2,3-Diphosphoglycerate (2,3-DPG), found primarily in red blood cells, plays a key role in regulating hemoglobin's (Hb) affinity for oxygen. Increased 2,3-DPG levels shift the oxygen dissociation curve to the right, reducing Hb's oxygen affinity and enhancing oxygen delivery to tissues-particularly important in conditions like anemia and high-altitude adaptation. Despite its physiological significance, research on 2,3-DPG is outdated and limited. This review aims to summarize current knowledge and identify research gaps. Measuring 2,3-DPG is challenging due to its instability and the need for careful sample handling. Chromatography and enzymatic methods are commonly used. Several factors influence 2,3-DPG levels, including diet, physiological state, and disease. Dietary phosphorus, for example, can acutely affect 2,3-DPG levels, though the impact of different meal compositions remains unexplored. Age, pregnancy, and physical activity also modulate 2,3-DPG, yet little is known about its role in infants and children. While changes in 2,3-DPG levels under various pathological conditions have been described, the molecular mechanisms behind these alterations remain poorly understood and warrant further investigation.

COVID-19 hinders oxygen transport to the consuming tissues by at least two mechanisms: In the injured lung, saturation of hemoglobin is compromised, and in the tissues, an associated anemia reduces the volume of delivered oxygen. For the first problem, increased hemoglobin oxygen affinity [left shift of the oxygen dissociation curve (ODC)] is of advantage, for the second, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-bisphosphoglycerate (2,3-BPG) concentration. In three investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin (MetHb), which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. However, this “useful effect” is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19, even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional “in vivo” left shift possibly results from various factors, e.g., concentration changes of Cl − , 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interst

Erythrocyte bisphosphoglycerate mutase (BPGM) plays a major role in regulating hemoglobin (Hb) oxygen affinity by controlling levels of its allosteric effector 2,3-bisphosphoglycerate (2,3-BPG). Besides its well-documented function in glycolysis, BPGM has been proposed as a regulator of serine pathway flux via 3-phosphoglycerate and as an antimalarial target. In humans, BPGM malfunction reduces intracellular concentrations of 2,3-BPG, producing a leftward shift in the hemoglobin‑oxygen dissociation curve. This shift enhances the affinity of hemoglobin for oxygen, thereby impairing oxygen release to peripheral tissues. The resulting tissue hypoxia induces a compensatory erythropoietic response that clinically manifests as polycythemia/ erythrocytosis, characteristic of familial erythrocytosis type 8 (ECYT8). BPGM deficiency is rare, and a comprehensive study has been conducted in only a few patients with this disease, revealing different missense mutations. In the present study, we structurally characterized clinical variants of human BPGM (hBPGM), i.e., Arg62Gln, Arg90Cys, Arg90His, and Gln102Lys, in order to explore the molecular basis of this rare disease. Analysis of the four structural models and of a new citrate-bound hBPGM structure yielded a partial description of further open/closed conformational changes associated with enzyme activity.

An impressive effect of the infection with SARS-Co-19 is the impairment of oxygen uptake due to lung injury. The reduced oxygen diffusion may potentially be counteracted by an increase in oxygen affinity of hemoglobin. However, hypoxia and anemia associated with COVID-19 usually decrease oxygen affinity due to a rise in [2,3-bisphosphoglycerate]. As such, COVID-19 related changes in the oxygen dissociation curve may be critical for oxygen uptake and supply, but are hard to predict. A Pubmed search lists 14 publications on oxygen affinity in COVID-19. While some investigations show no changes, three large studies found an increased affinity that was related to a good prognosis. Exact causes remain unknown. The cause of the associated anemia in COVID-19 is under discussion. Erythrocytes with structural alterations of membrane and cytoskeleton have been observed, and virus binding to Band 3 and also to ACE2 receptors in erythroblasts has been proposed. COVID-19 presentation is moderate in many subjects suffering from sickle cell disease. A possible explanation is that COVID-19 counteracts the unfavorable large right shift of the oxygen dissociation curve in these patients. Under discussion for therapy are mainly affinity-increasing drugs.

[Hemoglobins, XXVIII. Phosphate-protein-interaction, gene expression and function: the genetic and allosteric control of the oxygen affinity of the fetal blood (author's transl)]. This work describes possible molecular mechanisms concerning the control of oxygen affinity in fetal blood of mammalia. There is a genetic control of oxygen affinity through a fetal gene: at constant phosphate concentration (Hb less than P2-glycerate) in humans there is a hemoglobin with only five binding sites to 2,3-bisphosphoglycerate, resulting in an increased oxygen affinity. In several species (sheep, cattle, goat) with Met-Leu as the N-terminal group of the beta-chains, the 2,3-bisphosphoglycerate binding sites are deleted in positions beta 1 and beta 2, so that the regulation is phosphate-independent and thus providing a fetal hemoglobin with an increased oxygen affinity. The allosteric control is observed in pigs. In the postembryonal development "adult" hemoglobin with seven contacts (beta-chains) is demonstrated. The increased oxygen affinity is achieved here by a reduced biosynthesis of 2,3-bisphosphoglycerate (Hb greater than P2-glycerate) (Rapoport-Luebering-cycle).

Interaction of hemoglobin with chloride and 2,3-bisphosphoglycerate. A comparative approach. The equilibrium oxygen-binding properties of hemoglobins from reindeer (Rangifer tarandus tarandus), musk ox (Ovibos muschatos) and a bat (Rousettus aegyptiacus) have been investigated with special reference to the effect of heterotrophic ligands such as chloride and 2,3-bisphosphoglycerate [Gri(2,3)P2]. The results obtained with hemoglobins from reindeer and musk ox indicate that their low oxygen affinity and their insensitivity to Gri(2,3)P2 are not only an intrinsic property of the molecule, as proposed in the case of ruminant hemoglobins, but also the results of the interplay between chloride and Gri(2,3)P2 interactions. In other words, insensitivity of reindeer and musk ox hemoglobins to Gri(2,3)P2 is mainly due to a decreased affinity constant for this cofactor and to an increased affinity constant for chloride anions; this renders more effective the competition of chloride for th anion-binding site.