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Mechanisms of cellular s-nitrosation from free nitric oxide. Involviment of transition metals and reactive species

Grant number: 10/00550-2
Support type:Research Grants - Young Investigators Grants
Duration: September 01, 2010 - August 31, 2015
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:José Carlos Toledo Junior
Grantee:José Carlos Toledo Junior
Home Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):13/02981-9 - Synthesis of dinitrosyl iron complexes (DNIC) and activity against head and neck squamous cell carcinoma, BP.PD
12/20485-6 - A free radical mechanism for s-nitrosohemoglobin formation from nitrite, BP.IC


S-nitrosation affects activity, association and localization of proteins of several functional classes and influences several cellular and organismal physiological processes, emerging as a conserved, ubiquitous, nitric oxide dependent post-translation signaling mechanism. Yet, basic chemical principles of biosignaling such as kinetics, selectivity, and specificity of s-nitrosation, and thus whether they are consistent with cellular regulatory processes are not clear, raising a prudent skepticism to the definitive acceptance of s-nitrosation as a biossignaling process. Indeed, the main evidences for that come from studies exploring biological functional consequences of s-nitrosation of specific proteins. We understand that to study chemical fundaments of s-nitrosation it is critical to know the specific chemical mechanisms of cellular s-nitrosation. These mechanisms are not well characterized, but recent studies indicate that s-nitrosoprotein levels in cells coincide with deoxygenation, and directly correlate with reactive oxygen species (ROS) and dinitrosyl iron complexes (DNIC). Taking these findings into consideration, we intend to study the specific mechanisms of s-nitrosation from nitric oxide in cells. This is the general goal of the proposal. The following specific aims will be addressed: (1) to delineate the experimental/physiological conditions where s-nitrosation process is stimulated in cells; Then, after leaning the specific experimental conditions where DNIC and ROS promote s-nitrosation in cells from nitric oxide, it will be possible (2) to investigate the specific chemical mechanisms by which both DNIC and ROS cause s-nitrosoprotein formation; (3) to discriminate and to identify the main individual proteins that are s-nitrosated exclusively through DNIC and ROS. It is expected that these studies will allow controlling of the time, profile and extension of the cellular nitrosative chemistry by the manipulation of the conditions and relevant species. In addition, identification of individual s-nitrosoprotein formed under strictly known conditions will permit us to associate s-nitrosation of specific proteins to specific conditions and chemical mechanism, thus conferring a degree of specificity not yet available in s-nitrosation. Hopefully, this control will benefit studies of all nitric oxide induced biological processes known to be transduced through s-nitrosation. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DAMASCENO, FERNANDO CRUVINEL; CONDELES, ANDRE LUIS; BUENO LOPES, ANGELICA KODAMA; FACCI, ROMULO RODRIGUES; LINARES, EDLAINE; TRUZZI, DANIELA RAMOS; AUGUSTO, OHARA; TOLEDO, JR., JOSE CARLOS. The labile iron pool attenuates peroxynitrite-dependent damage and can no longer be considered solely a pro-oxidative cellular iron source. Journal of Biological Chemistry, v. 293, n. 22, p. 8530-8542, JUN 1 2018. Web of Science Citations: 4.
DAMASCENO, FERNANDO CRUVINEL; FACCI, ROMULO RODRIGUES; DA SILVA, THALITA MARQUES; TOLEDO, JR., JOSE CARLOS. Mechanisms and kinetic profiles of superoxide-stimulated nitrosative processes in cells using a diaminofluorescein probe. Free Radical Biology and Medicine, v. 77, p. 270-280, DEC 2014. Web of Science Citations: 4.

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