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.

[1]  J. Lehn,et al.  Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate , 2009, Proceedings of the National Academy of Sciences.

[2]  I. Queguiner,et al.  Anti‐angiogenic properties of myo‐inositol trispyrophosphate in ovo and growth reduction of implanted glioma , 2007, FEBS letters.

[3]  Eugene Y. Kim,et al.  Evidence against a Direct Interaction between Intracellular Carbonic Anhydrase II and Pure C-terminal Domains of SLC4 Bicarbonate Transporters* , 2007, Journal of Biological Chemistry.

[4]  C. Kieda,et al.  Suppression of hypoxia-induced HIF-1α and of angiogenesis in endothelial cells by myo-inositol trispyrophosphate-treated erythrocytes , 2006, Proceedings of the National Academy of Sciences.

[5]  J. Lehn,et al.  Inositol tripyrophosphate: a new membrane permeant allosteric effector of haemoglobin. , 2005, Bioorganic & medicinal chemistry letters.

[6]  H. Fasold,et al.  A study of the relationship between inhibition of anion exchange and binding to the red blood cell membrane of 4,4′-diisothiocyano stilbene-2,2′-disulfonic acid (DIDS) and its dihydro derivative (H2DIDS) , 1976, The Journal of Membrane Biology.

[7]  B. Deuticke Monocarboxylate transport in erythrocytes , 2005, The Journal of Membrane Biology.

[8]  P. Gane,et al.  AQP3 Deficiency in Humans and the Molecular Basis of a Novel Blood Group System, GIL* , 2002, The Journal of Biological Chemistry.

[9]  J. Foskett,et al.  Identification of the Erythrocyte Rh Blood Group Glycoprotein as a Mammalian Ammonium Transporter* , 2002, The Journal of Biological Chemistry.

[10]  M. Tanner Band 3 anion exchanger and its involvement in erythrocyte and kidney disorders , 2002, Current opinion in hematology.

[11]  J. Kaplan,et al.  Biochemistry of Na,K-ATPase. , 2002, Annual review of biochemistry.

[12]  M. Tanner,et al.  Human BTR1, a new bicarbonate transporter superfamily member and human AE4 from kidney. , 2001, Biochemical and biophysical research communications.

[13]  P. Bray-Ward,et al.  Cloning, Characterization, and Chromosomal Mapping of a Human Electroneutral Na+-driven Cl-HCO3Exchanger* , 2001, The Journal of Biological Chemistry.

[14]  B. André,et al.  The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast , 2000, Nature Genetics.

[15]  J. A. Payne,et al.  Molecular Cloning and Functional Expression of the K-Cl Cotransporter from Rabbit, Rat, and Human , 1996, The Journal of Biological Chemistry.

[16]  D. Abraham,et al.  Intrinsic activity at the molecular level: E. J. Ariëns' concept visualized. , 1995, Journal of molecular biology.

[17]  P. Ripoche,et al.  Cloning and functional expression of a urea transporter from human bone marrow cells. , 1994, The Journal of biological chemistry.

[18]  P. Fey,et al.  Molecular cloning, expression, and chromosomal localization of two isoforms of the AE3 anion exchanger from human heart. , 1994, Circulation research.

[19]  M. Jennings,et al.  Anion-proton cotransport through the human red blood cell band 3 protein. Role of glutamate 681. , 1992, The Journal of biological chemistry.

[20]  Peter Agre,et al.  Appearance of Water Channels in Xenopus Oocytes Expressing Red Cell CHIP28 Protein , 1992, Science.

[21]  H. Gehrig,et al.  Complete nucleotide sequence of band 3 related anion transport protein AE2 from human kidney. , 1992, Biochimica et biophysica acta.

[22]  K. Wang,et al.  Protein kinase C phosphorylates the carboxyl terminus of the plasma membrane Ca(2+)-ATPase from human erythrocytes. , 1991, The Journal of biological chemistry.

[23]  A. Halestrap,et al.  Reversible and irreversible inhibition, by stilbenedisulphonates, of lactate transport into rat erythrocytes. Identification of some new high-affinity inhibitors. , 1991, The Biochemical journal.

[24]  T. Vorherr,et al.  Peptide sequence analysis and molecular cloning reveal two calcium pump isoforms in the human erythrocyte membrane. , 1990, The Journal of biological chemistry.

[25]  H. Lodish,et al.  Cloning and characterization of band 3, the human erythrocyte anion-exchange protein (AE1). , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Janas,et al.  Kinetics of reversible DIDS inhibition of chloride self exchange in human erythrocytes. , 1989, The American journal of physiology.

