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Interactions of Peroxynitrite, Tetrahydrobiopterin, Ascorbic Acid, and Thiols
Open accessAbstract
Tetrahydrobiopterin (BH4) serves as a critical co-factor for the endothelial nitric-oxide synthase (eNOS). A deficiency of BH4 results in eNOS uncoupling, which is associated with increased superoxide and decreased NO* production. BH4 has been suggested to be a target for oxidation by peroxynitrite (ONOO-), and ascorbate has been shown to preserve BH4 levels and enhance endothelial NO* production; however, the mechanisms underlying these processes remain poorly defined. To gain further insight into these interactions, the reaction of ONOO- with BH4 was studied using electron spin resonance and the spin probe 1-hydroxy-3-carboxy-2,2,5-tetramethyl-pyrrolidine. ONOO- reacted with BH4 6-10 times faster than with ascorbate or thiols. The immediate product of the reaction between ONOO- and BH4 was the trihydrobiopterin radical (BH3.), which was reduced back to BH4 by ascorbate, whereas thiols were not efficient in recycling of BH4. Uncoupling of eNOS caused by peroxynitrite was investigated in cultured bovine aortic endothelial cells (BAECs) by measuring superoxide and NO* using spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine and the NO*-spin trap iron-diethyldithiocarbamate. Bolus ONOO-, the ONOO- donor 3-morpholinosydnonimine, and an inhibitor of BH4 synthesis (2,4-diamino-6-hydroxypyrimidine) uncoupled eNOS, increasing superoxide and decreasing NO* production. Exogenous BH4 supplementation restored endothelial NO* production. Treatment of BAECs with both BH4 and ascorbate prior to ONOO- prevented uncoupling of eNOS by ONOO-. This study demonstrates that endothelial BH4 is a crucial target for oxidation by ONOO- and that the BH4 reaction rate constant exceeds those of thiols or ascorbate. We confirmed that ONOO- uncouples eNOS by oxidation of tetrahydrobiopterin and that ascorbate does not fully protect BH4 from oxidation but recycles BH3. radical back to BH4.
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“The comparison of the crystal structures for XDH and XO indicates the movement of a loop that partially blocks the NAD+ binding site and alters the electrostatics of the FAD environment (268, 542).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [542]
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Metadata
- Authors
- Kuzkaya, N., Weissmann, N., Harrison, D. G., & Dikalov, S.
- Affiliations
- Emory University (US)
- Justus-Liebig-Universität Gießen (DE)
- Corresponding author
- Dikalov, Sergey
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 278
- Issue
- 25
- Pages
- 22546-22554
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2058242086
- Cited by
- 692
- References
- 50
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 17 · 2023: 20 · 2022: 23 · 2021: 29 · 2020: 22 · 2019: 24 · 2018: 31 · 2017: 23 · 2016: 24 · 2015: 33 · 2014: 33 · 2013: 25 · 2012: 44
- FWCI
- 20.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB-547)
- National Institutes of Health (HL058000, PO-1 HL058000)
- National Heart, Lung, and Blood Institute (R01HL039006, P0-1 HL058000-06, P01HL058000)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- peroxynitrite, tetrahydrobiopterin, vitamin C, thiols, endothelial nitric oxide synthase, eNOS uncoupling, superoxide, nitric oxide, SIN-1, 2,4-diamino-6-hydroxypyrimidine, endothelial cells
- MeSH terms
- Animals, Aorta, Ascorbic Acid, Biopterins, Cattle, Cells, Cultured, Endothelium, Vascular, Kinetics, Spin Labels, Sulfhydryl Compounds, Nitric Oxide Synthase, Nitric Oxide Donors, Peroxynitrous Acid, Nitric Oxide Synthase Type III
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