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Much of the toxicity of Hb has been linked to its redox activity; Hb may generate reactive oxygen species, such as the superoxide anion. Superoxide is intrinsically toxic, and superoxide dismutase (SOD) provides important cellular protection. However, if the Hb molecule is located outside the red blood cell, the normal protection systems involving SOD and catalase are no longer closely associated with it, exposing Hb and its cellular surroundings to oxidative damage. In order to produce less toxic Hb molecules, we have explored gene fusion to obtain homogeneous SOD-Hb conjugates. The chimeric protein was generated by coexpressing the human Hb α-chain/manganese SOD gene together with the β-chain gene in Escherichia coli. We show that the engineered SOD-Hb fusion protein retains the oxygen-binding capacity and, moreover, decreases cytotoxic ferrylHb (HbFe4+) formation when challenged with superoxide radicals. The SOD-Hb fusion protein also exhibits a 44% lower autoxidation rate and higher thermal stability than Hb alone.