Deoxygenated sickle hemoglobin. Modulation of its solubility by 2,3-diphosphoglycerate and other allosteric polyanions.

Poillon, William N.; ROBINSON, M. D.; Kim, B C

doi:10.1016/s0021-9258(17)38660-x

Cited by 29 publications

(9 citation statements)

References 31 publications

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“…P 50 is a measure of oxygen affinity and its increase is described by the Bohr effect (MacDonald, ). P 50 and 2,3‐DPG levels vary widely among patients with sickle cell disease (SCD), but elevated levels appear to decrease Hb S solubility (Poillon et al , , ; Poillon & Kim, ) and increase red cell sickling under hypoxia (Jensen, ; Rogers et al , ), although this has not confirmed by all investigators (Beutler et al , ; Swerdlow et al , ).…”

Section: Oxygen Affinity Of Sickle Erythrocytesmentioning

confidence: 99%

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

et al. 2016

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Summary The hallmark of sickle cell disease is the polymerization of sickle haemoglobin due to a point mutation in the β-globin gene (HBB). Under low oxygen saturation, sickle haemoglobin assumes the tense (T-state) deoxygenated conformation that can form polymers, leading to rigid erythrocytes with impaired blood vessel transit, compounded or initiated by adhesion of erythrocytes to endothelium, neutrophils and platelets. This process results in vessel occlusion and ischaemia, with consequent acute pain, chronic organ damage, morbidity and mortality. Pharmacological agents that stabilize the higher oxygen affinity relaxed state (R-state) and/or destabilize the lower oxygen affinity T-state of haemoglobin have the potential to delay the sickling of circulating red cells by slowing polymerization kinetics. Relevant classes of agents include aromatic aldehydes, thiol derivatives, isothiocyanates and acyl salicylates derivatives. The aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) increases oxygen affinity of sickle haemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials as treatment for sickle cell disease. A related molecule, GBT440, has shown R-state stabilization and increased oxygen affinity in preclinical testing. Allosteric modifiers of haemoglobin as direct anti-sickling agents target the fundamental pathophysiological mechanism of sickle cell disease.

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Section: Oxygen Affinity Of Sickle Erythrocytesmentioning

confidence: 99%

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

et al. 2016

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“…A therapeutic agent which leads to an increase in the oxygen affinity of blood may prove valuable in the treatment of the symptoms of sickle cell anemia since sickling is caused by a too high concentration of deoxyhemoglobin S (Dean & Schechter, 1978a-c). Vanadate may therefore be useful in treating this disease, especially in view of the elevated 2,3-DPG levels inside SS red cells (Poillon et al, 1985).…”

mentioning

confidence: 99%

2,3-Diphosphoglycerate phosphatase activity of phosphoglycerate mutase: stimulation by vanadate and phosphate

Stankiewicz¹,

Gresser²,

Tracey³

et al. 1987

Biochemistry

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The binding of inorganic vanadate (Vi) to rabbit muscle phosphoglycerate mutase (PGM), studied by using 51V nuclear magnetic resonance spectroscopy, shows a sigmoidal dependence on vanadate concentration with a stoichiometry of four vanadium atoms per PGM molecule at saturating [Vi]. The data are consistent with binding of one divanadate ion to each of the two subunits of PGM in a noncooperative manner with an intrinsic dissociation constant of 4 X 10(-6) M. The relevance of this result to other studies which have shown that the Vi-stimulated 2,3-diphosphoglycerate (2,3-DPG) phosphatase activity of PGM has a sigmoidal dependence on [Vi] with a Hill coefficient of 2.0 is discussed. At pH 7.0, inorganic phosphate has little effect on the 2,3-DPG phosphatase activity of PGM, even at concentrations as high as 50 mM. Similarly, 25 microM Vi has little effect on the phosphatase activity. However, in the presence of 25 microM Vi, a phosphate concentration of 20 mM increases the phosphatase activity by more than 3-fold. This behavior is rationalized in terms of activation of the phosphatase activity by a phosphate/vanadate mixed anhydride. This interpretation is supported by the observation of strong activation of the phosphatase activity by inorganic pyrophosphate. A molecular mechanism for the observed effects of vanadate is proposed, and the relevance of this study to the possible use of vanadate as a therapeutic agent for the treatment of sickle cell anemia is discussed.

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“…The activation mechanism of the phosphatase activity by 2-PG and the binding mode of 2-PG to BPGM are poorly understood (Ikura et al, 1976;Rose & Liebowitz, 1970;Reynolds, 1986;Yu et al, 1990). Pharmacologically, BPGM has long been suggested as a potential target to modulate the 2,3-BPG concentration in the cell, which has been implicated in the pathophysiology of sickle cell anemia (Poillon et al, 1985(Poillon et al, , 1995.…”

Section: Discussionmentioning

confidence: 99%

“…However, during a state of hypoxia, dissociation of oxygen from HbS exposes the mutated Val6 to a complementary hydrophobic site on the surface of an adjacent deoxygenated HbS, associating the molecules together and consequently forming polymers that convert the normal and flexible biconcave red blood cells (RBC) into rigid sickleshaped RBC (Harrington et al, 1997;Ghatge et al, 2016;Bunn & Forget, 1986;Eaton & Hofrichter, 1990). This hypoxiainduced HbS polymerization is the hallmark of SCD pathology, and the elevated 2,3-BPG in sickle RBC significantly contributes to this pathophysiology by decreasing the affinity of HbS for oxygen and increasing the concentration of deoxygenated HbS, consequently exacerbating HbS polymerization and RBC sickling (Poillon et al, 1985(Poillon et al, , 1995.…”

Section: Introductionmentioning

confidence: 99%

“…The reduction of intracellular levels of 2,3-BPG by activating BPGM phosphatase with the activator 2-PG has been investigated by Poillon and coworkers and has been shown to improve the solubility of HbS and prevent the sickling tendency of RBC (Poillon et al, 1985(Poillon et al, , 1995. A recent study reported that an SCD mouse model lacking the BPGM gene showed an improvement in the concentration of the nonpolymerizing oxygenated HbS and RBC sickling (Knee et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase

Aljahdali¹,

Musayev²,

Burgner³

et al. 2022

Acta Crystallogr D Struct Biol

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Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific multifunctional enzyme that is responsible for the regulation of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells through its synthase and phosphatase activities; the latter enzymatic function is stimulated by the endogenous activator 2-phosphoglycolate (2-PG). 2,3-BPG is a natural allosteric effector of hemoglobin (Hb) that is responsible for decreasing the affinity of Hb for oxygen to facilitate tissue oxygenation. Here, crystal structures of BPGM with 2-PG in the presence and absence of 3-phosphoglycerate are reported at 2.25 and 2.48 Å resolution, respectively. Structure analysis revealed a new binding site for 2-PG at the dimer interface for the first time, in addition to the expected active-site binding. Also, conformational non-equivalence of the two active sites was observed as one of the sites was found in an open conformation, with the residues at the active-site entrance, including Arg100, Arg116 and Arg117, and the C-terminus disordered. The kinetic result is consistent with the binding of 2-PG to an allosteric or noncatalytic site as well as the active site. This study paves the way for the rational targeting of BPGM for therapeutic purposes, especially for the treatment of sickle cell disease.

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Deoxygenated sickle hemoglobin. Modulation of its solubility by 2,3-diphosphoglycerate and other allosteric polyanions.

Cited by 29 publications

References 31 publications

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

2,3-Diphosphoglycerate phosphatase activity of phosphoglycerate mutase: stimulation by vanadate and phosphate

Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase

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