2,3-diphosphoglycerate: The Forgotten Metabolic Regulator of Oxygen Affinity.

2,3-Diphosphoglycerate (2,3-DPG), a metabolic intermediate in the Rapoport-Luebering pathway, is primarily present in red blood cells and regulates the affinity of hemoglobin (Hb) to oxygen. As the 2,3-DPG level in the erythrocyte increases, the oxygen dissociation curve shifts to the right, thus decreasing the oxygen affinity of Hb. This alteration in oxygen affinity is crucial for maintaining adequate oxygen supply to peripheral tissues, especially under hypoxic conditions such as high-altitude adaptation and anemia. Despite its crucial role in regulating oxygen affinity and its potential function as a modulator in various physiological and pathological adaptations, much of the research on 2,3-DPG is outdated and has largely been overlooked in recent years. The aim of this review is to compile the existing evidence on 2,3-DPG and highlight the gaps in our current understanding.The erythrocyte concentration of 2,3-DPG can be determined using chromatography or enzymatic methods. However, assessing 2,3-DPG poses a challenge due to its instability, which can rapidly degrade in the absence of proper storage conditions. Several factors can impact the erythrocyte concentration of 2,3-DPG, including diet, physiological conditions, and pathological conditions. Dietary intake, particularly phosphorus, can acutely influence 2,3-DPG levels in red blood cells. However, no information is available on the postprandial status of 2,3-DPG following the ingestion of meals with varied nutrient composition. Additionally, physiological factors such as age, pregnancy, and physical activity can affect 2,3-DPG levels, but its role during infancy and childhood is still not well understood. Although the levels of 2,3-DPG in various pathological conditions have been widely discussed, the underlying molecular mechanisms regulating these changes are still not well understood and require further investigations.