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Gene Review

ACO1  -  aconitase 1, soluble

Homo sapiens

Synonyms: ACONS, Aconitase, Citrate hydro-lyase, Cytoplasmic aconitate hydratase, Ferritin repressor protein, ...
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Disease relevance of ACO1

  • Since ACO1 is not linked with melanoma severity in X. helleri x X. maculatus Jp 163 A backcross hybrids, these data indicate that homozygosity for the X. helleri TP53 genotype in backcross hybrids of the cross type is not associated with genetically regulated malignant melanoma formation in the Gordon-Kosswig hybrid melanoma model [1].
  • Hypoxia also decreased cytosolic aconitase activity [2].
  • Our results contrast with previously reported data (Hanson, E. S., and Leibold, E. A. (1998) J. Biol. Chem. 273, 7588-7593) in which a 3% oxygen atmosphere reduced IRE/IRP-1 binding in rat hepatoma cells [2].
  • Two cDNA clones were isolated from a human brain cDNA library with IRP1 cDNA probes, and both of these cDNA probes recognized a single mRNA species (4.0 kb) from human astrocytoma cells [3].
  • We propose that early inactivation of aconitase and inhibition of the energy-producing and biosynthetic reactions of the citric acid cycle contribute to the sequelae of lung damage and edema seen during exposure to hyperoxia [4].

High impact information on ACO1

  • Unexpectedly, we find that the cap binding complex eIF4F (comprising eIF4E, eIF4G, and eIF4A) assembles even when IRP-1 is bound to the cap-proximal IRE [5].
  • Similarly, a morpholino oligodeoxynucleotide directed against the lon gene markedly decreases the amount of Lon protein, Lon activity and aconitase degradation in WI-38 VA-13 human lung fibroblasts and causes accumulation of oxidatively modified aconitase [6].
  • A mechanism for the dehydration of L-serine which is similar, but not identical, to that of the dehydration of citrate catalysed by aconitase is proposed [7].
  • Recently, we described a patient with severe exercise intolerance and episodic myoglobinuria, associated with marked impairment of succinate oxidation and deficient activity of succinate dehydrogenase and aconitase in muscle mitochondria (1) [8].
  • Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins [8].

Chemical compound and disease context of ACO1


Biological context of ACO1

  • Comparison of the nucleotide sequences of the cloned genomic regions with the cDNA clone pPHEFE indicated that ACO1 encoded the transcript in 4 exons interrupted by 3 introns [14].
  • The other three members of the petunia ACC oxidase gene family shared identical intron numbers and positions with ACO1 and their exons were greater than 80% homologous [14].
  • Nucleotide sequencing of these two regions of the genome showed that each contained two tandemly arranged genes designated ACO1, ACO2, ACO3 and ACO4 [14].
  • Here, the TR-ACO1 5' flanking sequence directs highest expression in the apical tissues, axillary buds, and leaf petiolules in younger tissues and then declines in the ageing tissues, while the TR-ACO2 5' flanking sequence directs expression in both younger, mature green and in ontologically ageing tissue [15].
  • Our results reveal a mechanism for regulating IRP1 action relevant to the control of iron homeostasis during cell proliferation, inflammation, and in response to diseases altering cytosolic Fe-S cluster assembly or disassembly [16].

Anatomical context of ACO1

  • Analysis of organellar preparations suggests that ACO1 and ACO4 are localized in the cytosolic and mitochondrial subcellular fractions, respectively [17].
  • The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase/iron regulatory protein-1 in cytosolic fractions from human myocardium [18].
  • Our data demonstrate that hypoxia powerfully enhances IRE/IRP-1 binding in human cell lines [2].
  • GEI-22/ACO-1 is expressed in the cytosol of cells of the hypodermis and the intestine [19].
  • Treatment of murine B6 fibroblasts with menadione sodium bisulfite (MSB), a redox cycling drug, causes a modest activation of IRP-1 to bind to IREs within 15-30 min [20].

