Linkage Isomerization in Nitrosothiols (RSNOs): The X-ray Crystal Structure of an S-nitrosocysteine and DFT Analysis of its Metastable MS₁ and MS₂ Isomers

Abstract

2015): Linkage isomerization in nitrosothiols (RSNOs): The X-ray crystal structure of an Snitrosocysteine and DFT analysis of its metastable MS 1 and MS 2 isomers, Comments on Inorganic Chemistry, Abstract: Nitrosation of protein cysteines to yield S-nitrosocysteine (cySNO) is an important component of nitric oxide biology. However, high-resolution structural data of cySNO in the absence of protein environment effects is lacking, as is information on cySNO linkage isomers.We report the ordered X-ray crystal structure of a cySNO compound. We employ density functional theory calculations to probe the ground state and linkage isomers of cySNO, CH3SNO, and CF3SNO. The HOMO of CH3SNO contains an intramolecular CH...O interaction that helps rationalize the stability of the cis conformation; this interaction is absent in CF3SNO which favors the trans conformation. We show that the isonitroso MS1 (RSON) and side-on MS2 (RS(2-ON)) linkage isomers are metastable species, with MS1 and MS2 energies similar to those of other experimentally observed nitroso linkage isomers.A c c e p t e d M a n u s c r i p t 2 2 ___________________________________________________________________________ Posttranslational nitrosations of cysteine side-chains in proteins to give cySNO (nitrosocysteine) derivatives are intimately connected with the biological chemistry of nitric oxide (NO). [1][2][3][4] Such posttranslational S-nitrosations can form part of a protein control mechanism, or can generate unwanted species during nitrosative stress events. In some cases, however, the formation of -S-N=O derivatives are critical for the correct function of the proteins as exemplified by the nitrosation of the axial Cys ligand in the active site of the heme nitrophorin from the blood-sucking Cimex bedbug. [5] The chemistry of nitrosothiols (RSNO; R = alkyl/aryl) has been reviewed. [4,6,7] Only a handful of X-ray crystal structures of RSNO derivatives in protein [5,[8][9][10][11][12] and nonprotein [13][14][15][16][17][18][19][20][21][22] environments have been reported. The general instability of RSNOs in biological media has made it a challenge to characterize these species at the molecular level. For example, RSNOs are prone to NO loss via reactions with trace metals, light, and with reactive oxygen species. Given the importance of primary (1°) RSNO derivatives in biology and their relative instability, it is thus not surprising that most studies have focused on the in vivo synthesis and physiological effects of RSNO formation. What is lacking is knowledge of accurate structural data for small-molecule -S-N=O moieties in 1° RSNOs such as cySNO in the absence of a protein environment. Indeed, the only reported non-protein 1° RSNO crystal structures are those of S-nitrosocaptopril (limited data available) [17] and that of the disordered S-nitrosocysteine ethyl ester hydrochloride [18] (disordered in the -S-N=O moiety), thus limiting the reliability of the metrical data in these two reports. Based on the limited structural data to date, it is wid...

Inorganic sulfur–nitrogen compounds: from gunpowder chemistry to the forefront of biological signaling

“…The apparent weakness of the S-N bond in nitrosothiols, leading to facile homolysis in solution, was initially something of a conceptual problem. Crystallographic data reveal that in RSNOs there is an elongated S-N bond of 1.76-1.85 Å 15,51,54 and that there are syn and anti-conformers, although the energy difference between the two is very small. 54,55 The dissociation energy of the S-N bond is reported 56,57 to range from 21 to 31 kcal mol −1 , an unexpectedly large variation.…”

“…Crystallographic data reveal that in RSNOs there is an elongated S-N bond of 1.76-1.85 Å 15,51,54 and that there are syn and anti-conformers, although the energy difference between the two is very small. 54,55 The dissociation energy of the S-N bond is reported 56,57 to range from 21 to 31 kcal mol −1 , an unexpectedly large variation. There have been a number of computational studies on this matter, and the results depend on the computational methods used.…”

“…In addition, recent density functional theory calculations revealed that substituent effects are significant in governing the stability and reactivity of nitrosothiols, as demonstrated for CH 3 SNO vs. CF 3 SNO. 54 A second reaction leading to decomposition of RSNOs is nucleophilic attack of a thiolate at the sulfur of the nitrosothiol with nitroxyl anion (NO − ) as a leaving group (eqn (3)). This is a possibility as thiolate is a very powerful nucleophile, more powerful according to Ritchie's scale than hydroxide.…”

Caged Nitric Oxide–Thiyl Radical Pairs

“…Rebinding R–S• and NO• can also yield isonitrosyl isomer RS–ON, which was computationally located as a true minimum with a long S–O bond length (ca. 2.3 Å) . Indeed, formation of X–ON (X = H, Cl and Br, CN, and HO) from the association of NO• with X• has been observed.…”

“…2.3 Å). 10 Indeed, formation of X−ON (X = H, 11 Cl and Br, 12 CN, 13 and HO 14 ) from the association of NO• with X• has been observed. Bonding analyses suggest that HO−ON, bearing the longest O−O bond (1.9149 ± 0.0005 Å), 14 Generally, S-nitrosothiols display two absorptions in the regions of 330−350 (n O → π*) and 550−600 nm (n N → π*).…”