glycogen debranching enzyme

• グリコーゲン脱分枝酵素

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glycogen debranching enzyme system

WordNet

1. one form in which body fuel is stored; stored primarily in the liver and broken down into glucose when needed by the body (同)animal_starch
2. any of several complex proteins that are produced by cells and act as catalysts in specific biochemical reactions

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1. グリコーゲン,糖原
2. 酵素

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/04/11 18:39:31」(JST)

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Image of debranching enzyme in E. Coli

AGL
Identifiers
Aliases	AGL, GDE, amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase
External IDs	MGI: 1924809 HomoloGene: 536 GeneCards: AGL
Gene ontology Molecular function • transferase activity • transferase activity, transferring glycosyl groups • hydrolase activity, acting on glycosyl bonds • protein binding • catalytic activity • hydrolase activity • 4-alpha-glucanotransferase activity • amylo-alpha-1,6-glucosidase activity • glycogen debranching enzyme activity • carbohydrate binding • polysaccharide binding • polyubiquitin binding Cellular component • cytoplasm • cytosol • isoamylase complex • extracellular region • secretory granule lumen • ficolin-1-rich granule lumen • nucleus • inclusion body • sarcoplasmic reticulum Biological process • glycogen biosynthetic process • glycogen catabolic process • metabolic process • neutrophil degranulation • glycogen metabolic process • response to nutrient • response to hormone • response to glucocorticoid Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	178	77559
Ensembl	ENSG00000162688	ENSMUSG00000033400
UniProt	P35573	n/a
RefSeq (mRNA)	NM_000028 NM_000642 NM_000643 NM_000644 NM_000645 NM_000646	NM_001081326
RefSeq (protein)	NP_000019 NP_000633 NP_000634 NP_000635 NP_000636 NP_000637	n/a
Location (UCSC)	Chr 1: 99.85 – 99.92 Mb	Chr 3: 116.74 – 116.81 Mb
PubMed search
Wikidata
View/Edit Human		View/Edit Mouse

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
Search PMC articles PubMed articles NCBI proteins

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
Search PMC articles PubMed articles NCBI proteins

A debranching enzyme is a molecule that helps facilitate the breakdown of glycogen, which serves as a store of glucose in the body, 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. Glycogen breakdown is highly regulated in the body, especially in the liver, by various hormones including insulin and glucagon, to maintain a homeostatic balance of blood-glucose levels. When glycogen breakdown is compromised by mutations in the glycogen debranching enzyme, metabolic diseases such as Glycogen storage disease type III can result.

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 catalyzed 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".

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. Glycogen debranching enzymes assist phosphorylase, the primary enzyme involved in glycogen breakdown, mobilize glycogen stores. Phosphorylase can only cleave α-1,4- glycosidic bond between adjacent glucose molecules in glycogen but branches exist as α-1,6 linkages. When phosphorylase reaches four residues from a branching point it stops cleaving; because 1 in 10 residues is branched, cleavage by phosphorylase alone would not be sufficient in mobilizing glycogen stores. 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 exposes a single glucose residue joined to the glucose chain through an α -1,6 glycosidic linkage
• 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. The mechanism by which the glucosidase cleaves the α -1,6-linkage is not fully known because the amino acids in the active site have not yet been identified. It is thought to proceed through a two step acid base assistance type mechanism, with an oxocarbenium ion intermediate, and retention of configuration in glucose. This is a common method through which to cleave bonds, with an acid below the site of hydrolysis to lend a proton and a base above to deprotinate a water which can then act as a nucleophile. These acids and bases are amino acid side chains in the active site of the enzyme. A scheme for the mechanism is shown in the figure below.

Thus the debranching enzymes, transferase and α-1,6- glucosidase converts the branched glycogen structure into a linear one, paving the way for further cleavage by phosphorylase.

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. 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. 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.

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.

