View source for PGAM2

{{Infobox gene}}
'''Phosphoglycerate mutase 2''' ('''PGAM2'''), also known as '''muscle-specific phosphoglycerate mutase''' ('''PGAM-M'''), is a [[phosphoglycerate mutase]] that, in humans, is encoded by the ''PGAM2'' [[gene]] on chromosome 7.<ref name="entrez">{{cite web | title = Entrez Gene: PGAM2, phosphoglycerate mutase 2 (muscle)| url = https://www.ncbi.nlm.nih.gov/gene/5224| accessdate = }}</ref><ref name="uniprot">{{cite web | title = UniProtKB: P15259| url = http://www.uniprot.org/uniprot/P15259| accessdate = }}</ref>

[[Phosphoglycerate mutase]] (PGAM) [[catalyze]]s the reversible reaction of [[3-phosphoglycerate]] (3-PGA) to [[2-phosphoglycerate]] (2-PGA) in the [[glycolytic]] pathway. The PGAM is a [[protein dimer|dimeric]] [[enzyme]] containing, in different tissues, different proportions of a slow-migrating muscle (MM) [[isozyme]], a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM [[protein subunit|subunit]]. Mutations in this gene cause muscle phosphoglycerate mutase deficiency, also known as [[glycogen storage disease]] X.[provided by RefSeq, Sep 2009]<ref name="entrez"/>

==Structure==
''PGAM2'' is one of two genes in humans encoding a PGAM subunit, the other being ''[[PGAM1]]''.

===Gene===
The ''PGAM2'' gene is composed of three [[exon]]s of lengths spanning 454, 180, and 202 [[basepair|bp]], separated by two [[intron]]s of 103 bp and 5.6 [[kilobase|kb]]. Located 29 bp upstream of the [[transcription start site]] is a [[TATA box]]-like element, and 40 bp upstream of this element is an inverted CCAAT box element (ATTGG). Despite its muscle-specific expression, no muscle-specific [[consensus sequence]]s were identified in the [[5']]-[[untranslated region]] of human ''PGAM2'', though one consensus sequence has been proposed in rat and chicken.<ref name=pmid2145198>{{cite journal | vauthors = Castella-Escola J, Ojcius DM, LeBoulch P, Joulin V, Blouquit Y, Garel MC, Valentin C, Rosa R, Climent-Romeo F, Cohen-Solal M | title = Isolation and characterization of the gene encoding the muscle-specific isozyme of human phosphoglycerate mutase | journal = Gene | volume = 91 | issue = 2 | pages = 225–32 | date = July 1990 | pmid = 2145198 | doi = 10.1016/0378-1119(90)90092-6 }}</ref><ref name=pmid2549058>{{cite journal | vauthors = Tsujino S, Sakoda S, Mizuno R, Kobayashi T, Suzuki T, Kishimoto S, Shanske S, DiMauro S, Schon EA | title = Structure of the gene encoding the muscle-specific subunit of human phosphoglycerate mutase | journal = The Journal of Biological Chemistry | volume = 264 | issue = 26 | pages = 15334–7 | date = September 1989 | pmid = 2549058 }}</ref> Unlike ''PGAM1'', which is present as several copies in the human genome, only one copy of ''PGAM2'' is found in the genome, indicating that this gene arose from gene duplication of and subsequent modifications in the ''PGAM1'' gene.<ref name=pmid2145198/>

===Protein===
The isozyme encoded by ''PGAM2'' spans 253 [[amino acid|residues]], which demonstrates highly sequence similarity (81% identity) to the protein PGAM1. Both form either homo- or [[heterodimer]]s.<ref name=pmid24786789>{{cite journal | vauthors = Xu Y, Li F, Lv L, Li T, Zhou X, Deng CX, Guan KL, Lei QY, Xiong Y | title = Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase | journal = Cancer Research | volume = 74 | issue = 13 | pages = 3630–42 | date = July 2014 | pmid = 24786789 | pmc = 4303242 | doi = 10.1158/0008-5472.CAN-13-3615 }}</ref> The MM homodimer is found primarily in adult muscle, while the MB heterodimer, composed of a subunit from each isozyme, is found in the heart.<ref name=pmid2549058/>

One key residue in the [[active site]] of PGAM2, lysine 100 (K100), is highly conserved across bacteria, to yeast, plant, and mammals, indicating its evolutionary importance. K100 directly contacts the substrate (3-PGA) and intermediate (2,3-PGA); however, the [[acetylation]] of this residue under normal cellular conditions neutralizes its positive charge and interferes with this binding.<ref name=pmid24786789/>

