Glycogen debranching enzyme


Glycogen debranching enzyme
Amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase
Identifiers
Symbols AGL; GDE
External IDs OMIM610860 MGI1924809 HomoloGene536 GeneCards: AGL Gene
EC number 2.4.1.25
Orthologs
Species Human Mouse
Entrez 178 77559
Ensembl ENSG00000162688 ENSMUSG00000033400
UniProt P35573 Q8CE68
RefSeq (mRNA) NM_000028.2 NM_001081326.1
RefSeq (protein) NP_000019.2 NP_001074795.1
Location (UCSC) Chr 1:
100.32 – 100.39 Mb
Chr 3:
116.44 – 116.51 Mb
PubMed search [1] [2]
4-α-glucanotransferase
Identifiers
EC number 2.4.1.25
CAS number 9032-09-1
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 / EGO
amylo-α-1,6-glucosidase
Identifiers
EC number 3.2.1.33
CAS number 9012-47-9
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 / EGO

A debranching enzyme is a molecule that helps facilitate the breakdown of glycogen through glucosyltransferase and glucosidase activity. Together with phosphorylases, debranching enzymes mobilize glucose reserves from glycogen deposits in the muscles and liver. This constitutes a major source of energy reserves in most organisms. When glycogen breakdown is compromised by mutations in the glycogen debranching enzyme, metabolic diseases such as Glycogen storage disease type III can result.[1][2]

Glucosyltransferase and glucosidase are performed by a single enzyme in mammals, yeast, and some bacteria, but by two distinct enzymes in E. coli and other bacteria, complicating nomenclature. Proteins that catalyze both functions are referred to as glycogen debranching enzymes (GDEs). When glucosyltransferase and glucosidase are catylized by distinct enzymes, "glycogen debranching enzyme" usually refers to the glucosidase enzyme. In some literature, an enzyme capable only of glucosidase is referred to as a "debranching enzyme".[3]

Contents

Function

Together with phosphorylase, glycogen debranching enzymes function in glycogen breakdown and glucose mobilization. When phosphorylase has digested a glycogen branch down to four glucose residues, it will not remove further residues. Before phosphorylase can resume catabolism, debranching enzymes perform two functions:

  • 4-α-D-glucanotransferase (EC 2.4.1.25), or glucosyltransferase, transfers three glucose residues from the four-residue glycogen branch to a nearby branch. This leaves on the donor branch a single glucose residue, connected to the main chain by an alpha-1,6 linkage.[4]
  • Amylo-α-1,6-glucosidase (EC 3.2.1.33), or glucosidase, cleaves the remaining alpha-1,6 linkage, producing glucose and a linear chain of glycogen.[4]

Structure and activity

Two enzymes

In E. coli and other bacteria, glucosyltransferase and glucosidase functions are performed by two distinct enzymes. In E. coli, Glucose transfer is performed by 4-alpha-glucanotransferase, a 78.5 kDa protein coded for by the gene malQ.[5] A second protein, referred to as debranching enzyme, performs α-1,6-glucose cleavage. This enzyme has a molecular mass of 73.6 kDa, and is coded for by the gene glgX.[6] Activity of the two enzymes is not always necessarily coupled. In E. coli glgX selectively catalyzes the cleavage of 4-subunit branches, without the action of glucanotransferase. The product of this cleavage, maltotetraose, is further degraded by maltodextrin phosphorylase.[1][7]

E. coli GlgX is structurally similar to the protein isoamylase. The monomeric protein contains a central domain in which eight parallel beta-strands are surrounded by eight parallel alpha strands. Notable within this structure is a groove 26 angstroms long and 9 angstroms wide, containing aromatic residues that are thought to stabilize a four-glucose branch before cleavage.[1]

One enzyme with two catalytic sites

In mammals and yeast, a single enzyme performs both debranching functions.[8] The human glycogen debranching enzyme (gene: AGL) is a monomer with a molecular weight of 175 kDa. The two catalytic actions of AGL can function independently of each other, demonstrating that multiple active sites are present. Glycogen debranching enzyme is the only known eukaryotic enzyme that contains multiple catalytic sites and is active as a monomer.[9][10]

Some studies have shown that the C-terminal half of yeast GDE is associated with glucosidase activity, while the N-terminal half is associated with glucosyltransferase activity.[8] In addition to these two active sites, AGL appears to contain a third active site that allows it to bind to a glycogen polymer.[11] Despite these advances, the complete structure of GDE in eukaryotes has yet to be determined.[3] The glycogen-degrading enzyme of the archaea Sulfolobus solfataricus is better characterized than those of eukaryotes. The GDE of S. solfataricus is known as treX. Although, like mammalian GDE, treX has both amylosidase and glucanotransferase functions, TreX is structurally similar to glgX, and hass a mass of 80kD and one active site.[3][12] Unlike either glgX or AGL, however, treX exists as a dimer and tetramer in solution. TreX's oligomeric form seems to play a significant role in altering both enzyme shape and function. Dimerization is thought to stabilize a "flexible loop" located close to the active site. This may be key to explaining why treX (and not glgX) shows glucosyltransferase activity. As a tetramer, the catalytic efficiency of treX is increased fourfold over its dimeric form.[1][13]

