Myophosphorylase: Difference between revisions
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{{protein | {{protein | ||
| Name = phosphorylase, glycogen; muscle (McArdle syndrome, glycogen storage disease type V) | | Name = phosphorylase, glycogen; muscle (McArdle syndrome, glycogen storage disease type V) | ||
| caption = Myophosphorylase<ref name="urlRCSB Protein Data Bank - Structure Summary for 3MSC - Glycogen phosphorylase complexed with 2-nitrobenzaldehyde-4-(beta-D-glucopyranosyl)-thiosemicarbazone">{{cite web |url=http://www.rcsb.org/pdb/explore/explore.do?structureId=3MSC |title=RCSB Protein Data Bank - Structure Summary for 3MSC - Glycogen phosphorylase complexed with 2-nitrobenzaldehyde-4-(beta-D-glucopyranosyl)-thiosemicarbazone |format= |work= | | | caption = Myophosphorylase<ref name="urlRCSB Protein Data Bank - Structure Summary for 3MSC - Glycogen phosphorylase complexed with 2-nitrobenzaldehyde-4-(beta-D-glucopyranosyl)-thiosemicarbazone">{{cite web |url=http://www.rcsb.org/pdb/explore/explore.do?structureId=3MSC |title=RCSB Protein Data Bank - Structure Summary for 3MSC - Glycogen phosphorylase complexed with 2-nitrobenzaldehyde-4-(beta-D-glucopyranosyl)-thiosemicarbazone |format= |work= |access-date=}}</ref> | ||
| image = 3MSC.png | | image = 3MSC.png | ||
| width = | | width = | ||
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| Band = 12 | | Band = 12 | ||
| LocusSupplementaryData = -q13.2 | | LocusSupplementaryData = -q13.2 | ||
}} | }}'''Myophosphorylase''' or '''glycogen phosphorylase, muscle associated (PYGM)''' is the muscle [[isoform]] of the [[enzyme]] ''[[glycogen phosphorylase]]'' and is encoded by the ''PYGM'' gene. This enzyme helps break down [[glycogen]] (a form of stored [[carbohydrate]]) into [[glucose-1-phosphate]] (not [[glucose]]), so it can be used within the [[muscle cell]]. Mutations in this gene are associated with [[McArdle disease]] (myophosphorylase deficiency), a glycogen storage disease of muscle.<ref name=":1">{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/5837|title=PYGM glycogen phosphorylase, muscle associated [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|language=en|access-date=2018-08-31}}{{PD-notice}}</ref> | ||
'''Myophosphorylase''' is the muscle [[isoform]] of the [[enzyme]] ''[[glycogen phosphorylase]]''. This enzyme helps break down [[glycogen]] (a form of stored [[carbohydrate]]) into [[glucose-1-phosphate]] (not [[glucose]]), so | |||
== Structure == | |||
''PYGM'' is located on the [[Locus (genetics)|q arm]] of [[chromosome 11]] in position 13.1 and has 20 [[Exon|exons]].<ref name=":1" /> PYGM, the [[protein]] encoded by this gene, is a member of the glycogen phosphorylase family and is a [[homodimer]] that associates into a [[tetramer]] to form the enzymatically active phosphorylase A. It contains an AMP binding site at p. 76, two sites involved in association of subunits at p. 109 and p. 143, and a site believed to be involved in [[Allosteric Control|allosteric control]] at p. 156. Its structure consists of 24 [[Beta sheet|beta strands]], 43 [[Alpha helix|alpha helixes]], and 11 turns. PYGM also has the following modified residues: N-acetylserine at p. 2, [[phosphoserine]] at p. 15, 2014, 227, 430, 473, 514, 747, and 748, and N6-(pyridoxal phosphate)[[lysine]] at p. 681. There is a [[post-translational modification]] in which [[phosphorylation]] of [[Serine|Ser]]-15 converts phosphorylase B (unphosphorylated) to phosphorylase A.