Oxidation reactions of cellular and acellular hemoglobins: Implications for human health

Abstract

Oxygen reversibly binds to the redox active iron, a transition metal in human Hemoglobin (Hb), which subsequently undergoes oxidation in air. This process is akin to iron rusting in non-biological systems. This results in the formation of non-oxygen carrying methemoglobin (ferric) (Fe3+) and reactive oxygen species (ROS). In circulating red blood cells (RBCs), Hb remains largely in the ferrous functional form (HbF2+) throughout the RBC's lifespan due to the presence of effective enzymatic and non-enzymatic proteins that keep the levels of metHb to a minimum (1%–3%). In biological systems Hb is viewed as a Fenton reagent where oxidative toxicity is attributed to the formation of a highly reactive hydroxyl radical (OH•) generated by the reaction between Hb's iron (Fe2+) and hydrogen peroxide (H2O2). However, recent research on both cellular and acellular Hbs revealed that the protein engages in enzymatic-like activity when challenged with H2O2, resulting in the formation of a highly reactive ferryl heme (Fe4+) that can target other biological molecules before it self-destructs. Accumulating evidence from several in vitro and in vivo studies are summarized in this review to show that Hb's pseudoperoxidase activity is physiologically more dominant than the Fenton reaction and it plays a pivotal role in the pathophysiology of several blood disorders, storage lesions associated with old blood, and in the toxicity associated with the infusion of Hb-derived oxygen therapeutics.

Preparation of oxygen-sensitive proteins for high-resolution cryoEM structure determination using (an)aerobic blot-free vitrification

“…Briefly, Hb is a heterotetramer (α 2 β 2 ) with each subunit harboring a heme cofactor that is capable of binding O 2 in solution when the heme iron is in a ferrous (Fe 2+ ) state. 35,36 Importantly, the oxidation and ligand-bound states of Hb can be readily monitored using UV-vis spectroscopy (Figure 1B) and further verified using cryoEM. [37][38][39] We first elected to limit the amount of O 2 that enters the sample prior to loading in the chameleon dispenser.…”

Hyperoxidized Species of Heme Have a Potent Capacity to Induce Autoreactivity of Human IgG Antibodies

“…Hydrogen peroxide is the most abounded oxidant in vivo and its release has been associated with hemolytic conditions [ 34 , 35 ]. As a result of their pseudoperoxidase catalytic activity, heme and some hemoproteins catalytically degrade hydrogen peroxide, a process that can be accompanied by formation of hyperoxidized heme species [ 36 , 38 , 39 , 40 , 41 ]. As previously described, [ 28 , 29 ] the exposure of human polyclonal IgG to heme (Fe 3+ ) resulted in an increase of Ab binding to human proteins ( Figure 1 a).…”

“…Under inflammatory conditions, hydrogen peroxide and hypochlorous acid are generated in large quantities by polymorphonuclear cells [ 69 ]. Accordingly, it has been observed that in hemolytic conditions, oxidized forms of heme are generated in vivo [ 36 , 37 , 41 , 51 ]. Therefore, it is most likely that in such pathological situation Abs experience the effects not only of heme (Fe 3+ ) but also of its oxidation derivatives.…”

The Influence of Magnetic Fields, Including the Planetary Magnetic Field, on Complex Life Forms: How Do Biological Systems Function in This Field and in Electromagnetic Fields?

“…The regulation of these iron ion-containing molecules is tightly controlled as their dysregulation may be harmful to human health [12,[25][26][27][28][29][30], as heme also appears to have toxic properties [31]. Further evidence for the tight regulation of iron ions during pregnancy [32], exercise [33], and hypoxia [34] indicate that this ion is very important biologically.…”