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Revisiting the interaction of heme with hemopexin: Recommendations for the responsible use of an emerging drug

In hemolytic disorders, erythrocyte lysis results in massive release of hemoglobin and, subsequently, toxic heme. Hemopexin is the major protective factor against heme toxicity in human blood and currently considered for therapeutic use. It has been widely accepted that hemopexin binds heme with extraordinarily high affinity in a 1:1 ratio. Here we show that hemopexin binds heme with lower affinity than previously assumed and that the interaction ratio tends to 2:1 (heme:hemopexin) or above. The heme-binding sites of hemopexin were characterized using hemopexin-derived peptide models and competitive displacement assays. In addition, in silico molecular modelling with a newly created homology model of human hemopexin allowed us to propose a recruiting mechanism by which heme consecutively binds to several histidine residues and is finally funnelled into the high-affinity binding pocket. Our findings have direct implications for the biomedical application of hemopexin and its potential administration in hemolytic disorders.