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词条 Glycogen synthase
释义

  1. Structure

  2. Mechanism

  3. Function

      Isozymes  

  4. Regulation

  5. Clinical significance

     Model organisms 

  6. References

  7. External links

{{enzyme
|Name = glycogen (starch) synthase
|EC_number = 2.4.1.11
|CAS_number = 9014-56-6
|IUBMB_EC_number = 2/4/1/11
|GO_code = 0004373
|image = GlycogenSyn_Wiki.png
|width =
|caption = Crystal structure of glycogen synthase 1 from Agrobacterium tumefaciens[1]
}}

Glycogen synthase (UDP-glucose-glycogen glucosyltransferase) is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase ({{EC number|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.

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.[2] 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.[3] 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.[4] Nonetheless, a more recent characterization of the Saccharomyces cerevisiae (yeast) glycogen synthase crystal structure reveals that the dimers may actually interact to form a tetramer. Specifically, The inter-subunit interactions are mediated by the α15/16 helix pairs, forming allosteric sites between subunits in one combination of dimers and active sites between subunits in the other combination of dimers. Since the structure of eukaryotic glycogen synthase is highly conserved among species, glycogen synthase likely forms a tetramer in humans as well.[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 are not well known, structural similarities to glycogen phosphorylase at the catalytic and substrate binding site suggest that the mechanism for synthesis is similar in glycogen synthase and glycogen phosphorylase.[3]

Function

Glycogen synthase catalyzes the conversion of the glucosyl (Glc) moiety of uridine diphosphate glucose (UDP-Glc) into glucose to be incorporated into glycogen via an α(1→4) glycosidic bond. However, since glycogen synthase requires an oligosaccharide primer as a glucose acceptor, it relies on glycogenin to initiate de novo glycogen synthesis.[5]

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 dephosphorylation.

Isozymes

In humans, there are two paralogous isozymes of glycogen synthase:

isozyme tissue distribution gene
glycogen synthase 1muscle and other tissuesGYS1}}[10]
glycogen synthase 2liverGYS2}}[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]

Meanwhile, the muscle isozyme plays a major role in the cellular response to long-term adaptation to hypoxia. Notably, hypoxia only induces expression of the muscle isozyme and not the liver isozyme. However, muscle-specific glycogen synthase activation may lead to excessive accumulation of glycogen, leading to damage in the heart and central nervous system following ischemic insults.[13]

{{infobox proteinName=glycogen synthase 1 (muscle)caption=image=width=HGNCid=4706Symbol=GYS1AltSymbols=EntrezGene=2997OMIM=138570RefSeq=NM_002103UniProt=P13807PDB=ECnumber=2.4.1.11Chromosome=19Arm=qBand=13.3LocusSupplementaryData=
}}		{{infobox proteinName=glycogen synthase 2 (liver)caption=image=width=HGNCid=4707Symbol=GYS2AltSymbols=EntrezGene=2998OMIM=138571RefSeq=NM_021957UniProt=P54840PDB=ECnumber=2.4.1.11Chromosome=12Arm=pBand=12.2LocusSupplementaryData=-11.2
}}

Regulation

The reaction is highly regulated by allosteric effectors such as glucose-6-phosphate (activator) and by phosphorylation reactions (deactivating). Glucose-6-phosphate allosteric activating action allows glycogen synthase to operate as a glucose-6-phosphate sensor. The inactivating phosphorylation is triggered by the hormone glucagon, which is secreted by the pancreas in response to decreased blood glucose levels. 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, protein kinase A (PKA), and casein kinase 2 (CK2). 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 ,[14][15]
Site 1b PKA ,[14][15]
Site 2 Serine 7 AMPK ,[16][17]
Site 2a Serine 10 CK2
Site 3a Serine 641 GSK3 [18]
Site 3b Serine 645 GSK3 [18]
Site 3c Serine 649 GSK3 [18]
Site 3d Serine 653 GSK3 [18]
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.[3] Glycogen synthase is also regulated by protein phosphatase 1 (PP1), which activates glycogen synthase via dephosphorylation.[19] PP1 is targeted to the glycogen pellet by four targeting subunits, GM, GL, PTG and R6. These regulatory enzymes are regulated by insulin and glucagon signaling pathways.

