
2022 Iron-dependent ferroptosis participated in benzene-induced anemia of inflammation through IRP1-DHODH-ALOX12 axis. Free radical biology & medicine 27 36244588
1997 Wound and ethylene induction of the ACC oxidase melon gene CM-ACO1 occurs via two direct and independent transduction pathways. Plant molecular biology 27 9426625
2018 Mutant huntingtin induces iron overload via up-regulating IRP1 in Huntington's disease. Cell & bioscience 26 30002810
2017 Thermodynamic and Kinetic Analyses of Iron Response Element (IRE)-mRNA Binding to Iron Regulatory Protein, IRP1. Scientific reports 26 28819260
2007 Alteration of iron regulatory proteins (IRP1 and IRP2) and ferritin in the brains of scrapie-infected mice. Neuroscience letters 26 17614197
2006 IRP1-independent alterations of cardiac iron metabolism in doxorubicin-treated mice. Journal of molecular medicine (Berlin, Germany) 26 16770644
2005 IRP1 Ser-711 is a phosphorylation site, critical for regulation of RNA-binding and aconitase activities. The Biochemical journal 26 15636585
2005 Increased IRP1 activity in Friedreich ataxia. Gene 25 15970401
2020 Defective mitochondrial ISCs biogenesis switches on IRP1 to fine tune selective mitophagy. Redox biology 24 32795936
2023 Iron response elements (IREs)-mRNA of Alzheimer's amyloid precursor protein binding to iron regulatory protein (IRP1): a combined molecular docking and spectroscopic approach. Scientific reports 23 36977734
2001 Repression of Manduca sexta ferritin synthesis by IRP1/IRE interaction. Insect molecular biology 23 11903622
2023 Kumatakenin inhibited iron-ferroptosis in epithelial cells from colitis mice by regulating the Eno3-IRP1-axis. Frontiers in pharmacology 21 37006994
2004 Blotting analysis of native IRP1: a novel approach to distinguish the different forms of IRP1 in cells and tissues. Biochemistry 20 14705945
2012 Dysregulation of IRP1-mediated iron metabolism causes gamma ray-specific radioresistance in leukemia cells. PloS one 17 23155415
2023 IRP1 mediated ferroptosis reverses temozolomide resistance in glioblastoma via affecting LCN2/FPN1 signaling axis depended on NFKB2. iScience 16 37520713
2020 Cellular iron sensing and regulation: Nuclear IRP1 extends a classic paradigm. Biochimica et biophysica acta. Molecular cell research 16 32199885
2013 Abnormal body iron distribution and erythropoiesis in a novel mouse model with inducible gain of iron regulatory protein (IRP)-1 function. Journal of molecular medicine (Berlin, Germany) 16 23455710
1994 The sequence of a 36 kb segment on the left arm of yeast chromosome X identifies 24 open reading frames including NUC1, PRP21 (SPP91), CDC6, CRY2, the gene for S24, a homologue to the aconitase gene ACO1 and two homologues to chromosome III genes. Yeast (Chichester, England) 16 7754713
2019 Relevance of the iron-responsive element (IRE) pseudotriloop structure for IRP1/2 binding and validation of IRE-like structures using the yeast three-hybrid system. Gene 15 31200088
2018 A novel splicing site IRP1 somatic mutation in a patient with pheochromocytoma and JAK2V617F positive polycythemia vera: a case report. BMC cancer 15 29534684
2024 Cell density impacts the susceptibility to ferroptosis by modulating IRP1-mediated iron homeostasis. Journal of neurochemistry 14 38382918
2023 Optimization of Biotinylated RNA or DNA Pull-Down Assays for Detection of Binding Proteins: Examples of IRP1, IRP2, HuR, AUF1, and Nrf2. International journal of molecular sciences 14 36835018
2021 A novel treatment strategy to prevent Parkinson's disease: focus on iron regulatory protein 1 (IRP1). The International journal of neuroscience 13 33535005
2008 Insights on regulation and function of the iron regulatory protein 1 (IRP1). Hemoglobin 11 18274988
2008 Differential translational regulation of IRE-containing mRNAs in Drosophila melanogaster by endogenous IRP and a constitutive human IRP1 mutant. Insect biochemistry and molecular biology 11 18675912
2006 Lys296 and Arg299 residues in the C-terminus of MD-ACO1 are essential for a 1-aminocyclopropane-1-carboxylate oxidase enzyme activity. Journal of structural biology 11 17046279
2003 A high-capacity RNA affinity column for the purification of human IRP1 and IRP2 overexpressed in Pichia pastoris. RNA (New York, N.Y.) 11 12592010
2001 Manduca sexta IRP1: molecular characterization and in vivo response to iron. Insect biochemistry and molecular biology 11 11719072
2024 Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms. Genome biology 10 38773499
2021 The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Transition in the Regulation of Ferritin Translation and Iron Hemostasis. Biomolecules 9 34572542
2011 Expression of ACO1, ERS1 and ERF1 genes in harvested bananas in relation to heat-induced defense against Colletotrichum musae. Journal of plant physiology 9 21511361
2010 Phytochrome-regulated EBL1 contributes to ACO1 upregulation in rice. Biotechnology letters 9 20872166
