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]

Persulfidation (S-sulfhydration) and H2S

“…In addition, Pálinkás et al (2014) have recently investigated interactions of H 2 S with human myeloperoxidase (MPO), a major contributor to inflammatory oxidative stress, to show that H 2 S inhibits the enzyme by reducing iron centre and by binding to the reduced Fe 2+ . It is still, however, unclear to which extent is the coordination and/or reduction of metal centres involved in signalling by H 2 S. Miljkovic et al (2013) demonstrated that metal centres in mitochondria are responsible for the H 2 S-stimulated haem centre-catalysed reduction of nitrite, a reaction which can explain the use of nitrite as an antidote for acute H 2 S poisoning.…”

“…3f). Namely, some iron haem centres are able to oxidize hydrogen sulfide forming HS• (Miljkovic et al 2013), which could in turn react with free thiols to finally generate protein persulfides (Zhang et al 2014). Cytochrome c, for example, readily reacts with H 2 S (Wedmann et al 2014).…”

Hydrogen Sulfide as an Oxygen Sensor

“…Myoglobin (Mb) heme appears to be key to hypoxic vasodilation, as it is present in rat aortic smooth muscle and in Mb null rats (Mb -y-) hypoxic vasodilation is impaired (170). Recently, Miljkovic et al (106) showed that H 2 S is a rapid mediator of nitrite reduction by providing reducing equivalents to Fe 3 + , thereby generating both NO and its reduced congener, nitroxyl (HNO). Vasodilation produced by acute hypoxia in mice in vivo appears to be independent of NO production, and it is associated with reduced plasma nitrite concentration and increased RSNOs (174).…”

Hydrogen sulfide as an oxygen sensor

“…Reduction of the iron forms a nitrosyl-Fe 2 + that then binds an additional H 2 S which results in the liberation of thionitrus acid (HSNO) and this can also give rise to H 2 S, polysulfide (HSSH), NO and its reduced congener, nitroxyl (HNO), and protein Snitrosothiol (RSNO), all of which could contribute to vascular signaling. Modified from Miljkovic et al (106).…”