Disease relevance of ACO2

• The major bifunctional aconitase of Escherichia coli (AcnB) serves as either an enzymic catalyst or a mRNA-binding post-transcriptional regulator, depending on the status of its iron sulfur cluster [1].
• These are typified by the 3Fe centers in aconitase, Desulfovibrio gigas FdII, and Azotobacter crooccocum Fd [2].

High impact information on ACO2

• This domain packs against the remainder of the protein to form a tunnel leading to the aconitase active site, potentially for substrate channeling [1].
• The reaction of fluorocitrate with aconitase and the crystal structure of the enzyme-inhibitor complex [3].
• When (+)-erythro-2-fluorocitrate is added to aconitase, the release of fluoride is stoichiometric with total substrate added, and HPLC analysis of the products indicates the formation of oxalosuccinate, and its derivative alpha-ketoglutarate [3].
• This enzyme is isolated largely in its active [4Fe-4S] form and has a turnover number similar to that of mitochondrial aconitase [4].
• However, there is a second aconitase, found only in the cytosol of mammalian tissues, that might serve as an IRE-BP [4].

Biological context of ACO2

• Somatic cell mapping of the mitochondrial aconitase gene (ACO2) to bovine chromosome 5 [5].
• At least 23 residues from all four domains of aconitase contribute to the active site [6].
• The crystal structures of mitochondrial aconitase with isocitrate and nitroisocitrate bound have been solved and refined to R factors of 0.179 and 0.161, respectively, for all observed data in the range 8.0-2.1 A [6].
• The trapping of exons for bovine ACO2 and ARR1 confirms the available mapping information based on synteny and provides a physical assignment for the genes [7].
• In spite of substantial homology between the amino acid sequences of mammalian mitochondrial aconitase and IRE-BP, the mitochondrial protein does not bind IREs [4].

Anatomical context of ACO2

• The soluble "high potential" type iron-sulfur protein from mitochondria is aconitase [8].
• Properties of soluble high potential type iron-sulfur protein (HiPIP) from beef heart mitochondria were compared to those of aconitase from pig heart [8].
• Mito-Q and MitoVit-E inhibited H(2)O(2)- and lipid peroxide-induced inactivation of complex I and aconitase, TfR overexpression, and mitochondrial uptake of (55)Fe, while restoring the mitochondrial membrane potential and proteasomal activity [9].
• H2O2-mediated inactivation of cytosolic aconitase was responsible for activation of iron regulatory protein-1 and increased expression of TfR, resulting in an increased iron uptake into endothelial cells [10].

Associations of ACO2 with chemical compounds

• In addition, the putative thiol ligands for the linear [3Fe-4S]+ cluster of aconitase are reported [11].
• In an accompanying paper (Kennedy, M. C., Spoto, G., Emptage, M. H., and Beinert, H. (1988) J. Biol. Chem. 263, 8190-8193), it was shown that one cysteine per mol of aconitase is modified by a variety of sulfhydryl reagents [12].
• We have also demonstrated that this cysteine is the primary site of modification by phenacyl bromide (2-bromoacetophenone), a spin label analogue of N-ethylmaleimide (HO-461) and iodoacetate in both the 3Fe and 4Fe forms of aconitase [12].
• Aconitase which has been oxidized with ferricyanide and from which the cluster iron has been removed by EDTA has been shown to have two di- or polysulfides (Kennedy, M. C., and Beinert, H. (1988) J. Biol. Chem. 263, 8194-8198) [11].
• Crystal structures of aconitase with isocitrate and nitroisocitrate bound [6].

Other interactions of ACO2

• C(2)-cer (20-50 microm) also resulted in H(2)O(2)-mediated dichlorodihydrofluorescein oxidation, reduced glutathione depletion, aconitase inactivation, TfR overexpression, TfR-dependent uptake of (55)Fe, release of cytochrome c from mitochondria into cytosol, caspase-3 activation, and DNA fragmentation [13].

Analytical, diagnostic and therapeutic context of ACO2

• Characterization of the Fe-S cluster in aconitase using low temperature magnetic circular dichroism spectroscopy [2].
• Mössbauer spectroscopy shows that purple aconitase has high-spin ferric ions, each residing in a tetrahedral environment of sulfur atoms [14].
• Crystallization of aconitase with the substrates citrate and cis-aconitate has not been possible because the enzyme turns over and selects enzyme with isocitrate bound into the crystal lattice [15].
• The protein is capable of catalysing the aconitase reaction after treatment with ferrous ions under anaerobic conditions [16].

References