Bisphosphoglycerate mutase
Encyclopedia
Bisphosphoglycerate mutase (BPGM) is an enzyme unique to erythrocytes and placental cells. It is responsible for the catalytic synthesis of 2,3-Bisphosphoglycerate
(2,3-BPG) from 1,3-bisphosphoglycerate
. BPGM also has a mutase
and a phosphatase
function, but these are much less active, in contrast to its glycolitic cousin, phosphoglycerate mutase
(PGM), which favors these two functions, but can also catalyze the synthesis
of 2,3-BPG to a lesser extent.
, converting 1,3-BPG to 2,3-BPG would be very inefficient, as it just adds another unnecessary step. Since the main role of 2,3-BPG is to shift the equilibrium of hemoglobin
toward the deoxy-state, its production is really only useful in the cells which contain hemoglobin- erythrocytes and placental cells.
. BPGM then takes this and converts it to 2,3-BPG, which serves an important function in oxygen
transport. 2,3-BPG binds with high affinity to Hemoglobin, causing a conformational change that results in the release of oxygen. Local tissues can then pick up the free oxygen. This is also important in the placenta, where fetal and maternal blood come within such close proximity. With the placenta producing 2,3-BPG, a large amount of oxygen is released from nearby maternal hemoglobin, which can then dissociate and bind with fetal hemoglobin, which has a much lower affinity for 2,3-BPG.
, which causes a conformational change
, in which the cleft around the active site closes in on the substrate
, securely locking it in place. 1,3-BPG forms a large number of hydrogen bonds to the surrounding residues, many which are positively charged, severely restricting its mobility. Its rigidity suggests a very enthalpically driven association. Conformational changes cause His11 to rotate, partially aided by hydrogen bonding to His188. His11 is brought in–line with the phosphate group, and then goes through an SN2 mechanism in which His11 is the nucleophile
that attacks the phosphate group. The 2’ hydroxy group then attacks the phosphate and removes it from His11, thereby creating 2,3-BPG.
2,3-Bisphosphoglycerate
2,3-Bisphosphoglyceric acid is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid . 2,3-BPG is present in human red blood cells at approximately 5 mmol/L...
(2,3-BPG) from 1,3-bisphosphoglycerate
1,3-Bisphosphoglycerate
1,3-Bisphosphoglyceric acid is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycle during photosynthesis...
. BPGM also has a mutase
Mutase
A mutase is an enzyme that catalyzes the shifting of a functional group from one position to another within the same molecule. Examples of this are bisphosphoglycerate mutase, which appears in red blood cells and phosphoglycerate mutase, which acts in glycolysis. In glycolysis, it changes...
and a phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
function, but these are much less active, in contrast to its glycolitic cousin, phosphoglycerate mutase
Phosphoglycerate mutase
-Overview:Phosphoglycerate mutase is an enzyme that catalyzes step 8 of glycolysis. It catalyzes the internal transfer of a phosphate group from C-3 to C-2 which results in the conversion of 3-phosphoglycerate to 2-phosphoglycerate through a 2,3-bisphosphoglycerate intermediate.This enzyme is...
(PGM), which favors these two functions, but can also catalyze the synthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of 2,3-BPG to a lesser extent.
Tissue distribution
Because the main function of bisphosphoglycerate mutase is the synthesis of 2,3-BPG, this enzyme is found only in erythrocytes and placental cells. In glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, converting 1,3-BPG to 2,3-BPG would be very inefficient, as it just adds another unnecessary step. Since the main role of 2,3-BPG is to shift the equilibrium of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
toward the deoxy-state, its production is really only useful in the cells which contain hemoglobin- erythrocytes and placental cells.
Function
1,3-BPG is formed as an intermediate in glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. BPGM then takes this and converts it to 2,3-BPG, which serves an important function in oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
transport. 2,3-BPG binds with high affinity to Hemoglobin, causing a conformational change that results in the release of oxygen. Local tissues can then pick up the free oxygen. This is also important in the placenta, where fetal and maternal blood come within such close proximity. With the placenta producing 2,3-BPG, a large amount of oxygen is released from nearby maternal hemoglobin, which can then dissociate and bind with fetal hemoglobin, which has a much lower affinity for 2,3-BPG.
Overall
BPGM is a dimer composed of two identical protein subunits, each with its own active site. Each subunit consists six β-strands, β A-F, and ten α-helices, α 1-10. Dimerization occurs along the faces of β C and α 3 of both monomers. BPGM is roughly 50% identical to its PGM counterpart, with the main active-site residues conserved in nearly all PGMs and BPGMs.Important residues
- HisHistidineHistidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
11: the nucleophile of the 1,2-BPG to 1,3-BPG reaction. Rotates back and forth with the help of His-188 to get in an in-line position in order to attack the 1’ phosphate group. - His-188: involved in overall stability of protein, as well as hydrogen bonding to substrate, as His-11, which it pulls into its catalytic position.
- ArgArginineArginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
90: although not involved directly in binding, this positively charged residue is essential to overall stability of the protein. Can be substituted with LysineLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
with little effect on catalysis. - CysCystineCystine is a dimeric amino acid formed by the oxidation of two cysteine residues that covalently link to make a disulfide bond. This organosulfur compound has the formula 2. It is a white solid, and melts at 247-249 °C...
23: has little effect on overall structure, but large effect on reactivity of the enzyme.
Mechanism of catalysis
1,3-BPG binds to the active siteActive site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
, which causes a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
, in which the cleft around the active site closes in on the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
, securely locking it in place. 1,3-BPG forms a large number of hydrogen bonds to the surrounding residues, many which are positively charged, severely restricting its mobility. Its rigidity suggests a very enthalpically driven association. Conformational changes cause His11 to rotate, partially aided by hydrogen bonding to His188. His11 is brought in–line with the phosphate group, and then goes through an SN2 mechanism in which His11 is the nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
that attacks the phosphate group. The 2’ hydroxy group then attacks the phosphate and removes it from His11, thereby creating 2,3-BPG.