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Aconitases: Non-redox Iron-Sulfur Proteins Sensitive to Reactive Species.
Acc Chem Res. 2019 09 17; 52(9):2609-2619.AC

Abstract

Mammalian aconitases (mitochondrial and cytosolic isoenzymes) are unique iron-sulfur cluster-containing proteins in which the metallic center participates in the catalysis of a non-redox reaction. Within the cubane iron-sulfur cluster of aconitases only three of the four iron ions have cysteine thiolate ligands; the fourth iron ion (Feα) is solvent exposed within the active-site pocket and bound to oxygen atoms from either water or substrates to be dehydrated. The catalyzed reaction is the reversible isomerization of citrate to isocitrate with an intermediate metabolite, cis-aconitate. The cytosolic isoform of aconitase is a moonlighting enzyme; when intracellular iron is scarce, the complete disassembly of the iron-sulfur cluster occurs and apo-aconitase acquires the function of an iron responsive protein and regulates the translation of proteins involved in iron metabolism. In the late 1980s and during the 1990s, cumulative experimental evidence pointed out that aconitases are main targets of reactive oxygen and nitrogen species such as superoxide radical (O2•-), hydrogen peroxide (H2O2), nitric oxide (•NO), and peroxynitrite (ONOO-). These intermediates are capable of oxidizing the cluster, which leads to iron release and consequent loss of the catalytic activity of aconitase. As the reaction of the Fe-S cluster with O2•- is fast (∼107 M-1 s-1), quite specific, and reversible in vivo, quantification of active aconitase has been used to evaluate O2•- formation in cells. While •NO is modestly reactive with aconitase, its reaction with O2•- yields ONOO-, a strong oxidant that readily leads to the disruption of the Fe-S cluster. In the case of cytosolic aconitase, it has been seen that H2O2 and •NO promote activation of iron responsive protein activity in cells. Proteomic advances in the 2000s confirmed that aconitases are main targets of reactive species in cellular models and in vivo, and other post-translational oxidative modifications such as protein nitration and carbonylation have been detected. Herein, we (1) outline the particular structural features of aconitase that make these proteins specific targets of reactive species, (2) characterize the reactions of O2•-, H2O2, •NO, and ONOO- and related species with aconitases, (3) discuss how different oxidative post-translational modifications of aconitase impact the different functions of aconitases, and (4) argue how these proteins might function as redox sensors within different cellular compartments, regulating citrate concentration and efflux from mitochondria, iron availability in the cytosol, and cellular oxidant production.

Authors+Show Affiliations

Departamento de Bioquímica, Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay. Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay.Departamento de Bioquímica, Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay. Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay. Departamento de Educación Médica, Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 , Montevideo , Uruguay.Departamento de Bioquímica, Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay. Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay.Departamento de Bioquímica, Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay. Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina , Universidad de la República , Av. General Flores 2125 , 11800 Montevideo , Uruguay.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

31287291

Citation

Castro, Laura, et al. "Aconitases: Non-redox Iron-Sulfur Proteins Sensitive to Reactive Species." Accounts of Chemical Research, vol. 52, no. 9, 2019, pp. 2609-2619.
Castro L, Tórtora V, Mansilla S, et al. Aconitases: Non-redox Iron-Sulfur Proteins Sensitive to Reactive Species. Acc Chem Res. 2019;52(9):2609-2619.
Castro, L., Tórtora, V., Mansilla, S., & Radi, R. (2019). Aconitases: Non-redox Iron-Sulfur Proteins Sensitive to Reactive Species. Accounts of Chemical Research, 52(9), 2609-2619. https://doi.org/10.1021/acs.accounts.9b00150
Castro L, et al. Aconitases: Non-redox Iron-Sulfur Proteins Sensitive to Reactive Species. Acc Chem Res. 2019 09 17;52(9):2609-2619. PubMed PMID: 31287291.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aconitases: Non-redox Iron-Sulfur Proteins Sensitive to Reactive Species. AU - Castro,Laura, AU - Tórtora,Verónica, AU - Mansilla,Santiago, AU - Radi,Rafael, Y1 - 2019/07/09/ PY - 2019/7/10/pubmed PY - 2020/8/12/medline PY - 2019/7/10/entrez SP - 2609 EP - 2619 JF - Accounts of chemical research JO - Acc Chem Res VL - 52 IS - 9 N2 - Mammalian aconitases (mitochondrial and cytosolic isoenzymes) are unique iron-sulfur cluster-containing proteins in which the metallic center participates in the catalysis of a non-redox reaction. Within the cubane iron-sulfur cluster of aconitases only three of the four iron ions have cysteine thiolate ligands; the fourth iron ion (Feα) is solvent exposed within the active-site pocket and bound to oxygen atoms from either water or substrates to be dehydrated. The catalyzed reaction is the reversible isomerization of citrate to isocitrate with an intermediate metabolite, cis-aconitate. The cytosolic isoform of aconitase is a moonlighting enzyme; when intracellular iron is scarce, the complete disassembly of the iron-sulfur cluster occurs and apo-aconitase acquires the function of an iron responsive protein and regulates the translation of proteins involved in iron metabolism. In the late 1980s and during the 1990s, cumulative experimental evidence pointed out that aconitases are main targets of reactive oxygen and nitrogen species such as superoxide radical (O2•-), hydrogen peroxide (H2O2), nitric oxide (•NO), and peroxynitrite (ONOO-). These intermediates are capable of oxidizing the cluster, which leads to iron release and consequent loss of the catalytic activity of aconitase. As the reaction of the Fe-S cluster with O2•- is fast (∼107 M-1 s-1), quite specific, and reversible in vivo, quantification of active aconitase has been used to evaluate O2•- formation in cells. While •NO is modestly reactive with aconitase, its reaction with O2•- yields ONOO-, a strong oxidant that readily leads to the disruption of the Fe-S cluster. In the case of cytosolic aconitase, it has been seen that H2O2 and •NO promote activation of iron responsive protein activity in cells. Proteomic advances in the 2000s confirmed that aconitases are main targets of reactive species in cellular models and in vivo, and other post-translational oxidative modifications such as protein nitration and carbonylation have been detected. Herein, we (1) outline the particular structural features of aconitase that make these proteins specific targets of reactive species, (2) characterize the reactions of O2•-, H2O2, •NO, and ONOO- and related species with aconitases, (3) discuss how different oxidative post-translational modifications of aconitase impact the different functions of aconitases, and (4) argue how these proteins might function as redox sensors within different cellular compartments, regulating citrate concentration and efflux from mitochondria, iron availability in the cytosol, and cellular oxidant production. SN - 1520-4898 UR - https://www.unboundmedicine.com/medline/citation/31287291/Aconitases:_Non_redox_Iron_Sulfur_Proteins_Sensitive_to_Reactive_Species_ L2 - https://doi.org/10.1021/acs.accounts.9b00150 DB - PRIME DP - Unbound Medicine ER -