Glycogen debranching enzyme: Difference between revisions

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{{Short description|Mammalian protein found in Homo sapiens}}

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The '''glycogen debranching enzyme''', in humans, is the protein encoded by the [[gene]] ''AGL''.<ref name=Gene/> This enzyme is essential for the [[Glycogenolysis|breakdown]] of [[glycogen]], which serves as a store of glucose in the body. It has separate glucosyltransferase and glucosidase activities.<ref name="Song"/><ref name="Bao"/>

A '''debranching enzyme''' is a molecule that helps facilitate the [[Glycogenolysis|breakdown]] of [[glycogen]], which serves as a store of glucose in the body, through glucosyltransferase and glucosidase activity. Together with [[phosphorylase]]s, 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.<ref name="Hers"/> When glycogen breakdown is compromised by mutations in the glycogen debranching enzyme, metabolic diseases such as [[Glycogen storage disease type III]] can result.<ref name="Song"/><ref name="Bao"/>

A '''debranching enzyme''' is a molecule that helps facilitate the [[Glycogenolysis|breakdown]] of [[glycogen]], which serves as a store of glucose in the body, through glucosyltransferase and glucosidase activity. Together with [[phosphorylase]]s, debranchingthe enzymesenzyme 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.<ref name="Hers"/> When glycogen breakdown is compromised by mutations in the glycogen debranching enzyme, metabolic diseases such as [[Glycogen storage disease type III]] can result.<ref name="Song"/><ref name="Bao"/>

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".<ref name=Woo/>

GlucosyltransferaseThe two steps of glycogen breakdown, 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"''.<ref name=Woo/>

== Function ==

Together with [[phosphorylase]], glycogen debranching enzymes function in [[glycogenolysis|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 [[Glycogenolysis|glycogen breakdown]], in the mobilization of glycogen stores. Phosphorylase can only cleave α-1,4- glycosidic bond between adjacent glucose molecules in glycogen but branches also 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.<ref name=Berg/><ref name=Hondoh/> Before phosphorylase can resume catabolism, debranching enzymes perform two functions:

* 4-α-D-glucanotransferase ({{EC number|2.4.1.25}}), or [[glucosyltransferase]], transfers three glucose [[residue (chemistry)|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<ref name="Berg"/>

* [[File:Glycosidase mechanism.png|thumb|Mechanism for cleaving of alpha-1,6 linkage.]]Amylo-α-1,6-glucosidase ({{EC number|3.2.1.33}}), or [[glucosidase]], cleaves the remaining alpha-1,6 linkage, producing glucose and a linear chain of glycogen.<ref name=Berg/> 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.<ref name=Molecule/> 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.<ref name=MCCarter/>

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.

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== Structure and activity ==

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[[File:Hypothesized substraight binding ___location.png|thumb|center|Hypothesized sidechain binding sites|600px]]

The structure of the ''Candida glabrata'' GDE has been reported.<ref>{{Citecite journal |last1 vauthors = Zhai|first1=Liting|last2= L, Feng|first2=Lingling|last3= L, Xia|first3=Lin|last4= L, Yin|first4=Huiyong|last5= H, Xiang S |first5=Song|date=2016-04-18| title = Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations | journal = Nature Communications |language=en| volume = 7 |pages article-number =ncomms11229 11229 |doi date =10.1038/ncomms11229 April 2016 | pmid = 27088557 | pmc = 4837477 | doi = 10.1038/ncomms11229 | bibcode = 2016NatCo...711229Z }}</ref> The structure revealed that distinct domains in GDE encode the glucanotransferase and glucosidase activities. Their catalyses are similar to that of alpha-amylase and glucoamylase, respectively. Their active sites are selective towards the respective substrates, ensuring proper activation of GDE. Besides the active sites GDE have additional binding sites for glycogen, which are important for its recruitment to glycogen. Mapping the disease-causing mutations onto the GDE structure provided insights into glycogen storage disease type III.

== 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 lp211p21.<ref name=Hondoh/> 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.<ref name=Gene/>

The gene is 85 kb long, has 35 [[exon]]s 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.<ref name= Bao/>

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.<ref name = Gillard /><ref name=Ding />

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{{Reflist | colwidth = 35em | refs =

<ref name="Song">{{cite journal | vauthors = Song HN, Jung TY, Park JT, Park BC, Myung PK, Boos W, Woo EJ, Park KH | title = Structural rationale for the short branched substrate specificity of the glycogen debranching enzyme GlgX | journal = Proteins | volume = 78 | issue = 8 | pages = 1847–551847–1855 | date = June 2010 | pmid = 20187119 | doi = 10.1002/prot.22697 | s2cid = 28334066 }}</ref>

<ref name="Bao">{{cite journal | vauthors = Bao Y, Dawson TL, Chen YT | title = Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region | journal = Genomics | volume = 38 | issue = 2 | pages = 155–65155–165 | date = December 1996 | pmid = 8954797 | doi = 10.1006/geno.1996.0611 }}</ref>