One enzyme with two catalytic sites

In mammals and yeast, a single enzyme performs both debranching functions. The human glycogen debranching enzyme (gene: AGL) is a monomer with a molecular weight of 175 kDa. It has been shown that the two catalytic actions of AGL can function independently of each other, demonstrating that multiple active sites are present. This idea has been reinforced with inhibitors of the active site, such as polyhydroxyamine, which were found to inhibit glucosidase activity while transferase activity was not measurably changed. Glycogen debranching enzyme is the only known eukaryotic enzyme that contains multiple catalytic sites and is active as a monomer.

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. In addition to these two active sites, AGL appears to contain a third active site that allows it to bind to a glycogen polymer. Though the complete structure of the GDE in Eukaryotes is yet to be determined it is thought to bind to six glucose molecules of the chain as well as the branched glucose, thus corresponding to 7 subunits within the active site, as shown in the figure below.

It was seen that when glucose ‘a’, ‘b’, ‘c’ and ‘0’ in the active site was hydrolyzed the most rapidly. This indicated that this region of the glycogen chain bond strongest to the active site because a stronger interaction between enzyme and substrate leads to a more rapid hydrolysis.

Despite these advances, the complete structure of GDE in eukaryotes has yet to be determined. 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. 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.

Genetic Location

The official name for the gene is “amylo- α- 1,6- glucosidase, 4- α- glucanotransferase,” with the official symbol AGL. AGL is an autosomal gene found on chromosome lp21. The AGL gene provides instructions for making several different versions, known as isoforms, of the glycogen debranching enzyme. These isoforms vary by size and are expressed in different tissues, such as liver and muscle. This gene has been studied in great detail, because mutation at this gene is the cause of Glycogen Storage Disease Type III. The gene is 85 kb long, has 35 exons and encodes for a 7.0 kb- mRNA. Translation of the gene begins at exon 3,which encodes for the first 27 amino acids of the AGL gene, because the first two exons (68kb) contain the 5’ untranslated region. Exons 4-35 encode the remaining 1505 amino acids of the AGL gene. Studies produced by the department of pediatrics at Duke University suggest that the human AGL gene contains at minimum 2 promotor regions, sites where the transcription of the gene begins, that result in differential expression of isoform, different forms of the same protein, mRNAs in a manner that is specific for different tissues.

Clinical Significance

Main article: Glycogen storage disease type III

When GDE activity is compromised, the body cannot effectively release stored glycogen, type III Glycogen Storage Disease (debrancher deficiency), an autosomal recessive disorder, can result. In GSD III glycogen breakdown is incomplete and there is accumulation of abnormal glycogen with short outer branches.

Most patients exhibit GDE defiency in both liver and muscle (TypeIIIa), although 15% of patients have retained GDE in muscle while having it absent from the liver (Type IIIb). Depending on mutation location, different mutations in the AGL gene can affect different isoforms of the gene expression. For example, mutations that occur on exon 3, affect the form which affect the isoform that is primarily expressed in the liver; this would lead to GSD type III.

These different manifestation produce varied symptoms, which can be nearly indistinguishable from Type I GSD, including hepatomegaly, hypoglycemia in children, short stature, myopathy, and cardiomyopathy. Type IIIa patients often exhibit symptoms related to liver disease and progressive muscle involvement, with variations caused by age of onset, rate of disease progression and severity. Patients with Type IIIb generally symptoms related to liver disease. Type III patients be distinguished by elevated liver enzymes, with normal uric acid and blood lactate levels, differing from other forms of GSD. In patients with muscle involvement, Type IIIa, the muscle weakness becomes predominant into adulthood and can lead to ventricular hypertrophy and distal muscle wasting.

References

External links

• GeneReviews/NCBI/NIH/UW entry on Glycogen Storage Disease Type III
• OMIM entries on Glycogen Storage Disease Type III
• Glycogen debranching enzyme at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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• 1. グリコーゲン分枝酵素欠損症（糖原病IV型、アンダーセン病） glycogen branching enzyme deficiency glycogen storage disease iv andersen disease
• 2. 肝グリコーゲン合成酵素欠損症（糖原病0型） liver glycogen synthase deficiency glycogen storage disease 0
• 3. グルコースおよびグリコーゲン代謝の遺伝性疾患の概要 overview of inherited disorders of glucose and glycogen metabolism
• 4. グリコーゲン脱分枝酵素欠損症（糖原病III型） glycogen debrancher deficiency glycogen storage disease iii
• 5. Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)

English Journal

• LC MS/MS identification of large structural proteins from bull muscle and their degradation products during post mortem storage.

