2,3-Bisphosphoglyceric acid (

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid gives a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as it loses a hydrogen ion in the reve ...

2,3-bisphosphoglycerate) (2,3-BPG), also known as 2,3-diphosphoglyceric acid (conjugate base 2,3-diphosphoglycerate) (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG). -2,3-BPG is present in human red blood cells (RBC;

erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...

) at approximately 5 mmol/L. It binds with greater affinity to deoxygenated

hemoglobin Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...

(e.g., when the red blood cell is near respiring tissue) than it does to oxygenated hemoglobin (e.g., in the lungs) due to conformational differences: 2,3-BPG (with an estimated size of about 9 Å) fits in the deoxygenated hemoglobin conformation (with an 11-Angstrom pocket), but not as well in the oxygenated conformation (5 Angstroms). It interacts with deoxygenated hemoglobin beta subunits and decreases the affinity for oxygen and allosterically promotes the release of the remaining oxygen molecules bound to the hemoglobin. Therefore, it enhances the ability of RBCs to release oxygen near tissues that need it most. 2,3-BPG is thus an

allosteric effector In biology, an effector is a general term that can refer to several types of molecules or cells. In the context of biological system regulation, an effector is an element of a regulation loop controlling a regulated quantity. Small molecule e ...

. Its function was discovered in 1967 by Reinhold Benesch and Ruth Benesch.

Metabolism

2,3-BPG is formed from 1,3-BPG by the enzyme BPG mutase. It can then be broken down by 2,3-BPG phosphatase to form 3-phosphoglycerate. Its synthesis and breakdown are, therefore, a way around a step of

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

, with the net expense of one ATP per molecule of 2,3-BPG generated as the high-energy carboxylic acid-phosphate mixed anhydride bond is cleaved by 2,3-BPG phosphatase. : The normal glycolytic pathway generates 1,3-BPG, which may be dephosphorylated by phosphoglycerate kinase (PGK), generating ATP, or it may be shunted into the Luebering-Rapoport pathway, where bisphosphoglycerate mutase catalyzes the transfer of a phosphoryl group from C1 to C2 of 1,3-BPG, giving 2,3-BPG. 2,3-BPG, the most concentrated organophosphate in the erythrocyte, forms 3-PG by the action of bisphosphoglycerate phosphatase. The concentration of 2,3-BPG varies proportionately to the + There is a delicate balance between the need to generate ATP to support energy requirements for cell metabolism and the need to maintain appropriate oxygenation/deoxygenation status of hemoglobin. This balance is maintained by isomerisation of 1,3-BPG to 2,3-BPG, which enhances the deoxygenation of hemoglobin.

Structural binding to hemoglobin

When 2,3-BPG binds to deoxyhemoglobin, it acts to stabilize the low oxygen affinity state (T state) of the oxygen carrier. It fits neatly into the cavity of the deoxy- conformation, exploiting the

molecular symmetry In chemistry, molecular symmetry describes the symmetry present in molecules and the classification of these molecules according to their symmetry. Molecular symmetry is a fundamental concept in chemistry, as it can be used to predict or explai ...

and positive polarity by forming salt bridges with

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

and

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

residues in the β subunits of

. The R state, with oxygen bound to a heme group, has a different conformation and does not allow this interaction. By itself, hemoglobin has sigmoid-like kinetics. In selectively binding to deoxyhemoglobin, 2,3-BPG stabilizes the T state conformation, making it harder for oxygen to bind hemoglobin and more likely to be released to adjacent tissues.

Physiological effects

An increase in 2,3-BPG essentially facilitates the delivery of oxygen from hemoglobin in target tissues, at a cost of also making it somewhat more difficult for hemoglobin to take up oxygen in the lungs. This mechanisms makes maternal-fetal oxygenation more efficient, as fetal 2,3-BPG is lower than maternal levels, resulting in a higher uptake of oxygen by the fetal blood in the placenta. 2,3-BPG may also serve to physiologically counteract certain metabolic disturbances to the oxygen-hemoglobin dissociation curve. For example, at

high altitude Altitude is a distance measurement, usually in the vertical or "up" direction, between a reference datum and a point or object. The exact definition and reference datum varies according to the context (e.g., aviation, geometry, geographical s ...

s, low atmospheric oxygen content of oxygen can cause

hyperventilation Hyperventilation is irregular breathing that occurs when the rate or tidal volume of breathing eliminates more carbon dioxide than the body can produce. This leads to hypocapnia, a reduced concentration of carbon dioxide dissolved in the blo ...

and resultant

metabolic alkalosis Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate (), or alternatively a dire ...

which causes an abnormal left-shift of the oxygen-hemoglobin dissociation curve, and this can be counteracted by an increase in 2,3-BPG. Traditional teaching has claimed that the physiologic increased 2,3-BPG seen at high altitudes is simply to make it easier for oxygen to be delivered in target tissues, but this mechanism by itself is refuted by the reasoning that the decreased oxygen affinity would also inhibit oxygen uptake in the lungs, and arguably result in a net decrease in total oxygen delivery to target tissues.

