Generation of HNO and HSNO from Nitrite by Heme‐Iron‐Catalyzed Metabolism with H₂S

Abstract

Nitrite has been shown in the past decade to be an important source of nitric oxide that acts as a vasodilator and intrinsic signaling molecule. [1] Numerous studies have proved that nitrite can be reduced in vivo, either non-enzymatically [2a,b] or enzymatically, in reactions catalyzed by xanthine oxidase, [2c] deoxyhaemoglobin, [2d] deoxymyoglobin, [2e] cytochrome c, [2f] or by thiol and metal-center-assisted processes inside the cell. [2g] The mechanism of the last process has recently been studied in detail, and has demonstrated that thiols (cysteine and gluthathione) stimulate water-soluble Fe 3+ -porphyrins to have nitrite reductase activity through an oxygen atom transfer (OAT) mechanism (Scheme 1) that leads to increased formation of Fe 2+ -NO-porphyrin and the corresponding sulfenic acid. [3a] Furthermore, the same research group showed recently that in fact the main products of this reaction are NO and its reduced congener, nitroxyl (HNO). [3b] However, the smallest thiol that can diffuse without any constrains [4a] and which could reach the active sites of most of the metalloproteins, that is, hydrogen sulfide, has not yet been considered as a possible regulator of this reaction. Nonetheless, in clinical praxis, nitrite is used as an antidote for Scheme 1. OAT mechanism. [3]

Spontaneous and Selective Formation of HSNO, a Crucial Intermediate Linking H2S and Nitroso Chemistries

“…Recently, HSNO has been detected under physiologically relevant conditions through protonation of [SNO] − or treatment of S-nitrosoglutathione with sodium sulde by infrared, 15 N NMR and mass spectroscopy. 2 Additionally, coordinated HSNO has been transiently observed by mass spectroscopy 17 and very recently a crystal structure was obtained of an RSNO coordinated to a copper complex. 18 However, these measurements provided only limited insight into the structure and subsequent reactivity of HSNO.…”

Mn porphyrin-based SOD mimic, MnTnHex-2-PyP5+, and non-SOD mimic, MnTBAP3−, suppressed rat spinal cord ischemia/reperfusion injuryviaNF-κB pathways

“…The spontaneity of the reaction would depend on pH; at a very low gastric pH, it would not be favored, but it would occur at neutral pH. Further, Filipovic et al have recently demonstrated that HNO and a metal center of an Fe porphyrin can eventually S -nitrosate proteins via H 2 S-assisted mechanism [102]. The same has been shown with Mn(II) cyclic polyamine-based SOD mimic [139].…”

“…Our work on rat kidney I/R injury demonstrated that MnTnHex-2-PyP 5+ (as a part of mixture containing growth factors and amino acids of Krebs cycle) upregulates a number of endogenous anti-oxidant enzymes — including mitochondrial and extracellular SOD, GPx, lactoperoxidase, inducible nitric oxide synthase (iNOS), and thioredoxin reductase 1—and a set of peroxiredoxins—heat shock protein 70 (HSP-70) and phospho-heat shock factor 1 (pHSF-1) [42]. Importantly, this study clearly showed that MnP had not acted as an SOD mimic, but perhaps as a pro-oxidant inducing adaptive responses such as activating Nrf2 via oxidation of Keap1, in a manner similar to Mn(II) cyclic polyamine [102,103]. Such mode of action is further substantiated with data from Tome’s group indicating that MnTE-2-PyP 5+ can S -glutathionylate other thiol-bearing proteins, such as complexes I, III, and IV of mitochondrial electron transport chain [99,100].…”

“…The mechanism of MnTBAP 3− action on NF-κB was hypothesized to be related to RNS-based modification of cysteine which would inhibit its activation. Such conclusions are based on the (i) MnTBAP 3− /RNS-related chemistry; (ii) Mn(III) N -substituted pyridylporphyrins-driven and N,N′ -disubstituted imidazolylporphyrins-driven inactivation of NF-κB in a stroke I/R rat injury [50,93,94]; (iii) curcumin-driven suppression of astrogliosis/scar formation via NF-kB pathways [111]; (iv) inhibition of NF-kB DNA binding due to the S -glutathionylation of p65 subunit in a cancer study [100,143]; (v) islet cell transplant study [144], where two analogous MnPs suppressed immune responses via oxidation of p50 subunit followed by subsequent inhibition of NF-kB DNA binding [11,142]; (vi) oxidation of Keap1 (cysteine) of Nrf2 by cyclic polyamine-based SOD mimic [102,103]; (vii) parthenolide oxidation of Keap1 and activation of Nrf2 in a normal tissue with subsequent upregulation of endogenous antioxidant defenses [145], which is similar to the effect of MnTnHex-2-PyP 5+ in suppression of rat kidney I/R injury [42,45]; viii) role of Nrf2 in the inhibition of NF-kB and p38 MAPK phosphorylation in the hyper-activation of microglia cells/astrogliosis [95]; and (ix) role of NF-kB in astrogliosis and CNS injuries in general [95,107,108,110,111]. …”

Toward reliable modeling of S-nitrosothiol chemistry: Structure and properties of methyl thionitrite (CH3SNO), an S-nitrosocysteine model

“…23,24 Later systematic high-level ab inito investigations focused on thionitrous acid HSNO, [25][26][27][28][29][30] the smallest RSNO model molecule that, due to its small size, could be feasibly investigated with the state-of-the-art electronic structure methods. Although HSNO has been recently proposed to be an important biological RSNO in its own right, [31][32][33] accurate high-level computational-and also recently reported 30 experimental-data on HSNO may have only limited utility for understanding the chemistry of the most biologically abundant cysteine-based RSNOs, because the nature of substituent R may significantly affect the properties of the -SNO group. 19,34 The smallest aliphatic RSNO, methyl thionitrite CH 3 SNO, is a far better model of S-nitrosated cysteine sidechain, a primary aliphatic RSNO.…”