Glycogen synthase

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glycogen (starch) synthase
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Glycogen synthase (UDP-glucose-glycogen glucosyltransferase) is a key

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

eukaryotic glycogen synthase is highly conserved among species, glycogen synthase likely forms a tetramer in humans as well.[4]

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.[5] The second family (GT5), which is from bacteria and plants, is approximately 50 kDA, uses ADP-glucose as a sugar donor, and is unregulated.[6]

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.[2]

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.[4]

In a recent study of transgenic mice, an overexpression of glycogen synthase[7] and an overexpression of phosphatase[8] 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

isozymes
of glycogen synthase:

isozyme tissue distribution gene
glycogen synthase 1 muscle and other tissues GYS1[9]
glycogen synthase 2 liver GYS2[10]

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.[11]

Meanwhile, the muscle isozyme plays a major role in the cellular response to long-term adaptation to

ischemic insults.[12]

glycogen synthase 1 (muscle)
Identifiers
SymbolGYS1
Chr. 19 q13.3
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StructuresSwiss-model
DomainsInterPro
glycogen synthase 2 (liver)
Identifiers
SymbolGYS2
Chr. 12 p12.2-11.2
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StructuresSwiss-model
DomainsInterPro

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

protein kinases
leads 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 GSK-3 [17]
Site 3b Serine 645 GSK-3 [17]
Site 3c Serine 649 GSK-3 [17]
Site 3d Serine 653 GSK-3 [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.[2] Glycogen synthase is also regulated by protein phosphatase 1 (PP1), which activates glycogen synthase via dephosphorylation.[18] 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.[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 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.[18]

References

  1. PMID 11340058
    .
  2. ^
    PMID 15272305
    .
  3. PMID 12691742
    .
  4. ^
    S2CID 25551676
    .
  5. PMID 11949930
    .
  6. PMID 14502990
    .
  7. S2CID 6226845
    .
  8. PMID 11522787
    .
  9. PMID 2493642
    .
  10. PMID 1731614
    .
  11. PMID 17928598
    .
  12. PMID 20300197
    .
  13. ^
    PMID 405007
    .
  14. ^
    S2CID 19507389
    .
  15. S2CID 32058496
    .
  16. PMID 6263629
    .
  17. ^
    PMID 6772446
    .
  18. ^
    S2CID 14259712
    .
  19. PMID 9691087
    .

External links

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