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Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo

Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo
Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo
There is mounting evidence that the established paradigm of nitric oxide (NO) biochemistry, from formation through NO synthases, over interaction with soluble guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part of a richer chemistry through which NO elicits biological signaling. Additional pathways have been suggested that include interaction of NO-derived metabolites with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls. Despite the overwhelming attention paid in this regard to RSNOs, little is known about the stability of these species, their significance outside the circulation, and whether other nitros(yl)ation products are of equal importance. We here show that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S-nitrosation in vivo and that the products of these reactions are constitutively present throughout the organ system. Our study further reveals that all NO-derived products are highly dynamic, have fairly short lifetimes, and are linked to tissue oxygenation and redox state. Experimental evidence further suggests that nitroso formation occurs substantially by means of oxidative nitrosylation rather than NO autoxidation, explaining why S-nitrosation can compete effectively with nitrosylation. Moreover, tissue nitrite can serve as a significant extravascular pool of NO during brief periods of hypoxia, and tissue nitrate/nitrite ratios can serve as indicators of the balance between local oxidative and nitrosative stress. These findings vastly expand our understanding of the fate of NO in vivo and provide a framework for further exploration of the significance of nitrosative events in redox sensing and signaling. The findings also raise the intriguing possibility that N-nitrosation is directly involved in the modulation of protein function.
nitrosothiols, nitrosamines, heme-nitrosyls, ascorbate, oxidative stress
0027-8424
4308-4313
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Rassaf, Tienush
a820a375-219a-4fa2-ae10-e77f4b1eb37c
Maloney, Ronald E.
ce656859-d89f-4fd3-93db-6c26f23fb7f4
Rodriguez, Cynthia M.
8804b0f8-ff78-4056-926f-452168b6889c
Saijo, Fumito
c66d3d87-1cdf-4f51-af1c-fdd1c7e772ea
Rodriguez, Juan R.
fe957534-bdee-417e-92fc-bd8b9b7da821
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Rassaf, Tienush
a820a375-219a-4fa2-ae10-e77f4b1eb37c
Maloney, Ronald E.
ce656859-d89f-4fd3-93db-6c26f23fb7f4
Rodriguez, Cynthia M.
8804b0f8-ff78-4056-926f-452168b6889c
Saijo, Fumito
c66d3d87-1cdf-4f51-af1c-fdd1c7e772ea
Rodriguez, Juan R.
fe957534-bdee-417e-92fc-bd8b9b7da821
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd

Bryan, Nathan S., Rassaf, Tienush, Maloney, Ronald E., Rodriguez, Cynthia M., Saijo, Fumito, Rodriguez, Juan R. and Feelisch, Martin (2004) Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proceedings of the National Academy of Sciences, 101 (12), 4308-4313. (doi:10.1073/pnas.0306706101). (PMID:15014175)

Record type: Article

Abstract

There is mounting evidence that the established paradigm of nitric oxide (NO) biochemistry, from formation through NO synthases, over interaction with soluble guanylyl cyclase, to eventual disposal as nitrite/nitrate, represents only part of a richer chemistry through which NO elicits biological signaling. Additional pathways have been suggested that include interaction of NO-derived metabolites with thiols and metals to form S-nitrosothiols (RSNOs) and metal nitrosyls. Despite the overwhelming attention paid in this regard to RSNOs, little is known about the stability of these species, their significance outside the circulation, and whether other nitros(yl)ation products are of equal importance. We here show that N-nitrosation and heme-nitrosylation are indeed as ubiquitous as S-nitrosation in vivo and that the products of these reactions are constitutively present throughout the organ system. Our study further reveals that all NO-derived products are highly dynamic, have fairly short lifetimes, and are linked to tissue oxygenation and redox state. Experimental evidence further suggests that nitroso formation occurs substantially by means of oxidative nitrosylation rather than NO autoxidation, explaining why S-nitrosation can compete effectively with nitrosylation. Moreover, tissue nitrite can serve as a significant extravascular pool of NO during brief periods of hypoxia, and tissue nitrate/nitrite ratios can serve as indicators of the balance between local oxidative and nitrosative stress. These findings vastly expand our understanding of the fate of NO in vivo and provide a framework for further exploration of the significance of nitrosative events in redox sensing and signaling. The findings also raise the intriguing possibility that N-nitrosation is directly involved in the modulation of protein function.

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More information

Published date: 23 March 2004
Keywords: nitrosothiols, nitrosamines, heme-nitrosyls, ascorbate, oxidative stress
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337846
URI: https://eprints.soton.ac.uk/id/eprint/337846
ISSN: 0027-8424
PURE UUID: d3e2b669-b6e3-4c5c-bdc3-a31de5ff41be
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

Catalogue record

Date deposited: 22 Jun 2012 09:15
Last modified: 06 Jun 2018 12:29

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