Caveolar Localization of Arginine Regeneration Enzymes, Argininosuccinate Synthase, and Lyase, with Endothelial Nitric Oxide Synthase

Flam, Brenda R.; Hartmann, Paul J.; Harrell-Booth, Melissa; Solomonson, Larry P.; Eichler, Duane C.

doi:10.1006/niox.2001.0340

Cited by 103Nitric Oxide and Endothelin EffectsCaveolin-1 and cellular processesAmino Acid Enzymes and Metabolism

Caveolar Localization of Arginine Regeneration Enzymes, Argininosuccinate Synthase, and Lyase, with Endothelial Nitric Oxide Synthase

Flam, Brenda R., Hartmann, Paul J., Harrell-Booth, Melissa, Solomonson, Larry P., Eichler, Duane C.·2001·Nitric Oxide

DOI 10.1006/niox.2001.0340

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Abstract

Although normal intracellular levels of arginine are well above the K(m), and should be sufficient to saturate nitric oxide synthase in vascular endothelial cells, nitric oxide production can, nonetheless, be stimulated by exogenous arginine. This phenomenon, termed the "arginine paradox," has suggested the existence of a separate pool of arginine directed to nitric oxide synthesis. In this study, we demonstrate that exogenous citrulline was as effective as exogenous arginine in stimulating nitric oxide production and that citrulline in the presence of excess intracellular and extracellular arginine further enhanced bradykinin stimulated endothelial nitric oxide production. The enhancement of nitric oxide production by exogenous citrulline could therefore be attributed to the capacity of vascular endothelial cells to efficiently regenerate arginine from citrulline. However, the regeneration of arginine did not affect the bulk intracellular arginine levels. This finding not only supports the proposal for a unique pool of arginine, but also suggested channeling of substrates that would require a functional association between nitric oxide production and arginine regeneration. To support this proposal, we showed that nitric oxide synthase, and the enzymes involved in arginine regeneration, argininosuccinate synthase and argininosuccinate lyase, cofractionated with plasmalemmal caveolae, a subcompartment of the plasma membrane. Overall, the results from this study strongly support the proposal for a separate pool of arginine for nitric oxide production that is defined by the cellular colocalization of enzymes involved in nitric oxide production and the regeneration of arginine.

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A membrane metabolon including arginine succinate lyase, argininosuccinate synthetase, hsp90, and eNOS associates in caveolae and is necessary for regular eNOS function.
“A membrane metabolon including arginine succinate lyase, argininosuccinate synthetase, hsp90, and eNOS associates in the caveolae and is necessary for regular eNOS function (270, 294, 634).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [294]

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Authors: Flam, B. R., Hartmann, P. J., Harrell-Booth, M., Solomonson, L. P., & Eichler, D. C.
Affiliations: University of South Florida (US)
Corresponding author: Eichler, Duane C.
Venue: Nitric Oxide
Publisher: Elsevier BV
Published: 2001-04
Volume: 5
Issue: 2
Pages: 187-197
ISSN: 1089-8603 (ISSN-L)
DOI: 10.1006/niox.2001.0340
OpenAlex: W2090957628
Cited by: 103
References: 33
Citations by year: 2026: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 7 · 2013: 7 · 2012: 8
FWCI: 4.18
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Nitric Oxide (publishedVersion)
PubMed (publishedVersion)
Funders: American Heart Association (9504007, 9950864V, 9701711, 9750222N)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: nitric oxide synthase, argininosuccinate synthetase, argininosuccinate lyase, citrulline, nitric oxide production, caveolae, endothelial cells, bradykinin, substrate channeling, enzyme colocalization
MeSH terms: Animals, Aorta, Arginine, Argininosuccinate Lyase, Argininosuccinate Synthase, Bradykinin, Cattle, Chromatography, High Pressure Liquid, Citrulline, Electrophoresis, Polyacrylamide Gel, Endothelium, Vascular, Blotting, Western, Nitric Oxide Synthase, Caveolae, Nitric Oxide Synthase Type III

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Caveolar Localization of Arginine Regeneration Enzymes, Argininosuccinate Synthase, and Lyase, with Endothelial Nitric Oxide Synthase

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