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Cited by 146Metalloenzymes and iron-sulfur proteinsMetal-Catalyzed Oxygenation MechanismsBiochemical Acid Research Studies

Aconitases: non-redox iron-sulfur proteins sensitive to reactive species

Castro, Laura, Tórtora, Verónica, Mansilla, Santiago, Radi, Rafael·2019·Accounts of Chemical Research
DOI 10.1021/acs.accounts.9b00150
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Abstract

Conspectus 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 (Fe α ) 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 (O 2 •– ), hydrogen peroxide (H 2 O 2 ), 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 O 2 •– is fast (∼10 7 M –1 s –1 ), quite specific, and reversible in vivo, quantification of active aconitase has been used to evaluate O 2 •– formation in cells. While • NO is modestly reactive with aconitase, its reaction with O 2 •– 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 H 2 O 2 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 O 2 •–, H 2 O 2, • 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.

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  • The 4Fe-4S cluster in ACO2 makes it susceptible to inactivation by ROS, contributing to TCA cycle deceleration upon ETC dysfunction.

    “Intriguingly, the 4Fe–4S cluster present within ACO2 makes it exquisitely susceptible to inactivation by ROS, serving as another example of TCA cycle deceleration upon ETC dysfunction (150).”

    From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [150]

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Authors
Castro, L., Tórtora, V., Mansilla, S., & Radi, R.
Affiliations
  • Universidad de la República de Uruguay (UY)
  • Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Av. General Flores 2125, 11800 Montevideo, Uruguay
Corresponding author
Castro, Laura
ORCID
Venue
Accounts of Chemical Research
Publisher
American Chemical Society (ACS)
Published
2019-07-09
Volume
52
Issue
9
Pages
2609-2619
ISSN
  • 0001-4842 (ISSN-L)
  • 1520-4898
DOI
10.1021/acs.accounts.9b00150
OpenAlex
W2959204530
Cited by
146
References
70
Citations by year
2026: 18 · 2025: 27 · 2024: 33 · 2023: 22 · 2022: 20 · 2021: 19 · 2020: 6 · 2019: 1
FWCI
2.45
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Accounts of Chemical Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Universidad de la Rep?blica Uruguay (EI 2015)
  • Comisi?n Sectorial de Investigaci?n Cient?fica (I+D 2016)
  • Fundaci?n Manuel Perez
Topics
  • Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
Keywords
aconitase, iron-sulfur clusters, reactive oxygen species, reactive nitrogen species, superoxide, peroxynitrite, hydrogen peroxide, nitric oxide, iron metabolism, cis-aconitate, protein nitration, protein carbonylation, iron deficiency, mitochondrial aconitase
MeSH terms
Aconitate Hydratase, Animals, Humans, Hydrogen Peroxide, Mitochondria, Models, Molecular, Nitric Oxide, Superoxides, Peroxynitrous Acid

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