View source for Bisphosphoglycerate mutase

{{Short description|Enzyme}}
{{cs1 config|name-list-style=vanc}}
{{infobox enzyme
| Name       = bisphosphoglycerate mutase
| EC_number  = 5.4.2.4
| CAS_number = 37211-69-1
| GO_code    = 0004082
| image      = 2h4z.jpg
| width      = 270
| caption    = Bisphosphoglycerate mutase homodimer, Human
}}
{{infobox protein
| Name = 2,3-bisphosphoglycerate mutase
| image = Whole_Enzyme.png
| width = 250
| caption = Crystallographic structure of dimeric human bisphosphoglycerate mutase.<ref name="Yang_2004">{{PDB|1T8P}}; {{cite journal |vauthors=Wang Y, Wei Z, Bian Q, Cheng Z, Wan M, Liu L, Gong W | title = Crystal structure of human bisphosphoglycerate mutase | journal = J. Biol. Chem. | volume = 279 | issue = 37 | pages = 39132–8 |date=September 2004 | pmid = 15258155 | doi = 10.1074/jbc.M405982200 | doi-access = free }}</ref>
| HGNCid = 1093
| Symbol = BPGM
| AltSymbols = 
| EntrezGene = 669
| OMIM = 222800
| RefSeq = NM_001724
| UniProt = P07738
| PDB = 
| ECnumber = 5.4.2.4
| Chromosome = 7
| Arm = q
| Band = 31
| LocusSupplementaryData = -q34
}}

'''Bisphosphoglycerate mutase''' ({{EnzExplorer|5.4.2.4}}, BPGM) is an enzyme expressed in [[erythrocytes]]<ref name="Rapoport1950">{{cite journal
 | last1       = Rapoport
 | first1      = Samuel Mitja
 | last2       = Luebering
 | first2      = Jane
 | title = The formation of 2,3-diphosphoglycerate in rabbit erythrocytes: The existence of a diphosphoglycerate mutase
 | journal = Journal of Biological Chemistry
 | volume = 183
 | number = 2
 | pages = 507-516
 | doi = 10.1016/S0021-9258(19)51175-9
 | year = 1950
| doi-access = free
 }}</ref> and [[placental]] cells.<ref name="Pritlove_2006">{{cite journal |vauthors=Pritlove DC, Gu M, Boyd CA, Randeva HS, Vatish M | title = Novel placental expression of 2,3-bisphosphoglycerate mutase | journal = Placenta | volume = 27 | issue = 8 | pages = 924–7 |date=August 2006 | pmid = 16246416 | doi = 10.1016/j.placenta.2005.08.010 }}</ref>  It is responsible for the catalytic synthesis of [[2,3-Bisphosphoglycerate]] (2,3-BPG) from [[1,3-bisphosphoglycerate]].  BPGM has both a [[mutase]] and a [[phosphatase]] function, but these are much less active, in contrast to its glycolytic cousin, [[phosphoglycerate mutase]] (PGM), which favors these two functions, but can also catalyze the [[Biosynthesis|synthesis]] 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.<ref name="Pritlove_2006"/>  In [[glycolysis]], converting 1,3-BPG to 2,3-BPG bypasses the ATP-generating [[phosphoglycerate kinase]] reaction, consequently, no net ATP is generated when glucose is metabolized through the [[Luebering–Rapoport pathway]].  Since the main role of 2,3-BPG is to shift the [[wikt:equilibrium|equilibrium]] of [[hemoglobin]] toward the deoxy-state, its production is really only useful in the cells which contain hemoglobin, such as erythrocytes and placental cells.

== Function ==

1,3-BPG is formed as an intermediate in [[glycolysis]].  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.<ref name="Pritlove_2006"/>

== Structure ==

=== 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.  [[protein dimerization|Dimerization]] occurs along the faces of β C and α 3 of both monomers.<ref name="Yang_2004"/>  BPGM is roughly 50% identical to its PGM counterpart, with the main active-site residues conserved in nearly all PGMs and BPGMs.<ref name="Yang_2004"/>