<ref>{{cite journal | vauthors = Carty TJ, Graves DJ | title = Regulation of glycogen phosphorylase. Role of the peptide region surrounding the phosphoserine residue in determining enzyme properties | journal = The Journal of Biological Chemistry | volume = 250 | issue = 13 | pages = 4980–5 | date = July 1975 | pmid = 1150650 }}</ref><ref name=":2">{{Cite web|url=https://www.uniprot.org/uniprot/P11217|title=PYGM - Glycogen phosphorylase, muscle form - Homo sapiens (Human) - PYGM gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-31}}{{CC-notice|cc=by4}}</ref><ref name=":0">{{cite journal | vauthors = | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158-D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref> Alternative splicing results in multiple transcript variants.<ref name=":1" /> | |||
== Function == | |||
<p>[[Phosphorylase]] is an important [[allosteric enzyme]] in [[carbohydrate metabolism]]. This gene, <i>PYGM,</i> encodes a muscle enzyme involved in [[glycogenolysis]]. PYGM has a [[Cofactor (biochemistry)|cofactor]], [[Pyridoxal phosphate|pyridoxal 5'-phosphate]], that aids this process. PYGM is located in the [[cytosol]], extracellular exosome, and the [[cytoplasm]]. Highly similar enzymes encoded by different genes are found in [[liver]] and [[brain]].<ref name=":1" /><ref name=":2" /><ref name=":0" /></p> | |||
=== Catalytic activity === | |||
<p>((1->4)-alpha-D-glucosyl)(n) + [[phosphate]] = ((1->4)-alpha-D-glucosyl)(n-1) + alpha-D-glucose 1-phosphate<ref name=":2" /><ref name=":0" /></p> | |||
==Clinical significance== | ==Clinical significance== | ||
A deficiency is associated with [[Glycogen storage disease type V]], also known as "McArdle's Syndrome". | <p>A myophosphorylase deficiency is associated with [[Glycogen storage disease type V]], also known as "McArdle's Syndrome".</p>A case study suggested that a deficiency in myophosphorylase may be linked with [[cognitive impairment]]. Besides muscle, this isoform is present in [[Astrocyte|astrocytes]], where it plays a key role in neural energy metabolism. A 55-year-old woman with [[McArdle disease]] has expressed cognitive impairment with bilateral dysfunction of [[Prefrontal cortex|prefrontal]] and [[frontal cortex]]. Further studies are needed to assess the validity of this claim.<ref name="pmid213827152">{{cite journal | vauthors = Mancuso M, Orsucci D, Volterrani D, Siciliano G | title = Cognitive impairment and McArdle disease: Is there a link? | journal = Neuromuscular Disorders | volume = 21 | issue = 5 | pages = 356–8 | date = May 2011 | pmid = 21382715 | doi = 10.1016/j.nmd.2011.02.013 }}</ref><p>Additionally, mutations in the genes for myophosphorylase along with [[deoxyguanosine kinase]] have been associated with muscle [[glycogenosis]] and mitochondrial hepatopathy. The G456A PYGM [[mutation]] and [[Duplication (chromosomal)|duplication]] in [[exon]] 6 of dGK that results in a truncated protein have been associated with phosphorylase deficiency in muscle, [[cytochrome c oxidase]] deficiency in liver, severe [[congenital hypotonia]], [[hepatomegaly]], and [[liver failure]]. This expands on the current understanding of McArdle disease and suggests that this combination of mutations could result in a complex disease with severe [[Phenotype|phenotypes]].<ref>{{cite journal | vauthors = Mancuso M, Filosto M, Tsujino S, Lamperti C, Shanske S, Coquet M, Desnuelle C, DiMauro S | title = Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes | journal = Archives of Neurology | volume = 60 | issue = 10 | pages = 1445–7 | date = October 2003 | pmid = 14568816 | doi = 10.1001/archneur.60.10.1445 }}</ref></p> | ||
A case study suggested that a deficiency in myophosphorylase may be linked with cognitive impairment. Besides muscle, this isoform is present in [[ | == Interactions == | ||
