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Inactivation of the 2‐oxo acid dehydrogenase complexes upon generation of intrinsic radical species
Open accessAbstract
Self‐regulation of the 2‐oxo acid dehydrogenase complexes during catalysis was studied. Radical species as side products of catalysis were detected by spin trapping, lucigenin fluorescence and ferricytochrome c reduction. Studies of the complexes after converting the bound lipoate or FAD cofactors to nonfunctional derivatives indicated that radicals are generated via FAD. In the presence of oxygen, the 2‐oxo acid, CoA‐dependent production of the superoxide anion radical was detected. In the absence of oxygen, a protein‐bound radical concluded to be the thiyl radical of the complex‐bound dihydrolipoate was trapped by α‐phenyl‐ N ‐ tert ‐butylnitrone. Another, carbon‐centered, radical was trapped in anaerobic reaction of the complex with 2‐oxoglutarate and CoA by 5,5′‐dimethyl‐1‐pyrroline‐ N ‐oxide (DMPO). Generation of radical species was accompanied by the enzyme inactivation. A superoxide scavenger, superoxide dismutase, did not protect the enzyme. However, a thiyl radical scavenger, thioredoxin, prevented the inactivation. It was concluded that the thiyl radical of the complex‐bound dihydrolipoate induces the inactivation by 1e – oxidation of the 2‐oxo acid dehydrogenase catalytic intermediate. A product of this oxidation, the DMPO‐trapped radical fragment of the 2‐oxo acid substrate, inactivates the first component of the complex. The inactivation prevents transformation of the 2‐oxo acids in the absence of terminal substrate, NAD + . The self‐regulation is modulated by thioredoxin which alleviates the adverse effect of the dihydrolipoate intermediate, thus stimulating production of reactive oxygen species by the complexes. The data point to a dual pro‐oxidant action of the complex‐bound dihydrolipoate, propagated through the first and third component enzymes and controlled by thioredoxin and the (NAD + + NADH) pool.
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“Pyruvate dehydrogenase (887), α-ketoglutarate dehydrogenase (130, 887, 952), and monoamine oxygenase A and B (290) have all been demonstrated to serve as ROS sources.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [130]
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Metadata
- Authors
- Bunik, V. I., & Sievers, C.
- Affiliations
- Lomonosov Moscow State University (RU)
- University of Tübingen (DE)
- ORCID
- Bunik, Victoria I.
- Venue
- European Journal of Biochemistry
- Publisher
- Wiley
- Published
- 2002-09-27
- Volume
- 269
- Issue
- 20
- Pages
- 5004-5015
- ISSN
- 0014-2956 (ISSN-L)
- 1432-1033
- OpenAlex
- W1488079166
- Cited by
- 134
- References
- 93
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 9 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 7 · 2015: 7 · 2014: 8 · 2013: 10 · 2012: 6
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- enzyme inactivation, thiyl radicals, FAD, superoxide, thioredoxin, reactive oxygen species, spin trapping, DMPO, alpha-ketoglutarate, NAD+, pro-oxidant activity
- MeSH terms
- Catalysis, Coenzyme A, Cyclic N-Oxides, Electron Spin Resonance Spectroscopy, Enzyme Activation, Flavin-Adenine Dinucleotide, Free Radicals, Ketone Oxidoreductases, Thioctic Acid, Multienzyme Complexes, NAD, Nitrogen Oxides, Spin Labels, Superoxides, Thioredoxins, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
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