==Mechanism==
PGAM2 catalyzes the 3-PG-to-2-PG [[isomerization]] via a 2-step process: 
# a [[phosphate]] group from the phospho[[histidine]] in the active site is transferred to the C-2 carbon of 3-PGA to form 2,3-bisphosglycerate (2,3-PGA), and then 
# the phosphate group linked to the C-3 carbon of 2,3-PG is transferred to the catalytic histidine to form 2-PGA and regenerate the phosphohistidine.<ref name=pmid24786789/>

== Function ==
PGAM2 is one of two PGAM subunits found in humans and is predominantly expressed in adult [[muscle]]. Both isozymes of PGAM are glycolytic enzymes that catalyze the reversible conversion of 3-PGA to 2-PGA using [[2,3-bisphosphoglycerate]] as a [[Cofactor (biochemistry)|cofactor]].<ref name=pmid2549058/><ref name=pmid24786789/><ref name=pmid8447317>{{cite journal | vauthors = Tsujino S, Shanske S, Sakoda S, Fenichel G, DiMauro S | title = The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency | journal = American Journal of Human Genetics | volume = 52 | issue = 3 | pages = 472–7 | date = March 1993 | pmid = 8447317 | pmc = 1682163 }}</ref> Since both 3-PGA and 2-PGA are [[allosteric]] regulators of the [[pentose phosphate pathway]] (PPP) and glycine and serine synthesis pathways, respectively, PGAM2 may contribute to the [[biosynthesis]] of amino acids, 5-carbon sugar, and nucleotides precursors.<ref name=pmid24786789/>

==Clinical significance==
PGAM activity is upregulated in [[cancer]]s, including [[lung cancer]], [[colon cancer]], [[liver cancer]], [[breast cancer]], and [[leukemia]]. One possible mechanism involves the deacetylation of residue K100 in the PGAM [[active site]] by sirtuin 2 ([[SIRT2]]) under conditions of [[oxidative stress]]. This deacetylation activates PGAM activity, resulting in increased NADPH production and cell proliferation, and thus [[tumor]] growth.<ref name=pmid24786789/>

In a patient with intolerance for strenuous exercise and persistent pigmenturia, PGAM2 activity was found to be decreased relative to other glycolytic enzymes.<ref name=pmid6262916>{{cite journal | vauthors = DiMauro S, Miranda AF, Khan S, Gitlin K, Friedman R | title = Human muscle phosphoglycerate mutase deficiency: newly discovered metabolic myopathy | journal = Science | volume = 212 | issue = 4500 | pages = 1277–9 | date = June 1981 | pmid = 6262916 | doi = 10.1126/science.6262916 }}</ref> This PGAM2 deficiency results in a [[metabolic myopathy]] ([[glycogenosis]] type X) and has been traced to mutations in the ''PGAM2'' gene. Currently, four mutations have been identified from African-American, Caucasian, and Japanese families.<ref name=pmid10545043>{{cite journal | vauthors = Hadjigeorgiou GM, Kawashima N, Bruno C, Andreu AL, Sue CM, Rigden DJ, Kawashima A, Shanske S, DiMauro S | title = Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene | journal = Neuromuscular Disorders | volume = 9 | issue = 6-7 | pages = 399–402 | date = October 1999 | pmid = 10545043 | doi = 10.1016/s0960-8966(99)00039-5 }}</ref> One G-to-A transition mutation in codon 78 produced a truncated protein product, while mutations at codons 89 and 90 may have disrupted the active site and resulted in an inactive protein product.<ref name=pmid8447317/> Meanwhile, two patients [[heterozygous]] for the G97D mutation presented with [[exercise intolerance]] and muscle cramps.<ref name=pmid10545043/>

== Interactions ==
PGAM2 is known to [[protein-protein interaction|interact]] with:
*[[SIRT2]].<ref name=pmid24786789/>

==Interactive pathway map==
{{GlycolysisGluconeogenesis_WP534|highlight=Phosphoglycerate_mutase}}

== See also ==
*[[Phosphoglycerate mutase]]
*[[PGAM1]]

== References ==
{{reflist|33em}}

{{NLM content|url=https://www.ncbi.nlm.nih.gov/gene/5224}}
{{Use dmy dates|date=April 2017}}

[[Category:Genes on human chromosome 7]]