ArticleThe Journal of biological chemistry2012
Control of electron transfer and catalysis in neuronal nitric-oxide synthase (nNOS) by a hinge connecting its FMN and FAD-NADPH domains.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Glutamine Substitution at LysineACS omega · 2026Article
- Conformational states and fluctuations in endothelial nitric oxide synthase under calmodulin regulation.Biophysical journal · 2021Article
- Nitric Oxide Synthase Inhibitors into the Clinic at Last.Handbook of experimental pharmacology · 2021Article
- Nitric oxide in cellular adaptation and disease.Redox biology · 2020Review
- Unbiased proteomics identifies plasminogen activator inhibitor-1 as a negative regulator of endothelial nitric oxide synthase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Nitric oxide synthase enzymology in the 20 years after the Nobel Prize.British journal of pharmacology · 2019Review
- Quantification of nitric oxide by high-performance liquid chromatography-fluorometric method in subgenomic hepatitis C virus-replicon expressing Huh7 cells upon treatment with acetylsalicylic acid.Experimental and therapeutic medicine · 2018Article
- Solution structure of the cytochrome P450 reductase-cytochromeThe Journal of biological chemistry · 2018Article
- A cross-domain charge interaction governs the activity of NO synthase.The Journal of biological chemistry · 2018Article
- The Hinge Segment of Human NADPH-Cytochrome P450 Reductase in Conformational Switching: The Critical Role of Ionic Strength.Frontiers in pharmacology · 2017Article
- Tetrahydrobiopterin redox cycling in nitric oxide synthase: evidence supports a through-heme electron delivery.The FEBS journal · 2016Article
- Phosphorylation Controls Endothelial Nitric-oxide Synthase by Regulating Its Conformational Dynamics.The Journal of biological chemistry · 2016Article
- Article
- Architecture of the nitric-oxide synthase holoenzyme reveals large conformational changes and a calmodulin-driven release of the FMN domain.The Journal of biological chemistry · 2014Article
- Energy landscapes and catalysis in nitric-oxide synthase.The Journal of biological chemistry · 2014Article
- Plasma metabolomic profiling to reveal antipyretic mechanism of Shuang-huang-lian injection on yeast-induced pyrexia rats.PloS one · 2014Article
- Dissecting regulation mechanism of the FMN to heme interdomain electron transfer in nitric oxide synthases.Journal of inorganic biochemistry · 2014Review
- Redox-linked domain movements in the catalytic cycle of cytochrome p450 reductase.Structure (London, England : 1993) · 2013Article
- Dynamic control of electron transfers in diflavin reductases.International journal of molecular sciences · 2012Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
In nitric-oxide synthases (NOSs), two flexible hinges connect the FMN domain to the rest of the enzyme and may guide its interactions with partner domains for electron transfer and catalysis. We investigated the role of the FMN-FAD/NADPH hinge in rat neuronal NOS (nNOS) by constructing mutants that either shortened or lengthened this hinge by 2, 4, and 6 residues. Shortening the hinge progressively inhibited electron flux through the calmodulin (CaM)-free and CaM-bound nNOS to cytochrome c, whereas hinge lengthening relieved repression of electron flux in CaM-free nNOS and had no impact or slowed electron flux through CaM-bound nNOS to cytochrome c. How hinge length influenced heme reduction depended on whether enzyme flavins were pre-reduced with NADPH prior to triggering heme reduction. Without pre-reduction, changing the hinge length was deleterious; with pre-reduction, the hinge shortening was deleterious, and hinge lengthening increased heme reduction rates beyond wild type. Flavin fluorescence and stopped-flow kinetic studies on CaM-bound enzymes suggested hinge lengthening slowed the domain-domain interaction needed for FMN reduction. All hinge length changes lowered NO synthesis activity and increased uncoupled NADPH consumption. We conclude that several aspects of catalysis are sensitive to FMN-FAD/NADPH hinge length and that the native hinge allows a best compromise among the FMN domain interactions and associated electron transfer events to maximize NO synthesis and minimize uncoupled NADPH consumption.
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