Biology:PGAM2
 Generic protein structure example |
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.[1][2]
Phosphoglycerate mutase (PGAM) catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. The PGAM is a 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 subunit. Mutations in this gene cause muscle phosphoglycerate mutase deficiency, also known as glycogen storage disease X.[provided by RefSeq, Sep 2009][1]
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 exons of lengths spanning 454, 180, and 202 bp, separated by two introns of 103 bp and 5.6 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 sequences were identified in the 5'-untranslated region of human PGAM2, though one consensus sequence has been proposed in rat and chicken.[3][4] 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.[3]
Protein
The isozyme encoded by PGAM2 spans 253 residues, which demonstrates highly sequence similarity (81% identity) to the protein PGAM1. Both form either homo- or heterodimers.[5] 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.[4]
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.[5]
Mechanism
PGAM2 catalyzes the 3-PG-to-2-PG isomerization via a 2-step process:
- a phosphate group from the phosphohistidine 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.[5]
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.[4][5][6] 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.[5]
Clinical significance
PGAM activity is upregulated in cancers, 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.[5]
In a patient with intolerance for strenuous exercise and persistent pigmenturia, PGAM2 activity was found to be decreased relative to other glycolytic enzymes.[7] 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.[8] 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.[6] Meanwhile, two patients heterozygous for the G97D mutation presented with exercise intolerance and muscle cramps.[8]
Interactions
PGAM2 is known to interact with:
- SIRT2.[5]
Interactive pathway map
See also
- Phosphoglycerate mutase
- PGAM1
References
- ↑ 1.0 1.1 "Entrez Gene: PGAM2, phosphoglycerate mutase 2 (muscle)". https://www.ncbi.nlm.nih.gov/gene/5224.
- ↑ "UniProtKB: P15259". https://www.uniprot.org/uniprot/P15259.
- ↑ 3.0 3.1 "Isolation and characterization of the gene encoding the muscle-specific isozyme of human phosphoglycerate mutase". Gene 91 (2): 225–32. July 1990. doi:10.1016/0378-1119(90)90092-6. PMID 2145198.
- ↑ 4.0 4.1 4.2 "Structure of the gene encoding the muscle-specific subunit of human phosphoglycerate mutase". The Journal of Biological Chemistry 264 (26): 15334–7. September 1989. doi:10.1016/S0021-9258(19)84831-7. PMID 2549058.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Oxidative stress activates SIRT2 to deacetylate and stimulate phosphoglycerate mutase". Cancer Research 74 (13): 3630–42. July 2014. doi:10.1158/0008-5472.CAN-13-3615. PMID 24786789.
- ↑ 6.0 6.1 "The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency". American Journal of Human Genetics 52 (3): 472–7. March 1993. PMID 8447317.
- ↑ "Human muscle phosphoglycerate mutase deficiency: newly discovered metabolic myopathy". Science 212 (4500): 1277–9. June 1981. doi:10.1126/science.6262916. PMID 6262916. Bibcode: 1981Sci...212.1277D.
- ↑ 8.0 8.1 "Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene". Neuromuscular Disorders 9 (6–7): 399–402. October 1999. doi:10.1016/s0960-8966(99)00039-5. PMID 10545043.
This article incorporates text from the United States National Library of Medicine ([1]), which is in the public domain.
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