<ref name="Berg">{{cite book | last1 vauthors = Stryer | first1 = Lubert | last2 =L, Berg | first2 = Jeremy Mark | last3 =JM, Tymoczko | first3 = John L. | name-list-style = vancJL | title = Biochemistry | edition = 6th | publisher = W.H. Freeman | ___location = San Francisco | year = 2007 | isbn = 978-0-7167-8724-2 }}</ref>

<ref name="Dauvillée">{{cite journal | vauthors = Dauvillée D, Kinderf IS, Li Z, Kosar-Hashemi B, Samuel MS, Rampling L, Ball S, Morell MK | title = Role of the Escherichia coli glgX gene in glycogen metabolism | journal = J.Journal Bacteriol.of Bacteriology | volume = 187 | issue = 4 | pages = 1465–731465–1473 | date = February 2005 | pmid = 15687211 | pmc = 545640 | doi = 10.1128/JB.187.4.1465-1473.2005 }}</ref>

<ref name="Nakayama">{{cite journal | vauthors = Nakayama A, Yamamoto K, Tabata S | title = Identification of the catalytic residues of bifunctional glycogen debranching enzyme | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 276 | issue = 31 | pages = 28824–828824–28828 | date = August 2001 | pmid = 11375985 | doi = 10.1074/jbc.M102192200 | doi-access = free }}</ref>

<ref name="Chen">{{cite journal | vauthors = Chen YT, He JK, Ding JH, Brown BI | title = Glycogen debranching enzyme: purification, antibody characterization, and immunoblot analyses of type III glycogen storage disease | journal = Am.American J.Journal Hum.of Human Genet.Genetics | volume = 41 | issue = 6 | pages = 1002–151002–1015 | date = December 1987 | pmid = 2961257 | pmc = 1684360 }}</ref>

<ref name="UniProt P35573">{{cite web | url = https://www.uniprot.org/uniprot/P35573 | title = Glycogen debranching enzyme - Homo sapiens (Human) | publisher = UniProt }}</ref>

<ref name="Gillard_80">{{cite journal | vauthors = Gillard BK, White RC, Zingaro RA, Nelson TE | title = 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 | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 255 | issue = 18 | pages = 8451–78451–8457 | date = September 1980 | pmid = 6447697 | doi = 10.1016/S0021-9258(18)43517-X | pmid = 6447697 | doi-access = free }}</ref>

<ref name="Gillard">{{cite journal | vauthors = Gillard BK, Nelson TE | title = Amylo-1,6-glucosidase/4-alpha-glucanotransferase: use of reversible substrate model inhibitors to study the binding and active sites of rabbit muscle debranching enzyme | journal = Biochemistry | volume = 16 | issue = 18 | pages = 3978–873978–3987 | date = September 1977 | pmid = 269742 | doi = 10.1021/bi00637a007 }}</ref>

<ref name="Woo">{{cite journal | vauthors = Woo EJ, Lee S, Cha H, Park JT, Yoon SM, Song HN, Park KH | title = Structural insight into the bifunctional mechanism of the glycogen-debranching enzyme TreX from the archaeon Sulfolobus solfataricus | journal = J.The Biol.Journal Chem.of Biological Chemistry | volume = 283 | issue = 42 | pages = 28641–828641–28648 | date = October 2008 | pmid = 18703518 | pmc = 2661413 | doi = 10.1074/jbc.M802560200 | doi-access = free }}</ref>

<ref name="UniProt A8QX06">{{cite web | url = https://www.uniprot.org/uniprot/A8QX06 | title = TreX - Actinoplanes sp. SN223/29 | publisher = UniProt }}</ref>

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<ref name="Park">{{cite journal |vauthors=Park JT, Park HS, Kang HK, Hong JS, Cha H, Woo EJ, Kim JW, Kim MJ, Boos W, Lee S, Park KH | title = Oligomeric and functional properties of a debranching enzyme (TreX) from the archaeon Sulfobus solfataricus P2. | journal = Biocatalysis and Biotransformation | year = 2008 | volume = 26 | issue = 1–2 | pages = 76–85 | doi = 10.1080/10242420701806652 | s2cid = 83831481 }}</ref>

<ref name="Talente">{{cite journal | vauthors = 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 | display-authors = 6 | title = Glycogen storage disease in adults | journal = Ann.Annals Intern.of Med.Internal Medicine | volume = 120 | issue = 3 | pages = 218–26218–226 | date = February 1994 | pmid = 8273986 | doi = 10.7326/0003-4819-120-3-199402010-00008 | s2cid = 24896145 }}</ref>

<ref name="Monga">{{cite book | first = Satdarshan P. S. | lastvauthors = Monga | name-list-style = vancSP | title = Molecular Pathology of Liver Diseases (Molecular Pathology Library) | publisher = Springer | ___location = Berlin | year = 2010 | isbn = 978-1-4419-7106-7 }}</ref>