• Wu G1, Clerens S2, Farouk MM3.Author information 1AgResearch, Ruakura Research Centre, Hamilton, New Zealand. Electronic address: guojie.wu@agresearch.co.nz.2AgResearch, Lincoln Research Centre, Christchurch, New Zealand.3AgResearch, Ruakura Research Centre, Hamilton, New Zealand.AbstractLarge proteins (>100kDa) in bovine M. longissimus dorsi and their degradation products during post mortem ageing were investigated by gel electrophoresis and LC-MS/MS analysis. Seventeen protein bands from SDS-PAGE were analysed and 26 proteins were identified. Intact titin, nebulin and filamin were shown to break down during post mortem ageing of meat. A number of myosin super-family members were revealed on SDS-PAGE. Myosin heavy chain 1 (MYH1), myosin heavy chain 2 (MYH2), and myosin heavy chain 7 (MYH7) were distributed broadly across the bands in the forms of cross-linked/aggregated polymers, and also as fragments. Three myomesin family members: myomesin 1 (185kDa isoform 1), myomesin (M-protein) 2, 165kDa, and myomesin family member 3, were identified in the muscle samples. Several other proteins such as synemin, myosin binding protein C (C-protein), glycogen debranching enzyme and ryanodine receptor 2 were also identified.
• Food chemistry.Food Chem.2014 May 1;150:137-44. doi: 10.1016/j.foodchem.2013.10.158. Epub 2013 Nov 2.
• Large proteins (>100kDa) in bovine M. longissimus dorsi and their degradation products during post mortem ageing were investigated by gel electrophoresis and LC-MS/MS analysis. Seventeen protein bands from SDS-PAGE were analysed and 26 proteins were identified. Intact titin, nebulin and filamin w
• PMID 24360430

• Role in Tumor Growth of a Glycogen Debranching Enzyme Lost in Glycogen Storage Disease.

• Guin S1, Pollard C, Ru Y, Ritterson Lew C, Duex JE, Dancik G, Owens C, Spencer A, Knight S, Holemon H, Gupta S, Hansel D, Hellerstein M, Lorkiewicz P, Lane AN, Fan TW, Theodorescu D.Author information 1Affiliations of authors: Department of Surgery (SGui, CP, YR, CRL, JED, GD, CO, DT) and Department of Pharmacology (SGui, CP, YR, CRL, JED, GD, CO, DT), University of Colorado, Denver, CO; Sigma-Aldrich Research Biotech, Saint Louis, MO (AS, SK, HH); Department of Pathology, Cleveland Clinic, Cleveland, OH (SGup, DH); Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA (MH); Department of Medicine, University of California at San Francisco, San Francisco, CA (MH); Center for Regulatory and Environmental Analytical Metabolomics, Department of Chemistry, University of Louisville, Louisville, KY (PL); Graduate Center of Toxicology, Biopharm Complex, University of Kentucky, Lexington, KY (ANL, TW-MF); University of Colorado Comprehensive Cancer Center, Denver, CO (DT). Present affiliations: Department of Biomedical Informatics, Windber Research Institute, Windber, PA (YR); Mathematics and Computer Science Department, Eastern Connecticut State University, Willimantic, CT (GD).AbstractBACKGROUND: Bladder cancer is the most common malignancy of the urinary system, yet our molecular understanding of this disease is incomplete, hampering therapeutic advances.
• Journal of the National Cancer Institute.J Natl Cancer Inst.2014 Apr 3. [Epub ahead of print]
• BACKGROUND: Bladder cancer is the most common malignancy of the urinary system, yet our molecular understanding of this disease is incomplete, hampering therapeutic advances.METHODS: Here we used a genome-wide functional short-hairpin RNA (shRNA) screen to identify suppressors of in vivo bladder tum
• PMID 24700805

• Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase.