Associations of ACO1 with chemical compounds

  • RNA-based PCR amplification of ACC oxidase cDNAs from ethylene-treated corollas and wounded leaves revealed transcripts for ACO1, ACO3 and ACO4 indicating that a least three of these genes are transcriptionally active [14].
  • Modulation of IRP1 abundance by iron did not require assembly of the Fe-S cluster, since a mutant with all cluster-ligating cysteines mutated to serine underwent iron-induced protein degradation [16].
  • In iron-replete cells, assembly of a cubane [4Fe-4S] cluster inhibits IRE-binding activity and converts IRP1 to a cytosolic aconitase [21].
  • Here we demonstrate that DOXol delocalizes low molecular weight Fe(II) from the [4Fe-4S] cluster of cytoplasmic aconitase [18].
  • Human cytoplasmic aconitase (Iron regulatory protein 1) is converted into its [3Fe-4S] form by hydrogen peroxide in vitro but is not activated for iron-responsive element binding [22].

Physical interactions of ACO1

  • The hypoxia-enhanced IRE/IRP-1 binding stabilized the transferrin receptor message, increased the cellular mRNA content by over 10-fold, and doubled surface receptor expression [2].
  • Iron regulates IRP-1 activity by converting it from an RNA-binding apoprotein into a [4Fe-4S] cluster protein exhibiting aconitase activity [19].
  • Purified human brain IRP protein has a molecular mass of approximately 100 kDa and is capable of forming two RNA-protein complexes with ferritin IRE RNA and reacts strongly with IRP1 antiserum [3].
  • Control experiments excluded IRP-1 binding to the IRP-2-specific sequence in vivo [23].
  • An increase in IRP1 IRE-binding was observed upon the sequential addition of SIN-1/SOD and low concentrations of 2-mercaptoethanol, whereas SIN-1 alone induced a decrease in binding capacity which was not reversed by 2-mercaptoethanol, even at high concentrations [24].

Regulatory relationships of ACO1

  • Here we report that purified recombinant IRP2 inhibits translation of ferritin mRNAs with a molar efficacy equal to that of recombinant IRP1 [25].

Other interactions of ACO1

  • This second gene product, which we call IRP2, is expressed in many tissues, but its mRNA abundance and tissue distribution are different from IRP1 [26].
  • Band-shift assays revealed that T. gondii infection resulted in increased activity in the iron response protein IRP1, which, in this state, stabilizes TfR mRNA from degradation [27].
  • This pointed to mitochondrial aconitase and ceruloplasmin (ferroxidase) [28].
  • In contrast to these physiologic mechanisms, DOXol-dependent iron release and cluster disassembly not only abolish aconitase activity, but also affect irreversibly the ability of the apoprotein to function as IRP-1 or to reincorporate iron within new Fe-S motifs [18].
  • However, ethanol did not alter the expression of transferrin receptor1 and ferritin or the activation of iron regulatory RNA-binding proteins, IRP1 and IRP2 [29].

Analytical, diagnostic and therapeutic context of ACO1

  • Western blot analysis and supershift assays showed that this cytosolic protein is neither IRP1 nor IRP2 [30].
  • Using protein footprinting, we have studied the structure of the two functional forms of IRP-1 and have mapped the surface of the iron-responsive element (IRE) binding site [31].
  • Crystallization and preliminary X-ray diffraction data for the aconitase form of human iron-regulatory protein 1 [32].
  • Sequence comparisons and site-directed mutagenesis experiments have supported a structural relationship between mitochondrial aconitase and iron regulatory protein 1 [33].
  • In cell culture, iron homeostasis is regulated by coordinate stabilization of TfR mRNA and translation inactivation of ferritin mRNA by iron regulatory proteins (IRP-1 and -2) which bind to iron-responsive elements (IREs) on the respective mRNAs [34].


