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Gene Review

Aco1  -  aconitase 1

Mus musculus

Synonyms: AI256519, Aco-1, Aconitase, Citrate hydro-lyase, Cytoplasmic aconitate hydratase, ...
 
 
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Disease relevance of Aco1

  • Six monoclonal antibodies were produced to whole cells of Shewanella colwelliana (Aco1 to Aco6) and two (Aco22 to Aco23) to purified exopolysaccharide (EPS) [1].
  • In contrast to the apparent toxicity of this reaction, the biological consequences of O2*- -mediated inactivation of the cytosolic counterpart of mitochondrial aconitase, commonly known as iron regulatory protein 1 (IRP1), are not clear [2].
  • Here, we show that inhibition of IRP1 aconitase activity and induction of its IRE-binding activity during exposure of L5178Y mouse lymphoma cells to NO are associated with an increase in LIP levels [3].
  • Conditioned medium (CM) from cultures of cytotoxic activated macrophages causes inhibition of mitochondrial respiration, DNA synthesis, and aconitase activity in murine EMT-6 mammary adenocarcinoma cells by an L-arginine dependent effector mechanism [4].
  • Both YadA- and Irp-1-deficient Yersinia mutants were still attenuated in IL-12(-/-) and IL-18(-/-) mice but were pathogenic in TNFRp55(-/-) mice [5].
 

High impact information on Aco1

 

Chemical compound and disease context of Aco1

 

Biological context of Aco1

  • Linkage was tested for four different genes on mouse chromosome 4: Aco-1, Mup-1, b, and Ifb [10].
  • We used mouse lines where a betaGeo gene trap construct was inserted into the second intron of the Irp1 and the Irp2 gene, generating hypomorphic alleles by interrupting the corresponding open reading frame near the amino-termini [11].
  • We show that cytosolic ISC aconitase activity of iron regulatory protein-1 progressively decreases, whereas its apo-RNA binding form increases despite the absence of oxidative stress, suggesting that in a mammalian system the mitochondrial ISC assembly machinery is essential for cytosolic ISC biogenesis [12].
  • IRP1 can also exist as an aconitase containing a [4Fe-4S] cluster bound to three cysteines at the active site [13].
  • Iron regulatory protein-1 (IRP-1) is a bifunctional [4Fe-4S] protein that functions as a cytosolic aconitase or as a trans-regulatory factor controlling iron homeostasis at a post-transcriptional level [14].
 

Anatomical context of Aco1

  • We show that nitration of endogenous IRP-1 in NO-producing macrophages boosted to produce O*2- was accompanied by aconitase inhibition and impairment of its capacity to bind the iron-responsive element (IRE) of ferritin mRNA [14].
  • Here, we show that in superoxide dismutase 1 (SOD1) knock-out mice, lacking Cu,Zn-SOD, an enzyme that acts to reduce the concentration of O2*- mainly in cytosol, not only is aconitase activity of IRP1 inhibited but the level of IRP1 is also strongly decreased [2].
  • The susceptibility of KGDHC and aconitase to inactivation in kidney cells exposed to cisplatin metabolites may be due to the proximity of mitAspAT to KGDHC and aconitase in mitochondria [15].
  • Biochemically, mitochondria from the hippocampus and cortex of these mice show reduced CoxII and increased aconitase activity [16].
  • These findings may explain how fluorocitrate selectively lowers the level of glutamine and inhibits glutamine formation in the brain in vivo, viz., not by depleting glial cells of ATP, but by causing a rerouting of 2-oxoglutarate from glutamine synthesis into the TCA cycle during inhibition of aconitase [17].
 

Associations of Aco1 with chemical compounds

  • As with other yeast genes proposed to function in Fe-S cluster assembly, mitochondrial iron concentration was significantly elevated in the isa mutants, and the activities of the Fe-S cluster-containing enzymes aconitase and succinate dehydrogenase were dramatically reduced [18].
  • Previous studies have shown that aconitase/IRP-1 may be a target of *NO or peroxynitrite (ONOO(-)), formed after reaction of *NO with superoxide anion (O(2)(*-)); however, the mechanisms and consequences of such interactions have remained uncertain [19].
  • Second, aconitase activity was recovered by reassembling Fe-S clusters with cysteine and ferrous ammonium sulfate [19].
  • We recently demonstrated that oxalomalate (OMA, alpha-hydroxy-beta-oxalosuccinic acid), a competitive inhibitor of aconitase, which is an enzyme of the citric acid cycle, remarkably decreases the binding activity of IRP1 [20].
  • The resulting peptide mass spectrum was compared with the Mascot and Protein Prospector databases and resulted in the specific identification of heart mitochondrial proteins, specifically Mn-superoxide dismutase (SOD), aconitase (ACN), and malate dehydrogenase (MDH) [21].
 

