Glutathionyl Hemoglobin and Its Emerging Role as a Clinical Biomarker of Chronic Oxidative Stress

Abstract

Hemoglobin is one of the proteins that are more susceptible to S-glutathionylation and the levels of its modified form, glutathionyl hemoglobin (HbSSG), increase in several human pathological conditions. The scope of the present review is to provide knowledge about how hemoglobin is subjected to S-glutathionylation and how this modification affects its functionality. The different diseases that showed increased levels of HbSSG and the methods used for its quantification in clinical investigations will be also outlined. Since there is a growing need for precise and reliable methods for markers of oxidative stress in human blood, this review highlights how HbSSG is emerging more and more as a good indicator of severe oxidative stress but also as a key pathogenic factor in several diseases.

Keywords: S-glutathionylation; clinical marker; glutathione; glutathionyl hemoglobin; glutathionylated hemoglobin; oxidative stress; post-translational modification.

Figure 1

Response of erythrocytes to transient and chronic conditions of oxidative stress via glutathionyl hemoglobin (HbSSG) formation. In mechanism 1 and 2, oxygen reactive species (ROS) catalyze the formation of Hb β-93-cysteine thiyl radical or sulfenic acid, respectively. These intermediates react with reduced glutathione (GSH) to generate HbSSG. In mechanism 3, ROS oxidize GSH to the sulfenic acid form, which reacts with Hb β-93-cysteine to generate HbSSG. In mechanism 4, ROS increase oxidized glutathione (GSSG) concentration that can be attacked by Hb β-93-cysteine in its thiolate anion form. O₂ dotted arrow represents the reduced oxygen delivery of HbSSG to targeted tissues. Hemoglobin is represented with its glutathionylation sites (αCys104, βCys93 and βCys112), where βCys93 corresponds with the favorite site for S-glutathionylation.