  1. Assignment of the TP53 orthologue to a new linkage group (LG XIV) in fish of the genus Xiphophorus (Teleostei: Poeciliidae). Nairn, R.S., Coletta, L.D., McEntire, B.B., Walter, R.B., Morizot, D.C. Cancer Genet. Cytogenet. (1996) [Pubmed]
  2. Hypoxia alters iron-regulatory protein-1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells. Toth, I., Yuan, L., Rogers, J.T., Boyce, H., Bridges, K.R. J. Biol. Chem. (1999) [Pubmed]
  3. Demonstration and characterization of the iron regulatory protein in human brain. Hu, J., Connor, J.R. J. Neurochem. (1996) [Pubmed]
  4. Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs. Gardner, P.R., Nguyen, D.D., White, C.W. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  5. IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F. Muckenthaler, M., Gray, N.K., Hentze, M.W. Mol. Cell (1998) [Pubmed]
  6. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Bota, D.A., Davies, K.J. Nat. Cell Biol. (2002) [Pubmed]
  7. Bacterial L-serine dehydratases: a new family of enzymes containing iron-sulfur clusters. Grabowski, R., Hofmeister, A.E., Buckel, W. Trends Biochem. Sci. (1993) [Pubmed]
  8. Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins. Hall, R.E., Henriksson, K.G., Lewis, S.F., Haller, R.G., Kennaway, N.G. J. Clin. Invest. (1993) [Pubmed]
  9. Serum citrate levels, haptoglobin haplotypes and transferrin receptor (CD71) in patients with HIV-1 infection. Pugliese, A., Gennero, L., Pescarmona, G.P., Beccattini, M., Morra, E., Orofino, G., Torre, D. Infection (2002) [Pubmed]
  10. Yersiniabactin production by Pseudomonas syringae and Escherichia coli, and description of a second yersiniabactin locus evolutionary group. Bultreys, A., Gheysen, I., de Hoffmann, E. Appl. Environ. Microbiol. (2006) [Pubmed]
  11. Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study. Rustin, P., von Kleist-Retzow, J.C., Chantrel-Groussard, K., Sidi, D., Munnich, A., Rötig, A. Lancet (1999) [Pubmed]
  12. Hypoxic response of synaptosomal proteins in term guinea pig fetuses. Buonocore, G., Liberatori, S., Bini, L., Mishra, O.P., Delivoria-Papadopoulos, M., Pallini, V., Bracci, R. J. Neurochem. (1999) [Pubmed]
  13. Attenuated Yersinia enterocolitica mutant strains exhibit differential virulence in cytokine-deficient mice: implications for the development of novel live carrier vaccines. Di Genaro, M.S., Waidmann, M., Kramer, U., Hitziger, N., Bohn, E., Autenrieth, I.B. Infect. Immun. (2003) [Pubmed]
  14. Organization and structure of the 1-aminocyclopropane-1-carboxylate oxidase gene family from Petunia hybrida. Tang, X., Wang, H., Brandt, A.S., Woodson, W.R. Plant Mol. Biol. (1993) [Pubmed]
  15. Expression of 1-aminocyclopropane-1-carboxylate (ACC) oxidase genes during the development of vegetative tissues in white clover (Trifolium repens L.) is regulated by ontological cues. Chen, B.C., McManus, M.T. Plant Mol. Biol. (2006) [Pubmed]
  16. Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. Clarke, S.L., Vasanthakumar, A., Anderson, S.A., Pondarré, C., Koh, C.M., Deck, K.M., Pitula, J.S., Epstein, C.J., Fleming, M.D., Eisenstein, R.S. EMBO J. (2006) [Pubmed]
  17. New isozyme systems for maize (Zea mays L.): aconitate hydratase, adenylate kinase, NADH dehydrogenase, and shikimate dehydrogenase. Wendel, J.F., Goodman, M.M., Stuber, C.W., Beckett, J.B. Biochem. Genet. (1988) [Pubmed]
  18. The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase/iron regulatory protein-1 in cytosolic fractions from human myocardium. Minotti, G., Recalcati, S., Mordente, A., Liberi, G., Calafiore, A.M., Mancuso, C., Preziosi, P., Cairo, G. FASEB J. (1998) [Pubmed]
