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

• The alternative pathway (citrate system) is particularly affected, since when citrate levels are low, both aconitase activity and HIV-1 replication need iron [9].
• HPLC-proven yersiniabactin-producing E. coli lacked modifications found in irp1 and irp2 in the human pathogen CFT073, and it is not clear whether CFT073 produces yersiniabactin [10].
• METHODS: Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone [11].
• Our data suggest that hypoxia extensively remodels the signaling pathway by switching off tyrosine phosphorylation of some cellular components (i.e., alpha-internexin) and switching on tyrosine phosphorylation of some other proteins (i.e., heat shock cognate 70, aconitase, 2',3'-cyclic nucleotide 3'-phosphodiesterase, and pyruvate kinase) [12].
• Yersinia enterocolitica mutant strains, including mutants deficient in the chaperone SycH resulting in a functional deficiency in tyrosine phosphatase (YopH), Mn-cofactored superoxide dismutase (SodA), iron-repressive protein 1 (IRP-1), and Yersinia adhesin A (YadA), were demonstrated to be highly attenuated in wild-type C57BL/6 mice [13].

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].

References