Nitrosonium Ions as Constituents of Dinitrosyl Iron Complexes with Glutathione Responsible for their S-Nitrosating Activity

Research Article

Austin J Anal Pharm Chem. 2018; 5(4): 1109.

Nitrosonium Ions as Constituents of Dinitrosyl Iron Complexes with Glutathione Responsible for their S-Nitrosating Activity

Anatoly F. Vanin*

N.N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow; Institute for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

*Corresponding author: Anatoly F. Vanin, N.N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow; Institute for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

Received: October 03, 2018; Accepted: November 05, 2018 Published: November 12, 2018

Abstract

It has been established that the S-nitrosating activity of biologically active binuclear dinitrosyl iron complexes with glutathione (B-DNIC-GSH, formula [(GS-)2Fe2(NO)4]) is determined by the presence in these complexes of nitrosonium ions (NO+). The release of the latter from B-DNIC-GSH during their decomposition in acid media is accompanied by the formation of S-nitrosoglutathione (GS-NO) both in the presence and in the absence of oxygen, whereas at neutral ?? nitrosonium ions released from B-DNIC are converted into nitrite anions by hydrolysis. It has been shown that the concentrations of nitrite anions and GS-NO correlate exactly with the concentration of Fe(NO)2 fragments of B-DNIC, being equivalent to the concentration of 50% of nitrosyl ligands in B-DNIC. The rest 50% of nitrosyl ligands are released from B-DNIC in the form of neutral molecules of NO. The data obtained are interpreted in terms of the d7 electronic configuration of iron in B-DNIC in the framework of our hypothetical mechanism of Fe(NO)2 formation in B-DNIC during interaction of bivalent iron with neutral molecules of NO and thiols.

Keywords: Dinitrosyl iron complexes; S-nitrosothiols; Nitrosonium ion; Nitric oxide

Abbreviations

B- or M-DNIC: Binuclear or Mononuclear Dinitrosyl Iron Complexes; EPR: Electron Paramagnetic Resonance; GS-NO: S-nitrosoglutathione; RS-NO: S-nitrosothiols.

Introduction

It has been established that the mononuclear and binuclear forms of dinitrosyl iron complexes with thiol-containing (RS-) ligands (M- and B-DNIC with chemical formulas [(RS)2Fe(NO)2] and [(RS-)2Fe2(NO)4], respectively) manifest a broad range of biological activities, which resemble those of nitric monoxide (NO), one of the most universal endogenous regulators of metabolic processes in living organisms. These complexes exert strong vasodilator and, correspondingly, hypotensive effects on animals and man [1-4]. They suppress platelet aggregation and thrombosis [5,6], accelerate healing of skin woulds [7,8], stimulate penile erectile activity in animals [9], trigger the synthesis of heat-shock proteins [10], possess potent antioxidant activity [11-13], modulate the functional activity of certain genes [14,15], key proteins and enzymes [16-19], initiate S-nitrosation of thiols [20-23], inhibit propagation of Coxsackie-3 virus (2Apro) in animal hearts [24], suppress the growth of endometrial tumours in animals with experimental endometriosis [25], etc. And, last but not least, they inhibit the growth of cultured tumour cells [26, 27] and cease malignant growth in animals [27,28]. All these findings leave hope that DNIC with thiol-containing ligands holds considerable promise as a basis in the design of medicinal drugs possessing a broad range of therapeutic activities. Several novel DNIC-based drugs are successfully used in the clinical practice for relieving hypertension crises and accelerating healing of skin wound [8,29].

There is evidence that biological activity of DNIC with thiolcontaining ligands is related to their ability to play the role of donors of NO and nitrosonium ions (NO+) in animal and human organisms. The NO-donating capacity of these DNIC can be illustrated by the fact that inhibition of the heme-containing protein guanylate cyclase, one of the main targets of NO, fully eliminates their vasodilatory effect [30]. As far as the ability of DNIC with thiol-containing ligands to generate nitrosonium ions possessing S-nitrosating activity is concerned, it was established for both isolated thiol-containing proteins and their intracellular counterparts [21-23]. This process was significantly attenuated in the presence of iron chelators inhibiting DNIC synthesis both in the presence and in the absence of oxygen [22,23]. The latter circumstance fully refutes the hypothesis according to which S-nitrosation of proteins induced by DNIC is a result of oxidation of NO released from DNIC to NO2 and subsequent formation of nitrogen trioxide responsible for S-nitrosation of thiols [31].

The ability of DNIC with thiol-containing ligands to donate NO and NO+ is determined by their electronic structure characterized by the d7 electronic configuration of iron (in the Enemark-Feltham classification it is described by the formula [Fe(NO)2]7 [32]). THe hypothetical mechanism of Μ-DNIC formation in a reaction between Fe2+, thiols and gaseous NO is shown in Scheme 1: