“…Obviously, in this case, steady-state concentration of NO + –NO − adducts does not reach the level necessary for forming a significant amount of nitrous acid in the process of nitrosonium cation hydrolysis, due to which NO cannot be considered as the acid anhydride in these conditions. Nevertheless, as I assumed in [ 12 , 14 ], disproportionation of NO molecules in living organisms with the formation of NO + and NO − in millimolar concentration is possible, if loosely bound Fe 2+ ions occur in intracellular space; these ions are known to have a close affinity with NO molecules [ 15 ]. This property of divalent iron ions underlying their ability to effectively bind NO molecules—two molecules per iron ion with the formation of rather a stable dinitrosyl iron complexes [Fe(NO) 2 ], or [Fe(NO) 2 ] motifs—ensures NO molecule disproportionation in these motifs following reaction 1 .…”
Section: Part 1 Dinitrosyl Iron Complexes With Thiol-containing Ligamentioning
confidence: 99%
“… Scheme 3. The proposed mechanism for decomposition of M-DNICs with thiol-containing ligands, which, in the presence or absence (blockade) of thiols, causes accumulation of S-nitrosothiols or nitrite, respectively [ 14 ] …”
Section: Part 1 Dinitrosyl Iron Complexes With Thiol-containing Ligamentioning
confidence: 99%
“…In my research I mainly used B-DNICs with glutathione (GSH) or N-acetyl- l -cysteine (NAC), primarily synthesized with respective S-nitrosothiols (GS-NO or S-NO-NAC) as NO sources [ 12 , 14 , 52 ]. The relevant method implies gradually introducing sodium ferric sulphate and sodium nitrite with the molar ratio of 2:1:1 into GSH(NAC) buffer solution [ 53 ].…”
Section: Part 2 Experimental Evidence Of the Ability Of Dnics With Tmentioning
confidence: 99%
“…The following research by our group showed that DNICs with other thiol-containing ligands (both in the mononuclear and binuclear forms) are capable of producing respective RS-NO in the process of decomposition, after acidification to pH of 1–2; at the same time, the process was enhanced sharply when the solution was heated to 70–80 ℃ [ 12 , 14 , 52 ]. At room temperature, B-DNICs remained in acidified solutions for up to one hour, like GS-NO—one of the most stable representatives of low-molecular-weight RS-NO.…”
Section: Part 2 Experimental Evidence Of the Ability Of Dnics With Tmentioning
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.
“…Obviously, in this case, steady-state concentration of NO + –NO − adducts does not reach the level necessary for forming a significant amount of nitrous acid in the process of nitrosonium cation hydrolysis, due to which NO cannot be considered as the acid anhydride in these conditions. Nevertheless, as I assumed in [ 12 , 14 ], disproportionation of NO molecules in living organisms with the formation of NO + and NO − in millimolar concentration is possible, if loosely bound Fe 2+ ions occur in intracellular space; these ions are known to have a close affinity with NO molecules [ 15 ]. This property of divalent iron ions underlying their ability to effectively bind NO molecules—two molecules per iron ion with the formation of rather a stable dinitrosyl iron complexes [Fe(NO) 2 ], or [Fe(NO) 2 ] motifs—ensures NO molecule disproportionation in these motifs following reaction 1 .…”
Section: Part 1 Dinitrosyl Iron Complexes With Thiol-containing Ligamentioning
confidence: 99%
“… Scheme 3. The proposed mechanism for decomposition of M-DNICs with thiol-containing ligands, which, in the presence or absence (blockade) of thiols, causes accumulation of S-nitrosothiols or nitrite, respectively [ 14 ] …”
Section: Part 1 Dinitrosyl Iron Complexes With Thiol-containing Ligamentioning
confidence: 99%
“…In my research I mainly used B-DNICs with glutathione (GSH) or N-acetyl- l -cysteine (NAC), primarily synthesized with respective S-nitrosothiols (GS-NO or S-NO-NAC) as NO sources [ 12 , 14 , 52 ]. The relevant method implies gradually introducing sodium ferric sulphate and sodium nitrite with the molar ratio of 2:1:1 into GSH(NAC) buffer solution [ 53 ].…”
Section: Part 2 Experimental Evidence Of the Ability Of Dnics With Tmentioning
confidence: 99%
“…The following research by our group showed that DNICs with other thiol-containing ligands (both in the mononuclear and binuclear forms) are capable of producing respective RS-NO in the process of decomposition, after acidification to pH of 1–2; at the same time, the process was enhanced sharply when the solution was heated to 70–80 ℃ [ 12 , 14 , 52 ]. At room temperature, B-DNICs remained in acidified solutions for up to one hour, like GS-NO—one of the most stable representatives of low-molecular-weight RS-NO.…”
Section: Part 2 Experimental Evidence Of the Ability Of Dnics With Tmentioning
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.
“…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].…”
Here we demonstrate that binuclear dinitrosyl iron complexes with thiol-containing ligands (glutathione and mercaptosuccinate, B-DNIC-GSH and B-DNIC-MS, respectively) exert cytotoxic effects on MCF7 human breast cancer cells. We showed that they are mediated by nitrosonium cations released from these complexes (NO + ). This finding is supported by the cytotoxic effect of both B-DNICs on MCF7 cells evidenced to retain or was even promoted in the presence of N-Methyl-D-glucamine dithiocarbamate (MGD). MGD recruits an iron nitrosyl group [Fe(NO)] from the iron-dinitrosyl fragment [Fe(NO) 2 ] of B-DNIC-MS forming stable mononitrosyl complexes of iron with MGD and releasing NO + cations from a [Fe(NO) 2 ] fragment.
HNO (nitroxyl, IUPAC name azanone) is an electrophilic reactive nitrogen species of growing pharmacological and biological significance. Here, we present data on the pH-dependent kinetics of azanone reactions with the low molecular thiols glutathione and N-acetylcysteine, as well as with important serum proteins: bovine serum albumin and human serum albumin. The competition kinetics method used is based on two parallel HNO reactions: with RSH/RS− or with O2. The results provide evidence that the reaction of azanone with the anionic form of thiols (RS−) is favored over reactions with the protonated form (RSH). The data are supported with quantum mechanical calculations. A comprehensive discussion of the HNO reaction with thiolates is provided.
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