myo-Inositol Trispyrophosphate: A Novel Allosteric Effector of Hemoglobin with High Permeation Selectivity across the Red Blood Cell Plasma Membrane

myo‐Inositol trispyrophosphate (ITPP), a novel membrane‐permeant allosteric effector of hemoglobin (Hb), enhances the regulated oxygen release capacity of red blood cells, thus counteracting the effects of hypoxia in diseases such as cancer and cardiovascular ailments. ITPP‐induced shifting of the oxygen–hemoglobin equilibrium curve in red blood cells (RBCs) was inhibited by DIDS and NAP‐taurine, indicating that band 3 protein, an anion transporter mainly localized on the RBC membrane, allows ITPP entry into RBCs. The maximum intracellular concentration of ITPP, determined by ion chromatography, was 5.5×10−3 M, whereas a drop in concentration to the limit of detection was observed in NAP‐taurine‐treated RBCs. The dissociation constant of ITPP binding to RBC ghosts was found to be 1.72×10−5 M. All data obtained indicate that ITPP uptake is mediated by band 3 protein and is thus highly tissue‐selective towards RBCs, a feature of major importance for its potential therapeutic use. Blood boosting: myo‐Inositol trispyrophosphate (ITPP), a novel membrane‐permeant allosteric effector of hemoglobin, enhances regulated oxygen release from red blood cells (RBCs), thus counteracting the effects of hypoxia. ITPP uptake appears to be mediated by the band 3 anion carrier RBC membrane protein and is thus highly tissue‐selective towards RBCs, a important feature for its potential therapeutic use.