Cited by 387Nitric Oxide and Endothelin EffectsProtein Kinase Regulation and GTPase SignalingHemoglobin structure and function

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Enhanced Electron Flux and Reduced Calmodulin Dissociation May Explain “Calcium-independent” eNOS Activation by Phosphorylation

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McCabe, Timothy J., Fulton, David, Roman, Linda J., Sessa, William C.·2000·Journal of Biological Chemistry

DOI 10.1074/jbc.275.9.6123

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Abstract

Bovine endothelial nitric oxide synthase (eNOS) is phosphorylated directly by the protein kinase Akt at serine 1179. Mutation of this residue to the negatively charged aspartate (S1179D eNOS) increases nitric oxide (NO) production constitutively, in the absence of agonist challenge. Here, we examine the potential mechanism of how aspartate at 1179 increases eNOS activity using purified proteins. Examination of NO production and cytochrome c reduction resulted in no substantial changes in the K(m)/EC(50) for L-arginine, calmodulin, and calcium, whereas there was a 2-fold increase in the rate of NO production for S1179D and a 2-4-fold increase in reductase activity (based on cytochrome c reduction). The observed increase in activity for both assays of NOS function indicates that a faster rate of electron flux through the reductase domain is likely the rate-limiting step in NO formation from eNOS. In addition, S1179D eNOS did show an increased resistance to inactivation by EGTA compared with wild type eNOS. These results suggest that a negative charge imposed at serine 1179, either by phosphorylation or by replacement with aspartate, increases eNOS catalytic activity by increasing electron flux at the reductase domain and by reducing calmodulin dissociation from activated eNOS when calcium levels are low.

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Background
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Self-citation
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BackgroundResultInfluentialSelf-citation
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Self-citation
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Background
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“in the oxygenase domain by guarding the steric hindrance due to some non-catalytic inserts [29].”
Background
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BackgroundInfluentialSelf-citation
Acidic Hydrolysis as a Mechanism for the Cleavage of the Glu298 → Asp Variant of Human Endothelial Nitric-oxide Synthase
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“Mutation of S1179 to D renders eNOS constitutively active, whereas S1179 to A is less activated (Dimmeler et al., 1999; Fulton et al., 1999; McCabe et al., 2000).”
BackgroundSelf-citation
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“The exact mechanism responsible for an increase of eNOS enzymatic activity is unclear, although the late phosphorylation at Ser1177 is thought to potentiate eNOS sensitivity for Ca2+/CaM complex (Dimmeler et al., 1999; Fulton et al., 1999; Gratton et al., 2000; McCabe et al., 2000).”
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Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone
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“During the experimental conditions of our study, insulin may have augmented the ACh vasodilator response because Ca2 -dependent activation of eNOS by ACh may be potentiated by Ca2 -independent eNOS phosporylation, through increased electron flux through the reductase domain of the enzyme at any concentration of intrac…”
Background
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“The increase in electron flow, which occurs with phosphorylation of eNOS, increases the release of NO or O2 from NOS (23).”
Background
Hypoxia increases Hsp90 binding to eNOS via PI3K-Akt in porcine coronary artery endothelium
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Authors: McCabe, T. J., Fulton, D., Roman, L. J., & Sessa, W. C.
Affiliations: Yale University (US)
The University of Texas at San Antonio Health Science Center (US)
Corresponding author: Sessa, William C.
ORCID: McCabe, Timothy J.
Fulton, David
Sessa, William C.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2000-03
Volume: 275
Issue: 9
Pages: 6123-6128
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.275.9.6123
OpenAlex: W2090688283
Cited by: 387
References: 32
Citations by year: 2025: 6 · 2024: 3 · 2023: 5 · 2022: 11 · 2021: 13 · 2020: 18 · 2019: 4 · 2018: 11 · 2017: 8 · 2016: 9 · 2015: 16 · 2014: 18 · 2013: 14 · 2012: 21
FWCI: 14.94
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7526 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: American Heart Association
National Institutes of Health (HL61371, HL64793)
National Heart, Lung, and Blood Institute (HL-61371, HL-64793, R01HL064793, HL 57665, R01HL057665)
National Institute of General Medical Sciences (R01GM052419)
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Keywords: endothelial nitric oxide synthase, eNOS phosphorylation, Akt, nitric oxide production, electron flux, reductase domain, calcium-independent activation, cytochrome c reduction, L-arginine
MeSH terms: Animals, Calcium, Calmodulin, Cattle, Egtazic Acid, Electrons, Enzyme Activation, Kinetics, Mutation, NADH Dehydrogenase, NADP, Nitric Oxide, Phosphorylation, Proto-Oncogene Proteins, Protein Serine-Threonine Kinases, Nitric Oxide Synthase, Dimerization, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III, Static Electricity

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Enhanced Electron Flux and Reduced Calmodulin Dissociation May Explain “Calcium-independent” eNOS Activation by Phosphorylation

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