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Mechanism of Superoxide and Hydrogen Peroxide Formation by Fumarate Reductase, Succinate Dehydrogenase, and Aspartate Oxidase
Open accessAbstract
Oxidative stress is created in aerobic organisms when molecular oxygen chemically oxidizes redox enzymes, forming superoxide (O2*-) and hydrogen peroxide (H2O2). Prior work identified several flavoenzymes from Escherichia coli that tend to autoxidize. Of these, fumarate reductase (Frd) is notable both for its high turnover number and for its production of substantial O2*- in addition to H2O2. We have sought to identify characteristics of Frd that predispose it to this behavior. The ability of excess succinate to block autoxidation and the inhibitory effect of lowering the flavin potential indicate that all detectable autoxidation occurs from its FAD site, rather than from iron-sulfur clusters or bound quinones. The flavin adenine dinucleotide (FAD) moiety of Frd is unusually solvent-exposed, as evidenced by its ability to bind sulfite, and this may make it more likely to react adventitiously with O2*-. The autoxidizing species is apparently fully reduced flavin rather than flavosemiquinone, since treatments that more fully reduce the enzyme do not slow its turnover number. They do, however, switch the major product from O2*- to H2O2. A similar effect is achieved by lowering the potential of the proximal [2Fe-2S] cluster. These data suggest that Frd releases O2*- into bulk solution if this cluster is available to sequester the semiquinone electron; otherwise, that electron is rapidly transferred to the nascent superoxide, and H2O2 is the product that leaves the active site. This model is supported by the behavior of "aspartate oxidase" (aspartate:fumarate oxidoreductase), an Frd homologue that lacks Fe-S clusters. Its dihydroflavin also reacts avidly with oxygen, and H2O2 is the predominant product. In contrast, succinate dehydrogenase, with high potential clusters, generates O2*- exclusively. The identities of enzyme autoxidation products are significant because O2*- and H2O2 damage cells in different ways.
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In the citing paper
“Both enzymes produced ROS with a linear dependence on the dissolved oxygen concentration, although SQR produced ROS at a much lower rate.”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [101]
In the citing paper
“E. coli SQR exclusively produces superoxide.In contrast, E. coli QFR produces mainly superoxide at lower succinate concentrations and comparably more hydrogen peroxide at higher substrate concentrations [101].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [101]
In the citing paper
“While a contribution of the Q site might occur in the respective mutants, the most likely source of ROS in wild-type complex II is the fully reduced FAD [37,101].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [101]
In the citing paper
“Messner and Imlay concluded that QFR releases superoxide from the fully reduced flavin if the [2Fe-2S] cluster is available to sequester the semiquinone electron; otherwise this electron is rapidly transferred to the nascent superoxide and hydrogen peroxide is released [101].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [101]
In the citing paper
“In principle, fully reduced FAD can either transfer one electron onto molecular oxygen which leads to the formation of superoxide (probably the major reaction in complex II, but only confirmed for E. coli SQR [101]) or it may also transfer both electrons onto O 2 which leads to the formation of H 2 O 2 (as shown for E. coli QFR [101]) (Fig. 2B).”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [101]
In the citing paper
“An impairment in the normal removal of electrons from the flavin group in SdhA could promote superoxide generation through the autoxidation of the reduced flavin group by O 2 in the matrix (34, 38, 46, 51).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [34]
In the citing paper
“Some evidence suggests that the flavin adenine dinucleotide site in SdhA is the principal source of superoxide generation, due to the exposure of that moiety to the aqueous environment and the high electron density that develops when the electron flux downstream from that site is obstructed (34, 51).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [34]
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Citations
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Cited by
Sorted by citations
Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release
Zorov, D. B., Juhaszova, M., & Sollott, S. J. (2014) · Physiological Reviews · doi:10.1152/physrev.00026.2013 · Cited by 5,383
“Some studies point to flavins (flavin adenine nucleotides, FAD) of SDH rather than other electron-carrying components (such as iron-sulfur clusters or quinones) as the site of autoxidation responsible for generating ROS (200, 293, 294).”
BackgroundImlay, J. A. (2003) · Annual Review of Microbiology · doi:10.1146/annurev.micro.57.030502.090938 · Cited by 2,201
Self-citationImlay, J. A. (2013) · Nature Reviews Microbiology · doi:10.1038/nrmicro3032 · Cited by 1,749
Self-citationWater-Splitting Chemistry of Photosystem II
McEvoy, J. P., & Brudvig, G. W. (2006) · Chemical Reviews · doi:10.1021/cr0204294 · Cited by 1,542
The sites and topology of mitochondrial superoxide production
Brand, M. D. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.01.003 · Cited by 1,217
“The rates during succinate oxidation by fumarate reductase, which catalyses the reverse reaction in Escherichia coli and lacks this mechanism, are much greater (Messner and Imlay, 2002).”
Background
Metadata
- Authors
- Messner, K. R., & Imlay, J. A.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Imlay, James A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 277
- Issue
- 45
- Pages
- 42563-42571
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2044412059
- Cited by
- 301
- References
- 57
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 14 · 2020: 18 · 2019: 13 · 2018: 17 · 2017: 14 · 2016: 8 · 2015: 12 · 2014: 16 · 2013: 21 · 2012: 18
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM49640)
- National Institute of General Medical Sciences (R01GM049640, GM 49640, T32 GM07283-20, T32GM007283)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
- Keywords
- fumarate reductase, succinate dehydrogenase, superoxide production, hydrogen peroxide production, FAD, flavin semiquinone, [2Fe-2S] cluster, oxidative stress, Escherichia coli
- MeSH terms
- Amino Acid Oxidoreductases, Cell Line, Cell Membrane, Escherichia coli, Flavin-Adenine Dinucleotide, Hydrogen Peroxide, Iron-Sulfur Proteins, Kinetics, Oxidation-Reduction, Solvents, Succinate Dehydrogenase, Superoxides, D-Aspartate Oxidase
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