<ref name="Hondoh">{{cite journal | vauthors = Hondoh H, Saburi W, Mori H, etalOkuyama M, Nakada T, Matsuura Y, Kimura A | title = Substrate recognition mechanism of alpha-1,6-glucosidic linkage hydrolyzing enzyme, dextran glucosidase from Streptococcus mutans | journal = J.Journal Mol.of Molecular Biol.Biology | volume = 378 | issue = 4 | pages = 913–22913–922 | date = May 2008 | pmid = 18395742 | doi = 10.1016/j.jmb.2008.03.016 }}</ref>

<ref name="MCCarter">{{cite journal | vauthors = McCarter JD, Withers SG | title = Mechanisms of enzymatic glycoside hydrolysis | journal = Curr.Current Opin.Opinion Struct.in Biol.Structural Biology | volume = 4 | issue = 6 | pages = 885–92885–892 | date = December 1994 | pmid = 7712292 | doi = 10.1016/0959-440X(94)90271-2 }}</ref>

<ref name="Yamamoto">{{cite journal | vauthors = Yamamoto E, Makino Y, Omichi K | title = Active site mapping of amylo-alpha-1,6-glucosidase in porcine liver glycogen debranching enzyme using fluorogenic 6-O-alpha-glucosyl-maltooligosaccharides | journal = J.Journal Biochem.of Biochemistry | volume = 141 | issue = 5 | pages = 627–34627–634 | date = May 2007 | pmid = 17317688 | doi = 10.1093/jb/mvm065 | doi-access = free }}</ref>

<ref name="Hers">{{cite journal | vauthors = Hers HG, Verhue W, Van hoof F | title = The determination of amylo-1,6-glucosidase | journal = Eur.European J.Journal Biochem.of Biochemistry | volume = 2 | issue = 3 | pages = 257–64257–264 | date = October 1967 | pmid = 6078537 | doi = 10.1111/j.1432-1033.1967.tb00133.x }}</ref>

<ref name="Ding">{{cite journal | vauthors = Ding JH, de Barsy T, Brown BI, Coleman RA, Chen YT | title = Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III | journal = J.The Pediatr.Journal of Pediatrics | volume = 116 | issue = 1 | pages = 95–100 | date = January 1990 | pmid = 2295969 | doi = 10.1016/S0022-3476(05)81652-X }}</ref>

<ref name="Molecule">{{cite journal | authorvauthors = Chiba S | title = Molecular mechanism in alpha-glucosidase and glucoamylase | journal = Biosci.Bioscience, Biotechnol.Biotechnology, Biochem.and Biochemistry | volume = 61 | issue = 8 | pages = 1233–91233–1239 | date = August 1997 | pmid = 9301101 | doi = 10.1271/bbb.61.1233 | doi-access = free }}</ref>

<ref name="Gene">{{cite web | url = httphttps://ghr.nlm.nihmedlineplus.gov/genetics/gene/AGLagl/ | title = Genes (Genetic Home Reference a service of U.S. National Library of Medicine. | access-date = February 29, 2012 }}</ref>

<ref name="Shen">{{cite journal | vauthors = Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT | title = Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle | journal = J.The Journal of Clin.Clinical Invest.Investigation | volume = 98 | issue = 2 | pages = 352–7352–357 | date = July 1996 | pmid = 8755644 | pmc = 507437 | doi = 10.1172/JCI118799 }}</ref>

<ref name="Kishnan">{{cite journal | vauthors = Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, Chung WK, Desai DM, El-Gharbawy A, Haller R, Smit GP, Smith AD, Hobson-Webb LD, Wechsler SB, Weinstein DA, Watson MS | display-authors = 6 | title = Glycogen storage disease type III diagnosis and management guidelines | journal = Genetics in Medicine | volume = 12 | issue = 7 | pages = 446–63446–463 | date = July 2010 | pmid = 20631546 | doi = 10.1097/GIM.0b013e3181e655b6 | doi-access = free }}</ref>

}}

== External links ==

{{Commons category}}

* [https://www.ncbi.nlm.nih.gov/bookshelfbooks/NBK26372/br.fcgi?book=gene&part=gsd3 GeneReviews/NCBI/NIH/UW entry on Glycogen Storage Disease Type III]

* [https://wwwomim.ncbi.nlm.nih.gov/omimorg/search?index=entry&start=1&limit=10&search=232400,+610860,+232400,+610860&sort=score+desc&field=number OMIM entries on Glycogen Storage Disease Type III]

* {{MeSH name|Glycogen+debranching+enzyme}}

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{{DEFAULTSORT:Glycogen Debranching Enzyme}}

[[Category:Carbohydrate metabolism]]

[[Category:EC 2.4.1]]

[[Category:EC 3.2.1]]