Sites and Mechanisms of Aconitase Inactivation by Peroxynitrite: Modulation by Citrate and Glutathione
Abstract
Aconitases are iron-sulfur cluster-containing proteins present both in mitochondria and cytosol of cells; the cubane iron-sulfur (Fe-S) cluster in the active site is essential for catalytic activity, but it also renders aconitase highly vulnerable to reactive oxygen and nitrogen species. This study examined the sites and mechanisms of aconitase inactivation by peroxynitrite (ONOO-), a strong oxidant and nitrating agent readily formed from superoxide anion and nitric oxide generated by mitochondria. ONOO- inactivated aconitase in a dose-dependent manner (half-maximal inhibition was observed with approximately 3 microM ONOO-). Low levels of ONOO- caused the conversion of the Fe-S cluster from the [4Fe-4S]2+ form to the inactive [3Fe-4S]1+ form with the loss of labile iron, as confirmed by low-temperature EPR analysis. In the presence of the substrate, citrate, 66-fold higher concentrations of ONOO- were required for half-maximal inhibition. The protective effects of citrate corresponded to its binding to the active site. The inactivation of aconitase in the presence of citrate was due to ONOO--mediated cysteine thiol loss and tyrosine nitration in the enzyme as shown by Western blot analyses. LC/MS/MS analyses revealed that ONOO- treatment to aconitase resulted in nitration of tyrosines 151 and 472 and oxidation to sulfonic acid of cysteines 126 and 385. The latter is one of the three cysteine residues in aconitase that binds to the Fe-S cluster. All other modified tyrosine and cysteine residues were adjacent to the binding site, thus suggesting that these modifications caused conformational changes leading to active-site disruption. Aconitase cysteine thiol modifications other than oxidation to sulfonic acid, such as S-glutathionylation, also decreased aconitase activity, thus indicating that glutathionylation may be an important means of modulating aconitase activity under oxidative and nitrative stress. Taken together, these results demonstrate that the Fe-S cluster in the active site, cysteine 385 bound to the Fe-S cluster, and tyrosine and cysteine residues in the vicinity of the active site are important targets of oxidative and/or nitrative attack, which is selectively controlled by the mitochondrial matrix citrate levels. The mechanisms inherent in aconitase inactivation by ONOO- are discussed in terms of the mitochondrial matrix metabolic and thiol redox state.
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Peroxynitrite reacts rapidly with Fe/S clusters leading to the inactivation of critical enzymes such as mitochondrial aconitase.
“Additionally, peroxynitrite reacts rapidly with Fe/S clusters leading to the inactivation of critical enzymes such as mitochondrial aconitase (155, 401).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [401]
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- Authors
- Han, D., Canali, R., Garcia, J., Aguilera, R., Gallaher, T. K., & Cadenas, E.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Cadenas, Enrique
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-08-18
- Volume
- 44
- Issue
- 36
- Pages
- 11986-11996
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2065252220
- Cited by
- 161
- References
- 41
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 10 · 2018: 12 · 2017: 4 · 2016: 10 · 2015: 11 · 2014: 10 · 2013: 4 · 2012: 13
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01 AG16718, R01AG016718)
- National Institute of Environmental Health Sciences (R01ES011342)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- aconitase, peroxynitrite, iron-sulfur clusters, [4Fe-4S] cluster, citrate, glutathione, cysteine thiol modification, tyrosine nitration, S-glutathionylation, oxidative stress, nitrative stress, protein inactivation, conformational change, mitochondrial enzymes, reactive oxygen and nitrogen species
- MeSH terms
- Aconitate Hydratase, Amino Acid Sequence, Amino Acids, Animals, Cysteine, Enzyme Activation, Glutathione, Molecular Sequence Data, Myocardium, Mass Spectrometry, Swine, Tyrosine, Citric Acid, Peroxynitrous Acid
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