PYGM has been shown to have 64 binary [[Protein–protein interaction|protein-protein interactions]] including 21 co-complex interactions. PYGM appears to interact with [[PRKAB2]], [[WDYHV1]], [[PYGL]], [[PYGB]], 5-aminoisatin, 5-nh2_caproyl-isatin, [[PHKG1]], [[PPP1CA]], [[PPP1R3A]], DEGS1, SET, [[MAP3K3]], [[INPP5K (gene)|INPP5K]], [[PACSIN3]], [[CLASP2]], NIPSNAP2, SRP72, [[LMNA]], [[TRAPPC2]], [[DNM2]], [[IGBP1]], [[SGCG]], [[PDE4DIP]], PPP1R3B, [[ARID1B]], [[TTN (gene)|TTN]], INTS4, FAM110A, TRIM54, [[TRIM55]], [[WWP1]], [[AGTPBP1 (gene)|AGTPBP1]], [[POMP]], and CDC42BPB.<ref>{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=PYGM | title = 64 binary interactions found for search term PYGM | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-09-05 }}</ref> | |||
==References== | == References == | ||
{{Reflist}} | {{Reflist}} | ||
==External links== | == External links == | ||
* {{MeshName|Myophosphorylase}} | * {{MeshName|Myophosphorylase}} | ||
{{ | {{NLM content}} | ||
{{Glycosyltransferases}} | {{Glycosyltransferases}} | ||
{{Enzymes}} | {{Enzymes}} | ||
{{Portal bar|Molecular and Cellular Biology|border=no}} | {{Portal bar|Molecular and Cellular Biology|border=no}} | ||
{{Portal bar|Mitochondria|Gene Wiki|border=no}} | |||
[[Category:Transferases]] | [[Category:Transferases]] | ||
[[Category:EC 2.4.1]] | [[Category:EC 2.4.1]] | ||
Latest revision as of 01:21, 6 September 2018
| phosphorylase, glycogen; muscle (McArdle syndrome, glycogen storage disease type V) | |
|---|---|
| File:3MSC.png Myophosphorylase[1] | |
| Identifiers | |
| Symbol | PYGM |
| Entrez | 5837 |
| HUGO | 9726 |
| OMIM | 608455 |
| RefSeq | NM_005609 |
| UniProt | P11217 |
| Other data | |
| EC number | 2.4.1.1 |
| Locus | Chr. 11 q12-q13.2 |
Myophosphorylase or glycogen phosphorylase, muscle associated (PYGM) is the muscle isoform of the enzyme glycogen phosphorylase and is encoded by the PYGM gene. This enzyme helps break down glycogen (a form of stored carbohydrate) into glucose-1-phosphate (not glucose), so it can be used within the muscle cell. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle.[2]
Structure
PYGM is located on the q arm of chromosome 11 in position 13.1 and has 20 exons.[2] PYGM, the protein encoded by this gene, is a member of the glycogen phosphorylase family and is a homodimer that associates into a tetramer to form the enzymatically active phosphorylase A. It contains an AMP binding site at p. 76, two sites involved in association of subunits at p. 109 and p. 143, and a site believed to be involved in allosteric control at p. 156. Its structure consists of 24 beta strands, 43 alpha helixes, and 11 turns. PYGM also has the following modified residues: N-acetylserine at p. 2, phosphoserine at p. 15, 2014, 227, 430, 473, 514, 747, and 748, and N6-(pyridoxal phosphate)lysine at p. 681. There is a post-translational modification in which phosphorylation of Ser-15 converts phosphorylase B (unphosphorylated) to phosphorylase A.[3][4][5] Alternative splicing results in multiple transcript variants.[2]
Function
Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. This gene, PYGM, encodes a muscle enzyme involved in glycogenolysis. PYGM has a cofactor, pyridoxal 5'-phosphate, that aids this process. PYGM is located in the cytosol, extracellular exosome, and the cytoplasm. Highly similar enzymes encoded by different genes are found in liver and brain.[2][4][5]
Catalytic activity
((1->4)-alpha-D-glucosyl)(n) + phosphate = ((1->4)-alpha-D-glucosyl)(n-1) + alpha-D-glucose 1-phosphate[4][5]
Clinical significance
A myophosphorylase deficiency is associated with Glycogen storage disease type V, also known as "McArdle's Syndrome".
