Glycogen synthase: Difference between revisions
Davebridges (talk | contribs) m →Regulation: removed inactive reference |
→Regulation: found suitable targets for red links; removed WP:OVERLINK |
||
| Line 120: | Line 120: | ||
|} |
|} |
||
For enzymes in the GT3 family, these regulatory kinases inactivate glycogen synthase by phosphorylating it at the N-terminal of the 25th residue and the C-terminal of the 120th residue.<ref name="pmid15272305"/> Glycogen synthase is also regulated by protein phosphatase 1 ([[PP1]]), which activates glycogen synthase via dephosphorylation<ref name="pmid11239409">{{cite journal | author = Saltiel AR | title = New perspectives into the molecular pathogenesis and treatment of type 2 diabetes | journal = Cell | volume = 104 | issue = 4 | pages = 517–29 | year = 2001 | month = | pmid = 11239409 | doi = 10.1016/S0092-8674(01)00239-2 | url = | issn = }}</ref> |
For enzymes in the GT3 family, these regulatory kinases inactivate glycogen synthase by phosphorylating it at the N-terminal of the 25th residue and the C-terminal of the 120th residue.<ref name="pmid15272305"/> Glycogen synthase is also regulated by protein phosphatase 1 ([[protein phosphatase 1|PP1]]), which activates glycogen synthase via dephosphorylation.<ref name="pmid11239409">{{cite journal | author = Saltiel AR | title = New perspectives into the molecular pathogenesis and treatment of type 2 diabetes | journal = Cell | volume = 104 | issue = 4 | pages = 517–29 | year = 2001 | month = | pmid = 11239409 | doi = 10.1016/S0092-8674(01)00239-2 | url = | issn = }}</ref> PP1 is targetted to the glycogen pellet by four targeting subunits, [[PPP1R3A|G<sub>M</sub>]], [[PPP1R3B | G<sub>L</sub>]], [[PPP1R3C|PTG ]] and [[PPP1R3D|R6]]. These regulatory enzymes are regulated by [[insulin]] and [[glucagon]] signaling pathways. |
||
== Pathology == |
== Pathology == |
||
Revision as of 05:28, 8 December 2010
| glycogen (starch) synthase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 | |||||||||
| Identifiers | |||||||||
| EC no. | 2.4.1.11 | ||||||||
| CAS no. | 9014-56-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Glycogen synthase (UDP-glucose-glycogen glucosyltransferase') is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers.
It is a glycosyltransferase enzyme (EC 2.4.1.11) that catalyses the reaction of UDP-glucose and (1,4-α-D-glucosyl)n to yield UDP and (1,4-α-D-glucosyl)n+1.
In other words, this enzyme converts excess glucose residues one by one into a polymeric chain for storage as glycogen. Its presence in the bloodstream is highest in the 30 to 60 minutes[2] following intense exercise. It is a key enzyme in glycogenesis.
Structure
Much research has been done on glycogen degradation through studying the structure and function of glycogen phosphorylase, the key regulatory enzyme of glycogen degradation.[3] On the other hand, much less is known about the structure of glycogen synthase, the key regulatory enzyme of glycogen synthesis. The crystal structure of glycogen synthase from Agrobacterium tumefaciens, however, has been determined at 2.3 A resolution.[4] In its asymmetric form, glycogen synthase is found as a dimer, whose monomers are composed of two Rossmann-fold domains. This structural property, among others, is shared with related enzymes, such as glycogen phosphorylase and other glycosyltransferases of the GT-B superfamily.[5]
Glycogen synthase can be classified in two general protein families. The first family (GT3), which is from mammals and yeast, is approximately 80 kDa, uses UDP-glucose as a sugar donor, and is regulated by phosphorylation and ligand binding.[6] The second family (GT5), which is from bacteria and plants, is approximately 50 kDA, uses ADP-glucose as a sugar donor, and is unregulated.[7]
Mechanism
Although the catalytic mechanisms used by glycogen synthase is not well-known, it is probably similar to that of glycogen phosphorylase due to the two enzymes’ structural similarities at the catalytic and substrate binding site.[4]
Function
In a recent study of transgenic mice, an overexpression of glycogen synthase[8] and an overexpression of phosphatase[9] both resulted in excess glycogen storage levels. This suggests that glycogen synthase plays an important biological role in regulating glycogen/glucose levels and is activated by phosphorylation.