Pathology

When GDE activity is compromised, the body cannot effectively release stored glycogen, resulting in Glycogen storage disease type III. Different types of Glycogen Storage Disease type III have been identified. All forms exhibit decreased GDE activity in the liver, but some show decreased activity in the muscles as well. These different manifestation produce varied symptoms, which can include hepatomegaly, hypoglycemia in children, short stature, myopathy, and cardiomyopathy.[2][14]

References

  1. ^ a b c d Song HN, Jung TY, Park JT, Park BC, Myung PK, Boos W, Woo EJ, Park KH (June 2010). "Structural rationale for the short branched substrate specificity of the glycogen debranching enzyme GlgX". Proteins 78 (8): 1847–55. doi:10.1002/prot.22697. PMID 20187119. 
  2. ^ a b Bao Y, Dawson TL, Chen YT (December 1996). "Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region". Genomics 38 (2): 155–65. doi:10.1006/geno.1996.0611. PMID 8954797. 
  3. ^ a b c Woo EJ, Lee S, Cha H, Park JT, Yoon SM, Song HN, Park KH (October 2008). "Structural insight into the bifunctional mechanism of the glycogen-debranching enzyme TreX from the archaeon Sulfolobus solfataricus". J. Biol. Chem. 283 (42): 28641–8. doi:10.1074/jbc.M802560200. PMC 2661413. PMID 18703518. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2661413. 
  4. ^ a b Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2007). Biochemistry (6th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-8724-5. 
  5. ^ "4-alpha-glucanotransferase - Escherichia coli (strain K12)". http://www.uniprot.org/uniprot/P15977. 
  6. ^ "Glycogen debranching enzyme - Escherichia coli O139:H28 (strain E24377A / ETEC)". UniProt. http://www.uniprot.org/uniprot/A7ZSW4. 
  7. ^ Dauvillée D, Kinderf IS, Li Z, Kosar-Hashemi B, Samuel MS, Rampling L, Ball S, Morell MK (February 2005). "Role of the Escherichia coli glgX gene in glycogen metabolism". J. Bacteriol. 187 (4): 1465–73. doi:10.1128/JB.187.4.1465-1473.2005. PMC 545640. PMID 15687211. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=545640. 
  8. ^ a b Nakayama A, Yamamoto K, Tabata S (August 2001). "Identification of the catalytic residues of bifunctional glycogen debranching enzyme". J. Biol. Chem. 276 (31): 28824–8. doi:10.1074/jbc.M102192200. PMID 11375985. 
  9. ^ Chen YT, He JK, Ding JH, Brown BI (December 1987). "Glycogen debranching enzyme: purification, antibody characterization, and immunoblot analyses of type III glycogen storage disease". Am. J. Hum. Genet. 41 (6): 1002–15. PMC 1684360. PMID 2961257. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1684360. 
  10. ^ "Glycogen debranching enzyme - Homo sapiens (Human)". UniProt. http://www.uniprot.org/uniprot/P35573. 
  11. ^ Gillard BK, White RC, Zingaro RA, Nelson TE (September 1980). "Amylo-1,6-glucosidase/4-alpha-glucanotransferase. Reaction of rabbit muscle debranching enzyme with an active site-directed irreversible inhibitor, 1-S-dimethylarsino-1-thio-beta-D-glucopyranoside". J. Biol. Chem. 255 (18): 8451–7. PMID 6447697. 
  12. ^ "TreX - Actinoplanes sp. SN223/29". UniProt. http://www.uniprot.org/uniprot/A8QX06. 
  13. ^ Park JT, Park HS, Kang HK, Hong JS, Cha H, Woo EJ, Kim JW, Kim MJ, Boos W, Lee S, Park KH (2008). "Oligomeric and functional properties of a debranching enzyme (TreX) from the archaeon Sulfobus solfataricus P2.". Biocatalysis and Biotransformation 26: 76–85. doi:10.1080/10242420701806652. 
  14. ^ Talente GM, Coleman RA, Alter C, Baker L, Brown BI, Cannon RA, Chen YT, Crigler JF, Ferreira P, Haworth JC, Herman GE, Issenman RM, Keating JP, Linde R, Roe TF, Senior B, Wolfsdorf JI (February 1994). "Glycogen storage disease in adults". Ann. Intern. Med. 120 (3): 218–26. PMID 8273986. 

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