A case study suggested that a deficiency in myophosphorylase may be linked with cognitive impairment. Besides muscle, this isoform is present in astrocytes, where it plays a key role in neural energy metabolism. A 55-year-old woman with McArdle disease has expressed cognitive impairment with bilateral dysfunction of prefrontal and frontal cortex. Further studies are needed to assess the validity of this claim.[6]
Additionally, mutations in the genes for myophosphorylase along with deoxyguanosine kinase have been associated with muscle glycogenosis and mitochondrial hepatopathy. The G456A PYGM mutation and duplication in exon 6 of dGK that results in a truncated protein have been associated with phosphorylase deficiency in muscle, cytochrome c oxidase deficiency in liver, severe congenital hypotonia, hepatomegaly, and liver failure. This expands on the current understanding of McArdle disease and suggests that this combination of mutations could result in a complex disease with severe phenotypes.[7]
Interactions
PYGM has been shown to have 64 binary protein-protein interactions including 21 co-complex interactions. PYGM appears to interact with PRKAB2, WDYHV1, PYGL, PYGB, 5-aminoisatin, 5-nh2_caproyl-isatin, PHKG1, PPP1CA, PPP1R3A, DEGS1, SET, MAP3K3, INPP5K, PACSIN3, CLASP2, NIPSNAP2, SRP72, LMNA, TRAPPC2, DNM2, IGBP1, SGCG, PDE4DIP, PPP1R3B, ARID1B, TTN, INTS4, FAM110A, TRIM54, TRIM55, WWP1, AGTPBP1, POMP, and CDC42BPB.[8]
References
- ↑ "RCSB Protein Data Bank - Structure Summary for 3MSC - Glycogen phosphorylase complexed with 2-nitrobenzaldehyde-4-(beta-D-glucopyranosyl)-thiosemicarbazone".
- ↑ 2.0 2.1 2.2 2.3 "PYGM glycogen phosphorylase, muscle associated [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-08-31.
This article incorporates text from this source, which is in the public domain.
- ↑ Carty TJ, Graves DJ (July 1975). "Regulation of glycogen phosphorylase. Role of the peptide region surrounding the phosphoserine residue in determining enzyme properties". The Journal of Biological Chemistry. 250 (13): 4980–5. PMID 1150650.
- ↑ 4.0 4.1 4.2 "PYGM - Glycogen phosphorylase, muscle form - Homo sapiens (Human) - PYGM gene & protein". www.uniprot.org. Retrieved 2018-08-31.File:CC-BY-icon-80x15.png This article incorporates text available under the CC BY 4.0 license.
- ↑ 5.0 5.1 5.2 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
- ↑ Mancuso M, Orsucci D, Volterrani D, Siciliano G (May 2011). "Cognitive impairment and McArdle disease: Is there a link?". Neuromuscular Disorders. 21 (5): 356–8. doi:10.1016/j.nmd.2011.02.013. PMID 21382715.
- ↑ Mancuso M, Filosto M, Tsujino S, Lamperti C, Shanske S, Coquet M, Desnuelle C, DiMauro S (October 2003). "Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes". Archives of Neurology. 60 (10): 1445–7. doi:10.1001/archneur.60.10.1445. PMID 14568816.
- ↑ "64 binary interactions found for search term PYGM". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-09-05.
External links
- Myophosphorylase at the US National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.