Isozymes
In humans, there are two paralogous isozymes of glycogen synthase:
| isozyme | tissue distribution | gene |
|---|---|---|
| glycogen synthase 1 | muscle and other tissues | GYS1[10] |
| glycogen synthase 2 | liver | GYS2[11] |
The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is widely expressed. Liver glycogen serves as a storage pool to maintain the blood glucose level during fasting, whereas muscle glycogen synthesis accounts for disposal of up to 90% of ingested glucose. The role of muscle glycogen is as a reserve to provide energy during bursts of activity.[12]
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Regulation
The reaction is highly regulated by allosteric effectors such as glucose-6-phosphate, by phosphorylation reactions, and indirectly triggered by the hormone insulin, which is secreted by the pancreas. Phosphorylation of glycogen synthase decreases its activity. The enzyme also cleaves the ester bond between the C1 position of glucose and the pyrophosphate of UDP itself.
The control of glycogen synthase is a key step in regulating glycogen metabolism and glucose storage. Glycogen synthase is directly regulated by glycogen synthase kinase 3 (GSK-3), AMPK and protein kinase A (PKA). Each of these protein kinases lead to phosphorylated and catalytically inactive glycogen synthase. The phosphorylation sites of glycogen synthase are summarized below.
| Name | Phosphorylation Site | Kinase | Reference(s) |
|---|---|---|---|
| Site 1a | PKA | [13],[14] | |
| Site 1b | PKA | [13],[14] | |
| Site 2 | Serine 7 | AMPK | [15],[16] |
| Site 2a | Serine 10 | CK2 | |
| Site 3a | Serine 641 | GSK3 | [17] |
| Site 3b | Serine 645 | GSK3 | [17] |
| Site 3c | Serine 649 | GSK3 | [17] |
| Site 3d | Serine 653 | GSK3 | [17] |
| Site 4 | Serine 727 |
For enzymes in the GT3 family, these regulatory kinases inactivate glycogen synthase by phosphorylating it at the N-terminal of the 25th residue and the C-terminal of the 120th residue.[4] Glycogen synthase is also regulated by protein phosphatase 1 (PP1), which activates glycogen synthase via dephosphorylation.[18] PP1 is targetted to the glycogen pellet by four targeting subunits, GM, GL, PTG and R6. These regulatory enzymes are regulated by insulin and glucagon signaling pathways.
Pathology
Mutations in the GYS2 gene are associated with glycogen storage disease type 0.[19]
In humans, defects in the tight control of glucose uptake and utilization are also associated with diabetes and hyperglycemia. Patients with type 2 diabetes normally exhibit low glycogen storage levels, and this indicates that insulin activates glycogen synthase by inhibiting its kinases.[18]
References
- ^ PDB: 1RZU; Buschazzio A, Ugalde JE, Guerin ME, Shepard W, Ugalde RA, Alzari PM (2004). "Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation". EMBO J. 23 (16): 3196–3205. doi:10.1038/sj.emboj.7600324. PMC 514502. PMID 15272305.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link); rendered using PyMOL. - ^ Jentjens R, Jeukendrup A (2003). "Determinants of post-exercise glycogen synthesis during short-term recovery". Sports Med. 33 (2): 117–44. doi:10.2165/00007256-200333020-00004. PMID 12617691.
- ^ Buchbinder JL, Rath VL, Fletterick RJ (2001). "Structural relationships among regulated and unregulated phosphorylases". Annu Rev Biophys Biomol Struct. 30: 191–209. doi:10.1146/annurev.biophys.30.1.191. PMID 11340058.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c Buschiazzo A, Ugalde JE, Guerin ME, Shepard W, Ugalde RA, Alzari PM (2004). "Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation". EMBO J. 23 (16): 3195–205. doi:10.1038/sj.emboj.7600324. PMC 514502. PMID 15272305.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Coutinho PM, Deleury E, Davies GJ, Henrissat B (2003). "An evolving hierarchical family classification for glycosyltransferases". J Mol Bio. 328 (2): 307–17. doi:10.1016/S0022-2836(03)00307-3. PMID 12691742.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Roach PJ (2002). "Glycogen and its Metabolism". Curr Mol Med. 2 (2): 101–20. doi:10.2174/1566524024605761. PMID 11949930.