=== Important residues ===
* [[Histidine|His]]<sup>11</sup>:  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.<ref name="Wang_2006"/>
* His-188:  involved in overall stability of protein,<ref name="Garel_1993">{{cite journal |vauthors=Garel MC, Lemarchandel V, Calvin MC, Arous N, Craescu CT, Prehu MO, Rosa J, Rosa R | title = Amino acid residues involved in the catalytic site of human erythrocyte bisphosphoglycerate mutase. Functional consequences of substitutions of His10, His187 and Arg89 | journal = Eur. J. Biochem. | volume = 213 | issue = 1 | pages = 493–500 |date=April 1993 | pmid = 8477721 | doi = 10.1111/j.1432-1033.1993.tb17786.x| doi-access = free }}</ref> as well as hydrogen bonding to substrate, as His-11, which it pulls into its catalytic position.
* [[Arginine|Arg]]<sup>90</sup>:  although not involved directly in binding, this positively charged residue is essential to overall stability of the protein.  Can be substituted with [[Lysine]] with little effect on catalysis.<ref name="Garel_1993"/>
* [[Cystine|Cys]]<sup>23</sup>:  has little effect on overall structure, but large effect on reactivity of the enzyme.<ref name="pmid9162026">{{cite journal |vauthors=Ravel P, Craescu CT, Arous N, Rosa J, Garel MC | title = Critical role of human bisphosphoglycerate mutase Cys22 in the phosphatase activator-binding site | journal = J. Biol. Chem. | volume = 272 | issue = 22 | pages = 14045–50 |date=May 1997 | pmid = 9162026 | doi = 10.1074/jbc.272.22.14045 | doi-access =  free}}</ref>

{{Gallery
| title=
| width = 300
| height = 350
| Image:Labeled Active Site.png|2-3 Bisphosphoglycerate in the active site of Bisphosphoglycerate Mutase.  Depicted and labeled are the residues that assist in holding the substrate in place: Arg<sup>10</sup>, Arg<sup>62</sup>, Arg<sup>100</sup>, Arg<sup>116</sup>, Arg<sup>117</sup>, His<sup>11</sup>, His<sup>188</sup>, Tyr<sup>92</sup>, [[Asparagine|Asn]]<sup>190</sup>, [[Glutamate|Glu]]<sup>89</sup>.
| Image:Coordination in Active site.png|2-D depiction of all residues in active site that help hold the substrate in the proper position for mutation.<ref name="Wang_2006">{{cite journal |vauthors=Wang Y, Liu L, Wei Z, Cheng Z, Lin Y, Gong W | title = Seeing the process of histidine phosphorylation in human bisphosphoglycerate mutase | journal = J. Biol. Chem. | volume = 281 | issue = 51 | pages = 39642–8 |date=December 2006 | pmid = 17052986 | doi = 10.1074/jbc.M606421200 | doi-access = free }}</ref>
|Image:Mechanism of 1-3BPG to 2-3BPG.png|Mechanism for conversion of 1-3BPG to 2-3 BPG.<ref name="Wang_2006"/>
}}

== Mechanism of catalysis ==

1,3-BPG binds to the [[active site]], which causes a [[conformational change]], in which the cleft around the active site closes in on the [[Substrate (biochemistry)|substrate]], securely locking it in place.<ref name="Wang_2006"/>  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 His<sup>11</sup> to rotate, partially aided by [[hydrogen bonding]] to His<sup>188</sup>.  His<sup>11</sup> is brought in–line with the phosphate group, and then goes through an S<sub>N</sub>2 mechanism in which His<sup>11</sup> is the [[nucleophile]] that attacks the phosphate group.<ref name="Wang_2006"/>  The 2’ hydroxy group then attacks the phosphate and removes it from His<sup>11</sup>, thereby creating 2,3-BPG.

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal |author=Fujita T |title=Human erythrocyte bisphosphoglycerate mutase: inactivation by glycation in vivo and in vitro |journal=J Biochem |volume=124 |issue=6 |pages=1237–44 |date=1 December 1998|pmid=9832630 |doi=10.1093/oxfordjournals.jbchem.a022243|display-authors=etal}}
{{refend}}

== External links ==
* {{MeshName|Bisphosphoglycerate Mutase}}
* {{EC number|5.4.2.4}}

{{Glycolysis enzymes}}
{{Mutases}}

{{DEFAULTSORT:Bisphosphoglycerate Mutase}}
[[Category:Carbohydrate metabolism]]
[[Category:EC 5.4.2]]