Clinical significance

Mutations in the GYS1 gene are associated with glycogen storage disease type 0.[20] 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 because of impairments in insulin-stimulated glycogen synthesis and suppression of glycogenolysis. Insulin stimulates glycogen synthase by inhibiting glycogen synthase kinases or/and activating protein phosphatase 1 (PP1) among other mechanisms.[19]

Model organisms

Model organisms have been used in the study of GYS2 function. A conditional knockout mouse line, called Gys2tm1a(KOMP)Wtsi[26][27] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[28][29][30] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[24][31] Twenty six tests were carried out and two significant phenotypes were reported. Homozygous mutant male adults displayed impaired glucose tolerance, whereas females had a significant decrease in circulating glucose levels as determined by clinical chemistry.[24]

References

1. ^{{PDB|1RZU}}; {{cite journal |vauthors=Buschazzio A, Ugalde JE, Guerin ME, Shepard W, Ugalde RA, Alzari PM | title = Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation | journal = EMBO J. | volume = 23 | issue = 16 | pages = 3196–3205 |date=August 2004 | pmid = 15272305 | pmc = 514502 | doi = 10.1038/sj.emboj.7600324 | url = | issn = }}; rendered using PyMOL.
2. ^{{cite journal |vauthors=Buchbinder JL, Rath VL, Fletterick RJ | title = Structural relationships among regulated and unregulated phosphorylases | journal = Annu Rev Biophys Biomol Struct | volume = 30 | issue = 1| pages = 191–209 | year = 2001 | pmid = 11340058 | doi = 10.1146/annurev.biophys.30.1.191| issn = }}
3. ^1 2 {{cite journal |vauthors=Buschiazzo A, Ugalde JE, Guerin ME, Shepard W, Ugalde RA, Alzari PM | title = Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation. | journal = EMBO J.| volume = 23 | issue = 16 | pages = 3195–205| year = 2004 | pmid = 15272305 | doi = 10.1038/sj.emboj.7600324| url = | issn = | pmc = 514502 }}
4. ^{{cite journal |vauthors=Coutinho PM, Deleury E, Davies GJ, Henrissat B | title = An evolving hierarchical family classification for glycosyltransferases | journal = J. Mol. Biol.| volume = 328 | issue = 2 | pages = 307–17| year = 2003 | pmid = 12691742 | doi = 10.1016/S0022-2836(03)00307-3| url = | issn = }}
5. ^1 {{cite journal|last1=Palm|first1=DC|last2=Rohwer|first2=JM|last3=Hofmeyr|first3=JH|title=Regulation of glycogen synthase from mammalian skeletal muscle--a unifying view of allosteric and covalent regulation.|journal=The FEBS Journal|date=January 2013|volume=280|issue=1|pages=2–27|pmid=23134486|doi=10.1111/febs.12059}}
6. ^{{cite journal | author = Roach PJ | title = Glycogen and its Metabolism | journal = Curr Mol Med | volume = 2 | issue = 2 | pages = 101–20| year = 2002 | pmid = 11949930 | doi = 10.2174/1566524024605761| url = | issn = }}
7. ^{{cite journal |vauthors=Ball SG, Morell MK | title = From bacterial glycogen to starch: understanding the biogenesis of the plant starch granule | journal = Annu Rev Plant Biol | volume = 54 | issue = 1| pages = 207–33| year = 2003 | pmid = 14502990 | doi = 10.1146/annurev.arplant.54.031902.134927| url = | issn = }}
8. ^{{cite journal |vauthors=Azpiazu I, Manchester J, Skurat AV, Roach PJ, ((Lawrence JC Jr)) | title = Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers | journal = Am J Physiol Endocrinol Metab | volume = 278 | issue = 2 | pages = E234–43| year = 2000 | pmid = 10662707 | doi = 10.1152/ajpendo.2000.278.2.E234| url = | issn = }}