Maternal-fetal oxygenation

In pregnant women, there is a 30% increase in intracellular 2,3-BPG. This lowers the maternal hemoglobin affinity for oxygen, and therefore allows more oxygen to be offloaded to the fetus in the maternal uterine arteries. The fetus has a low sensitivity to 2,3-BPG, so its hemoglobin has a higher affinity for oxygen. Therefore, although the pO2 in the uterine arteries is low, the fetal

umbilical artery The umbilical artery is a paired artery (with one for each half of the body) that is found in the abdominal and pelvic regions. In the fetus, it extends into the umbilical cord. Structure Development The umbilical arteries supply systemic arter ...

(which carries deoxygenated blood) can still get oxygenated from them. The increased maternal 2,3-BPG also causes a decreased affinity for oxygen takeup in the lungs, but this is usually compensated by a physiologic increased respiratory rate in pregnancy. Fetal hemoglobin (HbF), on the other hand, exhibits a low affinity for 2,3-BPG, resulting in a higher binding affinity for oxygen. This increased oxygen-binding affinity relative to that of adult hemoglobin (HbA) is due to HbF's having two α/γ dimers as opposed to the two α/β dimers of HbA. The positive

residues of HbA β-subunits that are essential for forming the 2,3-BPG binding pocket are replaced by

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

residues in HbF γ-subunits. Like that, histidine nº143 gets lost, so 2,3-BPG has difficulties in linking to the fetal hemoglobin, and it looks like the pure hemoglobin. Increased binding affinity of fetal hemoglobin relative to HbA facilitates the passage of oxygen across the placental membrane from the mother to the fetus. Differences between myoglobin (Mb), fetal hemoglobin (Hb F), adult hemoglobin (Hb A)

Diseases related to 2,3-BPG

Hyperthyroidism A 2004 study checked the effects of thyroid hormone on 2,3-BPG levels. The result was that the hyperthyroidism modulates in vivo 2,3-BPG content in erythrocytes by changes in the expression of phosphoglycerate mutase (PGM) and 2,3-BPG synthase. This result shows that the increase in the 2,3-BPG content of erythrocytes observed in hyperthyroidism doesn’t depend on any variation in the rate of circulating hemoglobin, but seems to be a direct consequence of the stimulating effect of thyroid hormones on erythrocyte glycolytic activity. Chronic anemia Red cells increase their intracellular 2,3-BPG concentration as much as five times within one to two hours in patients with chronic anemia, when the oxygen carrying capacity of the blood is diminished. This results in a rightward shift of the oxygen dissociation curve and more oxygen being released to the tissues. Chronic respiratory disease with hypoxia Recently, scientists have found similarities between low amounts of 2,3-BPG with the occurrence of

high altitude pulmonary edema High-altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic pulmonary edema that occurs in otherwise healthy people at altitudes typically above . HAPE is a severe presentation of altitude sickness. Cases have also been re ...

at high altitudes.

Hemodialysis

In a 1998 study, erythrocyte 2,3-BPG concentration was analyzed during the

hemodialysis Hemodialysis, American and British English spelling differences#ae and oe, also spelled haemodialysis, or simply ''"'dialysis'"'', is a process of filtering the blood of a person whose kidneys are not working normally. This type of Kidney dialys ...

process. The 2,3-BPG concentration was expressed relative to the hemoglobin tetramer (Hb4) concentration as the 2,3-BPG/Hb4 ratio. Physiologically, an increase in 2,3-BPG levels would be expected to counteract the hypoxia that is frequently observed in this process. Nevertheless, the results show a 2,3-BPG/Hb4 ratio decreased. This is due to the procedure itself: mechanical stress on the erythrocytes is believed to cause the 2,3-BPG escape, which is then removed by hemodialysis. The concentrations of

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...

creatinine Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass). Biological relevance Serum creatinine (a blood measurement) is an impor ...

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

and

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

did not correlate significantly with the total change in 2,3-BPG/Hb4 ratio. However, the ratio sampled just before dialysis correlated significantly and positively with the total weekly dosage of

erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...

(main hormone in

formation) given to the patients.

References

External links

A live model of the effect of changing 2,3 BPG on the oxyhaemoglobin saturation curve
{{DEFAULTSORT:Bisphosphoglyceric acid, 2,3- Organophosphates Respiratory physiology