Other interactions of Aco1

References

  1. Production and characterization of monoclonal antibodies specific for Shewanella colwelliana exopolysaccharide. Sledjeski, D.D., Weiner, R.M. Appl. Environ. Microbiol. (1993) [Pubmed]
  2. Down-regulation of iron regulatory protein 1 activities and expression in superoxide dismutase 1 knock-out mice is not associated with alterations in iron metabolism. Starzynski, R.R., Lipinski, P., Drapier, J.C., Diet, A., Smuda, E., Bartlomiejczyk, T., Gralak, M.A., Kruszewski, M. J. Biol. Chem. (2005) [Pubmed]
  3. Induction of iron regulatory protein 1 RNA-binding activity by nitric oxide is associated with a concomitant increase in the labile iron pool: implications for DNA damage. Lipinski, P., Starzynski, R.R., Drapier, J.C., Bouton, C., Bartlomiejczyk, T., Sochanowicz, B., Smuda, E., Gajkowska, A., Kruszewski, M. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  4. Activated macrophage conditioned medium: identification of the soluble factors inducing cytotoxicity and the L-arginine dependent effector mechanism. Amber, I.J., Hibbs, J.B., Parker, C.J., Johnson, B.B., Taintor, R.R., Vavrin, Z. J. Leukoc. Biol. (1991) [Pubmed]
  5. 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]
  6. Iron regulatory protein 1 is not required for the modulation of ferritin and transferrin receptor expression by iron in a murine pro-B lymphocyte cell line. Schalinske, K.L., Blemings, K.P., Steffen, D.W., Chen, O.S., Eisenstein, R.S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  7. The bifunctional iron-responsive element binding protein/cytosolic aconitase: the role of active-site residues in ligand binding and regulation. Philpott, C.C., Klausner, R.D., Rouault, T.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  8. The iron-responsive element binding protein: a target for synaptic actions of nitric oxide. Jaffrey, S.R., Cohen, N.A., Rouault, T.A., Klausner, R.D., Snyder, S.H. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  9. Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant. Mackensen, G.B., Patel, M., Sheng, H., Calvi, C.L., Batinic-Haberle, I., Day, B.J., Liang, L.P., Fridovich, I., Crapo, J.D., Pearlstein, R.D., Warner, D.S. J. Neurosci. (2001) [Pubmed]
  10. Linkage analysis of the murine mos proto-oncogene on chromosome 4. Dandoy, F., De Maeyer-Guignard, J., De Maeyer, E. Genomics (1989) [Pubmed]
  11. Generation of conditional alleles of the murine Iron Regulatory Protein (IRP)-1 and -2 genes. Galy, B., Ferring, D., Hentze, M.W. Genesis (2005) [Pubmed]
  12. Friedreich ataxia: the oxidative stress paradox. Seznec, H., Simon, D., Bouton, C., Reutenauer, L., Hertzog, A., Golik, P., Procaccio, V., Patel, M., Drapier, J.C., Koenig, M., Puccio, H. Hum. Mol. Genet. (2005) [Pubmed]
  13. Thioredoxin activation of iron regulatory proteins. Redox regulation of RNA binding after exposure to nitric oxide. Oliveira, L., Bouton, C., Drapier, J.C. J. Biol. Chem. (1999) [Pubmed]
  14. 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. Gonzalez, D., Drapier, J.C., Bouton, C. J. Biol. Chem. (2004) [Pubmed]
  15. Cisplatin-induced toxicity is associated with platinum deposition in mouse kidney mitochondria in vivo and with selective inactivation of the alpha-ketoglutarate dehydrogenase complex in LLC-PK1 cells. Zhang, L., Cooper, A.J., Krasnikov, B.F., Xu, H., Bubber, P., Pinto, J.T., Gibson, G.E., Hanigan, M.H. Biochemistry (2006) [Pubmed]
  16. Mitochondrial dysfunction and increased sensitivity to excitotoxicity in mice deficient in DNA mismatch repair. Francisconi, S., Codenotti, M., Toninelli, G.F., Uberti, D., Memo, M. J. Neurochem. (2006) [Pubmed]
  17. NMR spectroscopy of cultured astrocytes: effects of glutamine and the gliotoxin fluorocitrate. Hassel, B., Sonnewald, U., Unsgård, G., Fonnum, F. J. Neurochem. (1994) [Pubmed]
  18. Role of Saccharomyces cerevisiae ISA1 and ISA2 in iron homeostasis. Jensen, L.T., Culotta, V.C. Mol. Cell. Biol. (2000) [Pubmed]
  19. Nitric oxide and peroxynitrite activate the iron regulatory protein-1 of J774A.1 macrophages by direct disassembly of the Fe-S cluster of cytoplasmic aconitase. Cairo, G., Ronchi, R., Recalcati, S., Campanella, A., Minotti, G. Biochemistry (2002) [Pubmed]
  20. Induction of ferritin expression by oxalomalate. Santamaria, R., Irace, C., Festa, M., Maffettone, C., Colonna, A. Biochim. Biophys. Acta (2004) [Pubmed]
  21. Association of calcineurin with mitochondrial proteins. Tokheim, A.M., Martin, B.L. Proteins (2006) [Pubmed]
  22. Length of the chromosomal segment marked by galactose-1-phosphate uridyl transferase and soluble aconitase and conserved since divergence of lineages leading to mouse and man. Nadeau, J.H. Genet. Res. (1988) [Pubmed]
  23. Transfer of mink genes into mouse cells by means of isolated lipid-encapsulated nuclei. Sukoyan, M.A., Belyaev, N.D., Budker, V.G., Gradov, A.A., Pack, S.D., Serov, O.L. Mol. Gen. Genet. (1985) [Pubmed]
  24. The redox regulation of intermediary metabolism by a superoxide-aconitase rheostat. Armstrong, J.S., Whiteman, M., Yang, H., Jones, D.P. Bioessays (2004) [Pubmed]
  25. Effects of a manganese (III) porphyrin catalytic antioxidant in a mouse closed head injury model. Leinenweber, S.B., Sheng, H., Lynch, J.R., Wang, H., Batinić-Haberle, I., Laskowitz, D.T., Crapo, J.D., Pearlstein, R.D., Warner, D.S. Eur. J. Pharmacol. (2006) [Pubmed]
 
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