9. ^{{cite journal |vauthors=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 | title = The muscle-specific protein phosphatase PP1G/R(GL)(G(M))is essential for activation of glycogen synthase by exercise | journal = J Biol Chem | volume = 276 | issue = 43 | pages = 39959–67| year = 2001 | pmid = 11522787 | doi = 10.1074/jbc.M105518200| url = | issn = }}
10. ^{{cite journal |vauthors=Browner MF, Nakano K, Bang AG, Fletterick RJ | title = Human muscle glycogen synthase cDNA sequence: a negatively charged protein with an asymmetric charge distribution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 5 | pages = 1443–7 |date=March 1989 | pmid = 2493642 | pmc = 286712 | doi = 10.1073/pnas.86.5.1443| issn = }}
11. ^{{cite journal |vauthors=Westphal SA, Nuttall FQ | title = Comparative characterization of human and rat liver glycogen synthase | journal = Archives of Biochemistry and Biophysics | volume = 292 | issue = 2 | pages = 479–86 |date=February 1992 | pmid = 1731614 | doi = 10.1016/0003-9861(92)90019-S| url = | issn = }}
12. ^{{cite journal |vauthors=Kollberg G, Tulinius M, Gilljam T, Ostman-Smith I, Forsander G, Jotorp P, Oldfors A, Holme E | title = Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0 | journal = The New England Journal of Medicine | volume = 357 | issue = 15 | pages = 1507–14 |date=October 2007 | pmid = 17928598 | doi = 10.1056/NEJMoa066691 | url = | issn = }}
13. ^{{cite journal|last1=Pescador|first1=N|last2=Villar|first2=D|last3=Cifuentes|first3=D|last4=Garcia-Rocha|first4=M|last5=Ortiz-Barahona|first5=A|last6=Vazquez|first6=S|last7=Ordoñez|first7=A|last8=Cuevas|first8=Y|last9=Saez-Morales|first9=D|last10=Garcia-Bermejo|first10=ML|last11=Landazuri|first11=MO|last12=Guinovart|first12=J|last13=del Peso|first13=L|title=Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1.|journal=PLOS ONE|date=12 March 2010|volume=5|issue=3|pages=e9644|pmid=20300197|doi=10.1371/journal.pone.0009644|pmc=2837373}}
14. ^1 {{cite journal |vauthors=Huang TS, Krebs EG |title=Amino acid sequence of a phosphorylation site in skeletal muscle glycogen synthetase |journal=Biochem. Biophys. Res. Commun. |volume=75 |issue=3 |pages=643–50 |date=April 1977 |pmid=405007 |doi= 10.1016/0006-291X(77)91521-2|url=}}
15. ^1 {{cite journal |vauthors=Proud CG, Rylatt DB, Yeaman SJ, Cohen P |title=Amino acid sequences at the two sites on glycogen synthetase phosphorylated by cyclic AMP-dependent protein kinase and their dephosphorylation by protein phosphatase-III |journal=FEBS Lett. |volume=80 |issue=2 |pages=435–42 |date=August 1977 |pmid=196939 |doi= 10.1016/0014-5793(77)80493-6|url=}}
16. ^{{cite journal |vauthors=Rylatt DB, Cohen P |title=Amino acid sequence at the site on rabbit skeletal muscle glycogen synthase phosphorylated by the endogenous glycogen synthase kinase-2 activity |journal=FEBS Lett. |volume=98 |issue=1 |pages=71–5 |date=February 1979 |pmid=107044 |doi= 10.1016/0014-5793(79)80154-4|url=}}
17. ^{{cite journal |vauthors=Embi N, Parker PJ, Cohen P |title=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 |journal=Eur. J. Biochem. |volume=115 |issue=2 |pages=405–13 |date=April 1981 |pmid=6263629 |doi= 10.1111/j.1432-1033.1981.tb05252.x|url=}}
18. ^1 2 3 {{cite journal |vauthors=Rylatt DB, Aitken A, Bilham T, Condon GD, Embi N, Cohen P |title=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 |journal=Eur. J. Biochem. |volume=107 |issue=2 |pages=529–37 |date=June 1980 |pmid=6772446 |doi= 10.1111/j.1432-1033.1980.tb06060.x |url=}}
