Quantitative Regulation of Intracellular Endothelial Nitric-oxide Synthase (eNOS) Coupling by Both Tetrahydrobiopterin-eNOS Stoichiometry and Biopterin Redox Status
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Tetrahydrobiopterin (BH4) is a critical determinant of endothelial nitric-oxide synthase (eNOS) activity. In the absence of BH4, eNOS becomes "uncoupled" and generates superoxide rather than NO. However, the stoichiometry of intracellular BH4/eNOS interactions is not well defined, and it is unclear whether intracellular BH4 deficiency alone is sufficient to induce eNOS uncoupling. To address these questions, we developed novel cell lines with tet-regulated expression of human GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in BH4 synthesis, to selectively induce intracellular BH4 deficiency by incubation with doxycycline. These cells were stably co-transfected to express a human eNOS-green fluorescent protein fusion protein, selecting clones expressing either low (GCH/eNOS-LOW) or high (GCH/eNOS-HIGH) levels. Doxycycline abolished GTPCH mRNA expression and GTPCH protein, leading to markedly diminished total biopterin levels and a decreased ratio of BH4 to oxidized biopterins in cells expressing eNOS. Intracellular BH4 deficiency induced superoxide generation from eNOS, as assessed by N-nitro-L-arginine methyl ester inhibitable 2-hydroxyethidium generation, and attenuated NO production. Quantitative analysis of cellular BH4 versus superoxide production between GCH/eNOS-LOW and GCH/eNOS-HIGH cells revealed a striking linear relationship between eNOS protein and cellular BH4 stoichiometry, with eNOS uncoupling at eNOS:BH4 molar ratio >1. Furthermore, increasing the intracellular BH2 concentration in the presence of a constant eNOS:BH4 ratio was sufficient to induce eNOS-dependent superoxide production. This specific, reductionist approach in a cell-based system reveals that eNOS:BH4 reaction stoichiometry together with the intracellular BH4:BH2 ratio, rather than absolute concentrations of BH4, are the key determinants of eNOS uncoupling, even in the absence of exogenous oxidative stress.
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When NOS binds BH2 instead of BH4, not only is NO synthesis completely abolished but the protein also becomes an oxidase, generating superoxide instead of NO.
“Thus, not only is the NO synthesis completely abolished but the protein also becomes an oxidase, generating superoxide instead of NO (191, 972, 1007) (Table 6).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [191]
When NOS binds BH2 instead of BH4, the ferrous/oxy heme cannot hydroxylate l-arginine to NG-hydroxy-l-arginine, NO synthesis is blocked, and the oxygen is eventually oxidized to superoxide.
“Mechanistically, when NOS binds BH2 instead of BH4, the ferrous/oxy heme cannot hydroxylate l-arginine to NG-hydroxy-l-arginine, NO synthesis is blocked, and the oxygen is eventually oxidized to superoxide.”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [191]
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Self-citation
- Authors
- Crabtree, M. J., Tatham, A. L., Al-Wakeel, Y., Warrick, N., Hale, A. B., Cai, S., Channon, K. M., & Alp, N. J.
- Affiliations
- John Radcliffe Hospital (GB)
- Corresponding author
- Alp, Nicholas J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 284
- Issue
- 2
- Pages
- 1136-1144
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2069153850
- Cited by
- 200
- References
- 40
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 13 · 2017: 9 · 2016: 9 · 2015: 12 · 2014: 18 · 2013: 15 · 2012: 14
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (GR074428/Z/04/Z)
- British Heart Foundation (PG/05/141/20098, RG/02/006, RG/07/003/23133)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- endothelial nitric oxide synthase, tetrahydrobiopterin, eNOS uncoupling, GTP cyclohydrolase I, superoxide production, nitric oxide production, doxycycline, oxidative stress
- MeSH terms
- Animals, Biopterins, Cell Line, GTP Cyclohydrolase, Humans, Nitric Oxide, Oxidation-Reduction, Protein Binding, Superoxides, RNA, Small Interfering, Mice, Nitric Oxide Synthase Type III
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