Investigation of the dynamics of Dinitrosyl Iron Complexes (DNICs) formation

• Grant number: 21/11225-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: November 01, 2021
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Daniela Ramos Truzzi
• Grantee: Nathália Miranda de Medeiros
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/17483-0 - Dinitrosyl iron complexes (DNICs): formation, reactivity, and implications for the physiopathology of nitric oxide, AP.JP

Abstract

Dinitrosyl iron complexes (DNICs, [Fe(NO)2(L)2]-) are important NO-metabolites. Recently, we elucidated the formation mechanism of DNICs containing low molecular weight thiols. Thereby, we verify that the formation of {Fe(NO)2}9 moiety found in DNICs involves the reduction of Fe2+ to Fe+ promoted by low molecular weight thiols, which is in accordance with their function as biological reducers. However, it was demonstrated that non-thiol and poor reducers molecules such as phosphate, arsenate, benzoate, and non-thiol amino acids can also react with Fe2+ and NO giving rise to DNICs. In these cases, the formation mechanisms and the yield for the {Fe(NO)2}9 core are not known, therefore, the biological relevance of these reactions can not be evaluated. Thus, we intend to investigate the formation of {Fe(NO)2}9 in the absence of low molecular weight thiols. For that, DNICs formation will be evaluated in solutions containing only Fe2+ and NO, and in solutions containing Fe2+, NO, and non-thiol ligands such as phosphate, histidine, and tyrosine to verify the existence of additional vias for low molecular weight-DNICs formation. Next, we will verify if proteins (high molecular weight thiols) can form DNIC directly from the reaction between Fe2+ and NO. The understanding of the mechanism of high molecular weight-DNICs formation is relevant because the characteristic signal detectable by Electron Paramagnetic Resonance (EPR) in cells and tissues indicates that most of the biological DNICs are of high molecular weight. Since the reduction rate of Fe2+ to Fe+ can be modulated by the nature of the thiol, in this stage we will study the reaction between Fe2+, NO, and the thiol proteins serum albumin (SA) (pKa-SH ~ 8) and peroxiredoxin I (Prx1) (pKa-SH ~ 5) because their thiol groups have different acidities, allowing us to assess if the degree of deprotonation of the sulfhydryl groups interferes on the rate and/or formation mechanism of DNICs. These studies aim to elucidate the biological relevance of the formation of DNICs with biomolecules of low and high molecular weight. (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)

MEDEIROS, NATHALIA MIRANDA; GARCIA, FELIPE ALVES; TRUZZI, DANIELA RAMOS. Insight into the relevance of dinitrosyl iron complex (DNIC) formation in the absence of thiols in aqueous media. DALTON TRANSACTIONS, v. 53, n. 5, p. 5-pg., 2024-01-09. (13/07937-8, 21/11225-0, 19/17483-0)