19. ^1 {{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 = }}
20. ^{{cite journal |vauthors=Orho M, Bosshard NU, Buist NR, Gitzelmann R, Aynsley-Green A, Blümel P, Gannon MC, Nuttall FQ, Groop LC | title = Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0 | journal = The Journal of Clinical Investigation | volume = 102 | issue = 3 | pages = 507–15 |date=August 1998 | pmid = 9691087 | pmc = 508911 | doi = 10.1172/JCI2890 | url = | issn = }}
21. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MABV/plasma-chemistry/ |title=Clinical chemistry data for Gys2 |publisher=Wellcome Trust Sanger Institute}}
22. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MABV/salmonella-challenge/ |title=Salmonella infection data for Gys2 |publisher=Wellcome Trust Sanger Institute}}
23. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MABV/citrobacter-challenge/ |title=Citrobacter infection data for Gys2 |publisher=Wellcome Trust Sanger Institute}}
24. ^1 2 {{cite journal| doi = 10.1111/j.1755-3768.2010.4142.x| title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice| year = 2010| author = Gerdin AK| journal = Acta Ophthalmologica| volume = 88| issue = S248 }}
25. ^Mouse Resources Portal, Wellcome Trust Sanger Institute.
26. ^{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Gys2 |title=International Knockout Mouse Consortium}}
27. ^{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4364592 |title=Mouse Genome Informatics}}
28. ^{{Cite journal| last1 = Skarnes |first1 =W. C.| doi = 10.1038/nature10163 | last2 = Rosen | first2 = B.| last3 = West | first3 = A. P.| last4 = Koutsourakis | first4 = M.| last5 = Bushell | first5 = W.| last6 = Iyer | first6 = V.| last7 = Mujica | first7 = A. O.| last8 = Thomas | first8 = M.| last9 = Harrow | first9 = J.| last10 = Cox | first10 = T.| last11 = Jackson | first11 = D.| last12 = Severin | first12 = J.| last13 = Biggs | first13 = P.| last14 = Fu | first14 = J.| last15 = Nefedov | first15 = M.| last16 = De Jong | first16 = P. J.| last17 = Stewart | first17 = A. F.| last18 = Bradley | first18 = A. | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–342 | year = 2011 | pmid = 21677750 | pmc =3572410 }}
29. ^{{cite journal |author=Dolgin E |title=Mouse library set to be knockout |journal=Nature |volume=474 |issue=7351 |pages=262–3 |date=June 2011 |pmid=21677718 |doi=10.1038/474262a }}
30. ^{{cite journal |vauthors=Collins FS, Rossant J, Wurst W |title=A mouse for all reasons |journal=Cell |volume=128 |issue=1 |pages=9–13 |date=January 2007 |pmid=17218247 |doi=10.1016/j.cell.2006.12.018 }}
31. ^{{cite journal|vauthors=van der Weyden L, White JK, Adams DJ, Logan DW | title=The mouse genetics toolkit: revealing function and mechanism. | journal=Genome Biol | year= 2011 | volume= 12 | issue= 6 | pages= 224 | pmid=21722353 | doi=10.1186/gb-2011-12-6-224 | pmc=3218837}}

External links

{{Commonscat}}
  • {{MeshName|Glycogen+Synthase|3=Glycogen Synthase}}
  • {{cite web|last=Newcastle University Centre for Cancer Education|url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?glycogen+synthetase|title=Glycogen synthetase|date=October 9, 1997|accessdate=2007-11-05}}
{{Glycogenesis and glycogenolysis}}{{Glycosyltransferases}}{{Enzymes}}{{Portal bar|Molecular and Cellular Biology|border=no}}

4 : Carbohydrates|Transferases|EC 2.4.1|Genes mutated in mice
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