  19. Cytosolic aconitase and ferritin are regulated by iron in Caenorhabditis elegans. Gourley, B.L., Parker, S.B., Jones, B.J., Zumbrennen, K.B., Leibold, E.A. J. Biol. Chem. (2003) [Pubmed]
  20. Inactivation of both RNA binding and aconitase activities of iron regulatory protein-1 by quinone-induced oxidative stress. Gehring, N.H., Hentze, M.W., Pantopoulos, K. J. Biol. Chem. (1999) [Pubmed]
  21. A phosphomimetic mutation at Ser-138 renders iron regulatory protein 1 sensitive to iron-dependent degradation. Fillebeen, C., Chahine, D., Caltagirone, A., Segal, P., Pantopoulos, K. Mol. Cell. Biol. (2003) [Pubmed]
  22. Human cytoplasmic aconitase (Iron regulatory protein 1) is converted into its [3Fe-4S] form by hydrogen peroxide in vitro but is not activated for iron-responsive element binding. Brazzolotto, X., Gaillard, J., Pantopoulos, K., Hentze, M.W., Moulis, J.M. J. Biol. Chem. (1999) [Pubmed]
  23. Translational regulation of mRNAs with distinct IRE sequences by iron regulatory proteins 1 and 2. Menotti, E., Henderson, B.R., Kühn, L.C. J. Biol. Chem. (1998) [Pubmed]
  24. Nitric oxide and peroxynitrite promote complete disruption of the [4Fe-4S] cluster of recombinant human iron regulatory protein 1. Soum, E., Drapier, J.C. J. Biol. Inorg. Chem. (2003) [Pubmed]
  25. Translational repressor activity is equivalent and is quantitatively predicted by in vitro RNA binding for two iron-responsive element-binding proteins, IRP1 and IRP2. Kim, H.Y., Klausner, R.D., Rouault, T.A. J. Biol. Chem. (1995) [Pubmed]
  26. Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2. Structure, function, and post-translational regulation. Samaniego, F., Chin, J., Iwai, K., Rouault, T.A., Klausner, R.D. J. Biol. Chem. (1994) [Pubmed]
  27. Transferrin receptor induction in Toxoplasma gondii-infected HFF is associated with increased iron-responsive protein 1 activity and is mediated by secreted factors. Gail, M., Gross, U., Bohne, W. Parasitol. Res. (2004) [Pubmed]
  28. Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. Efferth, T., Benakis, A., Romero, M.R., Tomicic, M., Rauh, R., Steinbach, D., Häfer, R., Stamminger, T., Oesch, F., Kaina, B., Marschall, M. Free Radic. Biol. Med. (2004) [Pubmed]
  29. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. Harrison-Findik, D.D., Schafer, D., Klein, E., Timchenko, N.A., Kulaksiz, H., Clemens, D., Fein, E., Andriopoulos, B., Pantopoulos, K., Gollan, J. J. Biol. Chem. (2006) [Pubmed]
  30. Regulation of the 75-kDa subunit of mitochondrial complex I by iron. Lin, E., Graziano, J.H., Freyer, G.A. J. Biol. Chem. (2001) [Pubmed]
  31. Ligand-induced structural alterations in human iron regulatory protein-1 revealed by protein footprinting. Gegout, V., Schlegl, J., Schläger, B., Hentze, M.W., Reinbolt, J., Ehresmann, B., Ehresmann, C., Romby, P. J. Biol. Chem. (1999) [Pubmed]
  32. Crystallization and preliminary X-ray diffraction data for the aconitase form of human iron-regulatory protein 1. Dupuy, J., Darnault, C., Brazzolotto, X., Kühn, L.C., Moulis, J.M., Volbeda, A., Fontecilla-Camps, J.C. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2005) [Pubmed]
  33. Structural changes associated with switching activities of human iron regulatory protein 1. Brazzolotto, X., Timmins, P., Dupont, Y., Moulis, J.M. J. Biol. Chem. (2002) [Pubmed]
  34. Increased placental iron regulatory protein-1 expression in diabetic pregnancies complicated by fetal iron deficiency. Georgieff, M.K., Berry, S.A., Wobken, J.D., Leibold, E.A. Placenta (1999) [Pubmed]
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