• Liu Y1, Zeng L, Ma K, Baba O, Zheng P, Liu Y, Wang Y.Author information 1Center for Cancer and Immunology Research, Children's National Medical Center and George Washington University, 111 Michigan Avenue NW, Washington, DC, 20010, USA, ynliu@childrensnational.org.AbstractIn Lafora disease (LD), the deficiency of either EPM2A or NHLRC1, the genes encoding the phosphatase laforin and E3 ligase, respectively, causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells including neurons. The biochemical mechanism underlying the PB accumulation, however, remains undefined. We recently demonstrated that laforin is a phosphatase of muscle glycogen synthase (GS1) in PBs, and that laforin recruits malin, together reducing PBs. We show here that accomplishment of PB degradation requires a protein assembly consisting of at least four key enzymes: laforin and malin in a complex, and the glycogenolytic enzymes, glycogen debranching enzyme 1 (AGL1) and brain isoform glycogen phosphorylase (GPBB). Once GS1-synthesized polyglucosan accumulates into PBs, laforin recruits malin to the PBs where laforin dephosphorylates, and malin degrades the GS1 in concert with GPBB and AGL1, resulting in a breakdown of polyglucosan. Without fountional laforin-malin complex assembled on PBs, GPBB and AGL1 together are unable to efficiently breakdown polyglucosan. All these events take place on PBs and in cytoplasm. Deficiency of each of the four enzymes causes PB accumulation in the cytoplasm of affected cells. Demonstration of the molecular mechanisms underlying PB degradation lays a substantial biochemical foundation that may lead to understanding how PB metabolizes and why mutations of either EPM2A or NHLRC1 in humans cause LD. Mutations in AGL1 or GPBB may cause diseases related to PB accumulation.
• Molecular neurobiology.Mol Neurobiol.2014 Apr;49(2):645-57. doi: 10.1007/s12035-013-8546-z. Epub 2013 Sep 26.
• In Lafora disease (LD), the deficiency of either EPM2A or NHLRC1, the genes encoding the phosphatase laforin and E3 ligase, respectively, causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells includi
• PMID 24068615

Japanese Journal

• Discrimination of porcine glycogen debranching enzyme isozymes by the ratios of their 4-α-glucanotransferase and amylo-α-1,6-glucosidase activities

• Doi Seiko,Makino Yasushi,Omichi Kaoru
• The journal of biochemistry 147(6), 851-856, 2010-06-01
• NAID 10027876511

• Novel AGL mutation in a Turkish patient with glycogen storage disease type IIIa

• AOYAMA Yoshiko,ENDO Yoriko,EBARA Tetsu,MURASE Toshio,SHIN Yoon S.,PODSKARBI Teodor,OZER Isil,DEMIRKOL Mubeccel,GOKCAY Gulden,OKUBO Minoru
• Pediatrics international : official journal of the Japan Pediatric Society 52(1), 145-147, 2010-02-01
• NAID 10028181453

• Inspection of the Activator Binding Site for 4-α-Glucanotransferase in Porcine Liver Glycogen Debranching Enzyme with Fluorogenic Dextrins

• Yamamoto Eriko,Watanabe Yumiko,Makino Yasushi [他],OMICHI Kaoru
• The journal of biochemistry 145(5), 585-590, 2009-05-01
• NAID 10025588794

Related Links

• Glycogen debranching enzyme - Mashpedia, the Video ...

When GDE activity is compromised, the body cannot effectively release stored glycogen, type III Glycogen Storage Disease (debrancher deficiency), an autosomal recessive disorder, can result. In GSD III glycogen breakdown is ...

• Glycogen debranching enzyme - definition of Glycogen ...

debrancher enzyme /de·branch·er en·zyme/ (de-branch´er en´zīm) see under enzyme. enzyme [en´zīm] any protein that acts as a catalyst, increasing the rate at which a chemical reaction occurs. The human body probably contains ...

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関連記事	「debranching enzyme」「glycogen」

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脱分枝酵素、枝切り酵素

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