How is Nitric Oxide (NO) Converted into Nitrosonium Cations (NO+) in Living Organisms? (Based on the Results of Optical and EPR Analyses of Dinitrosyl Iron Complexes with Thiol-Containing Ligands)

Abstract

The present work provides theoretical and experimental foundations for the ability of dinitrosyl iron complexes (DNICs) with thiol - containing ligands to be not only the donors of neutral NO molecules, but also the donors of nitrosonium cations (NO + ) in living organisms ensuring S-nitrosation of various proteins and low-molecular-weight compounds. It is proposed that the emergence of those cations in DNICs is related to disproportionation reaction of NO molecules, initiated by their binding with Fe 2+ ions (two NO molecules per one ion). At the same time, possible hydrolysis of iron-bound nitrosonium cations is prevented by the electron density transition to nitrosonium cations from sulfur atoms of thiol-containing ligands, which are included in the coordination sphere of iron. It allows supposing that iron in iron–nitrosyl complexes of DNICs has a d 7 electronic configuration. This supposition is underpinned by experimental data revealing that a half of nitrosyl ligands are converted into S-nitrosothiols (RSNOs) when those complexes decompose, with the other half of those ligands released in the form of neutral NO molecules.

Nitrosonium Cation as a Cytotoxic Component of Dinitrosyl Iron Complexes with Thiol-containing Ligands (based on the Experimental Work on MCF7 Human Breast Cancer Cell Culture)

“…In most cases, the concentration of S-nitrosothiols (RS-NO) generated upon B-DNIC breakdown was equal to the concentration of the complexes in terms of 1 iron atom (0.5 mM RS-NO for 0.5 mM B-DNIC). This is entirely consistent with the mechanism of the transformation of these complexes into corresponding RS-NO proposed in [ 20 – 22 ].…”

“…2 , panels B and C). Such a transformation occurring at low pH described by us before [ 20 – 22 ] was observed in the case of B-DNIC-GSH as well but only after 30 s heating at 70–80 °С (Fig. 2 , panel A, curve 4).…”

“…2 , panel B, curve 6). The transformation of both B-DNIC derivatives into appropriate RS-NO was mediated by the breakdown of the complexes upon protonation of thiol ligands and their subsequent binding to nitrosonium cations released from the complexes as it was shown in [ 20 – 22 ].…”

“…One of the resonance structures of paramagnetic mononuclear DNIC with thiol-containing ligands formed according to Scheme 1 can be represented as [(RS - ) 2 Fe + (NO + ) 2 ] + . The reaction corresponding to the suggested mechanism of M-DNIC formation described in detail in [ 1 – 3 , 6 , 13 , 19 – 22 ]. is as follows (reaction 1 ): …”

“…As a result, DNIC with thiol-containing ligands can serve as NO donors as well as NO + donors. Nitrosonium cations are crucial for S-nitrosylation of biologically active thiol-containing proteins and small molecules, thus, performing an essential biological activity of the endogenous NO network [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. DNIC with thiol-containing ligands have been shown to induce this process for isolated proteins [5,[7][8][9][10]17] as well as endogenous proteins [9-11, 14, 16, 18].…”