[27]  H. Lodish,et al.  Sequence and structure of a human glucose transporter. , 1985, Science.

[28]  C. Nicolau,et al.  Physiological effects of high-P50 erythrocyte transfusion on piglets. , 1985, Journal of applied physiology.

[29]  M. Ramjeesingh,et al.  The red cell band 3 protein: its role in anion transport. , 1982, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[30]  R. Kaul,et al.  The aldolase-binding site of the human erythrocyte membrane is at the NH2 terminus of band 3. , 1981, The Journal of biological chemistry.

[31]  M. Kasai,et al.  Inhibition of anion permeability of sarcoplasmic reticulum vesicles by stilbene derivatives and the identification of an inhibitor-binding protein. , 1981, Biochimica et biophysica acta.

[32]  D. Branton,et al.  Reassociation of ankyrin with band 3 in erythrocyte membranes and in lipid vesicles. , 1980, The Journal of biological chemistry.

[33]  H. Kliman,et al.  Association of glyceraldehyde-3-phosphate dehydrogenase with the human red cell membrane. A kinetic analysis. , 1980, The Journal of biological chemistry.

[34]  V. Bennett,et al.  Association between ankyrin and the cytoplasmic domain of band 3 isolated from the human erythrocyte membrane. , 1980, The Journal of biological chemistry.

[35]  K. Uyeda,et al.  The interaction of phosphofructokinase with erythrocyte membranes. , 1979, The Journal of biological chemistry.

[36]  J. Yu,et al.  Syndeins: the spectrin-binding protein(s) of the human erythrocyte membrane. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[37]  R. Reithmeier Fragmentation of the band 3 polypeptide from human erythrocyte membranes. Size and detergent binding of the membrane-associated domain. , 1979, The Journal of biological chemistry.

[38]  D. Branton,et al.  Identification by peptide analysis of the spectrin-binding protein in human erythrocytes. , 1979, The Journal of biological chemistry.

[39]  W. Breuer,et al.  N-(4-azido-2-nitrophenyl)-2-aminoethylsulfonate (NAP-taurine) as a photoaffinity probe for identifying membrane components containing the modifier site of the human red blood cell anion exchange system , 1978, The Journal of general physiology.

[40]  P. Knauf,et al.  The anion transport system of the red blood cell. The role of membrane protein evaluated by the use of 'probes'. , 1978, Biochimica et biophysica acta.

[41]  T. Steck The band 3 protein of the human red cell membrane: a review. , 1978, Journal of supramolecular structure.

[42]  J. Yguerabide,et al.  Classification and localization of hemoglobin binding sites on the red blood cell membrane. , 1977, Biochemistry.

[43]  J. Yguerabide,et al.  Interaction of hemoglobin with red blood cell membranes as shown by a fluorescent chromophore. , 1977, Biochemistry.

[44]  T. Steck,et al.  Interaction of the aldolase and the membrane of human erythrocytes. , 1977, Biochemistry.

[45]  R. Edalji,et al.  Binding of inostiol hexaphosphate to deoxyhemoglobin. , 1976, The Journal of biological chemistry.

[46]  T. Steck,et al.  Isolation and characterization of band 3, the predominant polypeptide of the human erythrocyte membrane. , 1975, The Journal of biological chemistry.

[47]  M. Perutz,et al.  Structure of inositol hexaphosphate–human deoxyhaemoglobin complex , 1974, Nature.

[48]  R. Benesch,et al.  The mechanism of interaction of red cell organic phosphates with hemoglobin. , 1974, Advances in protein chemistry.

[49]  T. Steck,et al.  Specificity in the association of glyceraldehyde 3-phosphate dehydrogenase with isolated human erythrocyte membranes. , 1973, The Journal of biological chemistry.

[50]  W. Gratzer,et al.  Cofactor binding and oxygen equilibria in haemoglobin. , 1971, Nature: New biology.

[51]  M. Perutz,et al.  Three-dimensional Fourier Synthesis of Horse Oxyhaemoglobin at 2.8 Å Resolution: The Atomic Model , 1968, Nature.

[52]  R. Benesch,et al.  Reciprocal binding of oxygen and diphosphoglycerate by human hemoglobin. , 1968, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. Benesch,et al.  The effect of organic phosphates from the human erythrocyte on the allosteric properties of hemoglobin. , 1967, Biochemical and biophysical research communications.

[54]  J. Dodge,et al.  The preparation and chemical characteristics of hemoglobin-free ghosts of human erythrocytes. , 1963, Archives of biochemistry and biophysics.