βCysteine 93 in human hemoglobin: a gateway to oxidative stability in health and disease

This mini-review summarizes the role of beta cysteine 93 in oxidative stability of hemoglobin in human blood. beta Cys93 has been recognized as an end point for radicals originating from heme during oxidative stress and therefore it may be an important biological marker of oxidative stability of hemoglobin within red blood cells intended for transfusion or in hemoglobinopathies. beta cysteine 93 residue plays a key role in oxygen (O-2)-linked conformational changes in the hemoglobin (Hb) molecule. This solvent accessible residue is also a target for binding of thiol reagents that can remotely alter O(2)affinity, cooperativity, and Hb's sensitivity to changes in pH. In recent years, beta Cys93 was assigned a new physiological role in the transport of nitric oxide (NO) through a process of S-nitrosylation as red blood cells (RBCs) travel from lungs to tissues. beta Cys93 is readily and irreversibly oxidized in the presence of a mild oxidant to cysteic acid, which causes destabilization of Hb resulting in improper protein folding and the loss of heme. Under these oxidative conditions, ferryl heme (HbFe(4+)), a higher oxidation state of Hb is formed together with its protein radical ((.)HbFe(4+)). This radical migrates to beta Cys93 and interacts with other "hotspot" amino acids that are highly susceptible to oxidative modifications. Oxidized beta Cys93 may therefore be used as a biomarker of oxidative stress, reflecting the deterioration of Hb within RBCs intended for transfusion or RBCs from patients with hemoglobinopathies. Site specific mutation of a redox active amino acid(s) to reduce the ferryl heme or direct chemical modifications that can shield beta Cys93 have been proposed to improve oxidative resistance of Hb and may offer a protective therapeutic strategy.