Redox reactions of hemoglobin: mechanisms of toxicity and control

Abstract

In the last several years, significant work has been done studying hemoglobin (Hb) oxidative reactions and clearance mechanisms using both in vitro and in vivo model systems. One active research area involves the study of molecular chaperones and other proteins that are thought to mitigate the toxicity of acellular Hb. For example, the plasma protein haptoglobin (Hp) and the pre-erythroid protein alpha-hemoglobin-stabilizing protein (AHSP) bind to acellular Hb and alpha-subunits of Hb, respectively, to reduce these adverse effects. Moreover, there has been significant work studying hemopexin and alpha-1 microglobulin, both of which are thought to be involved with hemin degradation. These studies have coincided with the timely publication of the first crystal structure of the Hb-Hp complex. In constructing this Forum, we have invited a number of researchers in the area of Hb and myoglobin (Mb) redox biochemistry, as well as those who have contributed fundamentally to our knowledge of Hp function. Our goal has been to update this critically important research area, because we believe that it will ultimately impact the practice of transfusion medicine in a number of important ways.

FIG. 1.

Iron-centered oxidative transitions within hemoglobin (Hb). Hemin iron atoms within Hb undergo spontaneous oxidation from ferrous to ferric oxidation states. This process indirectly produces hydrogen peroxide, which can further react with ferric and ferrous Hb to produce ferryl species. Reductases within red blood cells keep the heme iron in the ferrous state. Redox potentials were obtained from Banerjee et al. (3). Figure constructed using the Illustrator (Adobe Systems Incorporated, Mountain View, CA) and PyMOL Molecular Graphics System (Schroödinger, LLC, New York, NY).