- ^ Ball SG, Morell MK (2003). "From bacterial glycogen to starch: understanding the biogenesis of the plant starch granule". Annu Rev Plant Biol. 54: 207–33. doi:10.1146/annurev.arplant.54.031902.134927. PMID 14502990.
- ^ Azpiazu I, Manchester J, Skurat AV, Roach PJ, Lawrence JC Jr (2000). "Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers". Am J Physiol Endocrinol Metab. 278 (2): E234–43. PMID 10662707.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Aschenbach WG, Suzuki Y, Breeden K, Prats C, Hirshman MF, Dufresne SD, Sakamoto K, Vilardo PG, Steele M, Kim JH, Jing SL, Goodyear LJ, DePaoli-Roach AA (2001). "The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise". J Biol Chem. 276 (43): 39959–67. doi:10.1074/jbc.M105518200. PMID 11522787.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Browner MF, Nakano K, Bang AG, Fletterick RJ (1989). "Human muscle glycogen synthase cDNA sequence: a negatively charged protein with an asymmetric charge distribution". Proceedings of the National Academy of Sciences of the United States of America. 86 (5): 1443–7. doi:10.1073/pnas.86.5.1443. PMC 286712. PMID 2493642.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Westphal SA, Nuttall FQ (1992). "Comparative characterization of human and rat liver glycogen synthase". Archives of biochemistry and biophysics. 292 (2): 479–86. doi:10.1016/0003-9861(92)90019-S. PMID 1731614.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Kollberg G, Tulinius M, Gilljam T, Ostman-Smith I, Forsander G, Jotorp P, Oldfors A, Holme E (2007). "Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0". The New England journal of medicine. 357 (15): 1507–14. doi:10.1056/NEJMoa066691. PMID 17928598.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Huang TS, Krebs EG (1977). "Amino acid sequence of a phosphorylation site in skeletal muscle glycogen synthetase". Biochem. Biophys. Res. Commun. 75 (3): 643–50. PMID 405007.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ a b Proud CG, Rylatt DB, Yeaman SJ, Cohen P (1977). "Amino acid sequences at the two sites on glycogen synthetase phosphorylated by cyclic AMP-dependent protein kinase and their dephosphorylation by protein phosphatase-III". FEBS Lett. 80 (2): 435–42. PMID 196939.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rylatt DB, Cohen P (1979). "Amino acid sequence at the site on rabbit skeletal muscle glycogen synthase phosphorylated by the endogenous glycogen synthase kinase-2 activity". FEBS Lett. 98 (1): 71–5. PMID 107044.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Embi N, Parker PJ, Cohen P (1981). "A reinvestigation of the phosphorylation of rabbit skeletal-muscle glycogen synthase by cyclic-AMP-dependent protein kinase. Identification of the third site of phosphorylation as serine-7". Eur. J. Biochem. 115 (2): 405–13. PMID 6263629.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c d Rylatt DB, Aitken A, Bilham T, Condon GD, Embi N, Cohen P (1980). "Glycogen synthase from rabbit skeletal muscle. Amino acid sequence at the sites phosphorylated by glycogen synthase kinase-3, and extension of the N-terminal sequence containing the site phosphorylated by phosphorylase kinase". Eur. J. Biochem. 107 (2): 529–37. PMID 6772446.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Saltiel AR (2001). "New perspectives into the molecular pathogenesis and treatment of type 2 diabetes". Cell. 104 (4): 517–29. doi:10.1016/S0092-8674(01)00239-2. PMID 11239409.
{{cite journal}}: Cite has empty unknown parameter:|month=(help) - ^ Orho M, Bosshard NU, Buist NR, Gitzelmann R, Aynsley-Green A, Blümel P, Gannon MC, Nuttall FQ, Groop LC (1998). "Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0". The Journal of clinical investigation. 102 (3): 507–15. doi:10.1172/JCI2890. PMC 508911. PMID 9691087.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
External links
- Glycogen Synthase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Newcastle University Centre for Cancer Education (October 9, 1997). "Glycogen synthetase". Retrieved 2007-11-05.