PGAM2
| PGAM2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Идентификаторы | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Псевдонимы | PGAM2 , GSD10, PGAM-M, PGAMM, фосфоглицератная мутаза 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Внешние идентификаторы | Омим : 612931 ; MGI : 1933118 ; Гомологен : 56228 ; GeneCards : PGAM2 ; OMA : PGAM2 - ортологи | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Фосфоглицератная мутаза 2 ( PGAM2 ), также известная как мышечная фосфоглицератная мутаза ( PGAM-M ), представляет собой фосфоглицератную мутазу , которая у людей кодируется PGAM2 геном на хромосоме 7. [ 5 ] [ 6 ]
Фосфоглицератная мутаза (PGAM) катализирует обратимую реакцию 3-фосфоглицерата (3-PGA) на 2-фосфоглицерат (2-PGA) в гликолитическом пути. PGAM представляет собой димерный фермент с медленной мигрирующей мышцей (MM) , содержащий в разных тканях различные пропорции изозима , быстро мигрирующего мозга (BB) и гибридной формы (MB). Этот ген кодирует мышечную субъединицу PGAM . Мутации в этом гене вызывают дефицит мышечной фосфоглицератной мутазы, также известный как болезнь хранения гликогена X. [Предоставлено Refseq, Sep 2009]] [ 5 ]
Структура
[ редактировать ]PGAM2 is one of two genes in humans encoding a PGAM subunit, the other being PGAM1.
Gene
[edit]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.[7][8] 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.[7]
Protein
[edit]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.[9] 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.[8]
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.[9]
Mechanism
[edit]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.[9]
Function
[edit]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.[8][9][10] 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.[9]
Clinical significance
[edit]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.[9]
In a patient with intolerance for strenuous exercise and persistent pigmenturia, PGAM2 activity was found to be decreased relative to other glycolytic enzymes.[11] 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.[12] 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.[10] Meanwhile, two patients heterozygous for the G97D mutation presented with exercise intolerance and muscle cramps.[12]
Interactions
[edit]PGAM2 is known to interact with:
Interactive pathway map
[edit]Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
See also
[edit]References
[edit]- ^ Jump up to: a b c GRCh38: Ensembl release 89: ENSG00000164708 – Ensembl, May 2017
- ^ Jump up to: a b c GRCm38: Ensembl release 89: ENSMUSG00000020475 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Jump up to: a b "Entrez Gene: PGAM2, phosphoglycerate mutase 2 (muscle)".
- ^ "UniProtKB: P15259".
- ^ Jump up to: a b Castella-Escola J, Ojcius DM, LeBoulch P, Joulin V, Blouquit Y, Garel MC, Valentin C, Rosa R, Climent-Romeo F, Cohen-Solal M (July 1990). "Isolation and characterization of the gene encoding the muscle-specific isozyme of human phosphoglycerate mutase". Gene. 91 (2): 225–32. doi:10.1016/0378-1119(90)90092-6. PMID 2145198.
- ^ Jump up to: a b c Tsujino S, Sakoda S, Mizuno R, Kobayashi T, Suzuki T, Kishimoto S, Shanske S, DiMauro S, Schon EA (September 1989). "Structure of the gene encoding the muscle-specific subunit of human phosphoglycerate mutase". The Journal of Biological Chemistry. 264 (26): 15334–7. doi:10.1016/S0021-9258(19)84831-7. PMID 2549058.
- ^ Jump up to: а беременный в дюймовый и фон глин Xu Y, Li F, Lv L, Li T, Zhou X, Deng CX, Guan KL, Lei QY, Xiong Y (июль 2014 г.). «Окислительный стресс активирует SIRT2 до деацетилата и стимулирует фосфоглицератную мутазу» . РАНКА . 74 (13): 3630–42. doi : 10.1158/0008-5472.can-13-3615 . PMC 4303242 . PMID 24786789 .
- ^ Jump up to: а беременный Цудзино С., Шанске С., Сакода С., Феничель Г., Димауро С. (март 1993 г.). «Молекулярная генетическая основа мышечной фосфоглицератной мутазы (PGAM)» . Американский журнал человеческой генетики . 52 (3): 472–7. PMC 1682163 . PMID 8447317 .
- ^ Димауро С., Миранда А.Ф., Хан С., Гитлин К., Фридман Р. (июнь 1981 г.). «Дефицит мускул -фосфоглицерат человека: недавно обнаруженная метаболическая миопатия». Наука . 212 (4500): 1277–9. Bibcode : 1981sci ... 212.1277d . doi : 10.1126/science.6262916 . PMID 6262916 .
- ^ Jump up to: а беременный Hadjigeorgiou GM, Kawashima N, Bruno C, Andreu AL, Sue CM, Rigden DJ, Kawashima A, Shanske S, Dimauro S (октябрь 1999 г.). «Проявляющие гетерозиготы в японском семействе с новой мутацией в мышечной специфической фосфоглицератной мутазе (PGAM-M)». Нервно -мышечные расстройства . 9 (6–7): 399–402. doi : 10.1016/s0960-8966 (99) 00039-5 . PMID 10545043 . S2CID 33450920 .
Эта статья включает в себя текст из Национальной медицины Соединенных Штатов ( [1] ), которая находится в общественном доступе .