2002 Role of hypolipidemic drug clofibrate in altering iron regulatory proteins IRP1 and IRP2 activities and hepatic iron metabolism in rats fed a low-iron diet. Toxicology and applied pharmacology 9 11969379
2022 ISCA2 deficiency leads to heme synthesis defects and impaired erythroid differentiation in K562 cells by indirect ROS-mediated IRP1 activation. Biochimica et biophysica acta. Molecular cell research 8 35714932
2020 Exploiting the passenger ACO1-deficiency arising from 9p21 deletions to kill T-cell lymphoblastic neoplasia cells. Carcinogenesis 8 31734690
2017 A drastic superoxide-dependent oxidative stress is prerequisite for the down-regulation of IRP1: Insights from studies on SOD1-deficient mice and macrophages treated with paraquat. PloS one 8 28542246
2014 RNA interference of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO1 and ACO2) genes expression prolongs the shelf life of Eksotika (Carica papaya L.) papaya fruit. Molecules (Basel, Switzerland) 8 24950439
2023 H2S regulation of iron homeostasis by IRP1 improves vascular smooth muscle cell functions. Cellular signalling 7 37487913
2012 Postharvest analysis of lowland transgenic tomato fruits harboring hpRNAi-ACO1 construct. TheScientificWorldJournal 7 22919320
2010 Interaction of iron regulatory protein-1 (IRP-1) with ATP/ADP maintains a non-IRE-binding state. The Biochemical journal 7 20569198
1988 Confirmation of avian sex-chromosome linkage of liver cytosolic aconitase (ACO1). Cytogenetics and cell genetics 7 3248382
2025 A bulge uridine in the HIF2α IRE allows IRP1 but not IRP2 to selectively regulate HIF2α expression and ensuing EPO levels. Blood 6 39316647
2022 Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis. Frontiers in pharmacology 5 35910393
2006 [The role of iron regulatory proteins (IRPs) in the regulation of systemic iron homeostasis: lessons from studies on IRP1 and IRP2 knock out mice]. Postepy higieny i medycyny doswiadczalnej (Online) 5 16819431
2001 Binding of IRE-BP to its cognate RNA sequence: SFM studies on a universal RNA backbone for the analysis of RNA-protein interaction. Biological chemistry 5 11592396
2024 Nuclear translocation of STAT5 initiates iron overload in huntington's disease by up-regulating IRP1 expression. Metabolic brain disease 4 38261161
2022 Human IRP1 Translocates to the Nucleus in a Cell-Specific and Iron-Dependent Manner. International journal of molecular sciences 4 36142654
2001 [Cloning of promoter of banana fruit ripening-related ACO1 and primary study on its function]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 4 11702702
2024 SlERF109-like and SlNAC1 Coordinately Regulated Tomato Ripening by Inhibiting ACO1 Transcription. International journal of molecular sciences 3 38339150
2014 On the molecular relationships between high-zinc tolerance and aconitase (Aco1) in Saccharomyces cerevisiae. Metallomics : integrated biometal science 3 24503898
2004 Rat duodenal IRP1 activity and iron absorption in iron deficiency and after HO perfusion. European journal of clinical investigation 3 15086359
2003 IRP1 activity and expression are increased in the liver and the spleen of rats fed fish oil-rich diets and are related to oxidative stress. The Journal of nutrition 3 12672910
2007 [The expression of TfR1 mRNA and IRP1 mRNA in the placenta from different maternal iron status]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 2 17877204
1993 Iron responsive element-binding protein (IRE-BP) in leukemic cells: analysis using enzyme-linked immunosorbent assay and semiquantitative polymerase chain reaction. Leukemia research 2 8412298
2024 Characterization and Potential Action Mode Divergences of Homologous ACO1 Genes during the Organ Development and Ripening Process between Non-Climacteric Grape and Climacteric Peach. International journal of molecular sciences 1 38255862
2024 Molecular Cloning, Characterization, and Function of Insulin-Related Peptide 1 (IRP1) in the Haliotis discus hanna. Genes 1 39062739
2026 IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies. JCI insight 0 41493805
2026 MUSTN1 prevents muscle atrophy through ferroptosis suppression: A ACO1-dependent and exosome-mediated mechanism. International journal of biological macromolecules 0 41547500
2026 An endometrial tissue-based predictive model for polycystic ovary syndrome constructed from immuno-metabolic dysregulation features mediated by ACO1. Journal of ovarian research 0 41731522
2026 Iron overload reprogramming lipid metabolism through the IRP1-SCAP axis in fibroblast-like synoviocytes aggravates bone destruction in rheumatoid arthritis. Experimental & molecular medicine 0 42067621
2026 5-O-Methylembelin disrupts the ACO1-TPI1 interaction to promote ferroptosis in clear cell renal cell carcinoma. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 42166976
2025 ACO1 OGDH axis drives mitochondrial immune crosstalk in preeclampsia through systems biology enabling dual target therapy. Scientific reports 0 40887492

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