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Nomenclature

This enzyme belongs to the family of transferases, to be specific, those glycosyltransferases that transfer hexoses (hexosyltransferases). The systematic name of this enzyme class is 1,4-alpha-D-glucan:1,4-alpha-D-glucan 6-alpha-D-(1,4-alpha-D-glucano)-transferase. Other names in common use include branching enzyme, amylo-(1,4→1,6)-transglycosylase, Q-enzyme, alpha-glucan-branching glycosyltransferase, amylose isomerase, enzymatic branching factor, branching glycosyltransferase, enzyme Q, glucosan transglycosylase, 1,4-alpha-glucan branching enzyme 1, plant branching enzyme, alpha-1,4-glucan:alpha-1,4-glucan-6-glycosyltransferase, and starch branching enzyme. This enzyme participates in starch and sucrose metabolism.

Gene

GBE is encoded by the GBE1 gene.³⁴⁵⁶

Through Southern blot analysis of DNA derived from human/rodent somatic cell hybrids, GBE1 has been identified as an autosomal gene located on the short arm of chromosome 3 at position 12.3.⁷⁸⁹¹⁰ The human GBE gene was also isolated by a function complementation of the Saccharomyces cerevisiae GBE deficiency.¹¹ From the isolated cDNA, the length of the gene was found to be approximately 3 kb.¹² Additionally, the coding sequence was found to comprise 2,106 base pairs and encode a 702-amino acid long GBE. The molecular mass of human GBE was calculated to be 80,438 Da.¹³

Structure

Glycogen branching enzyme belongs to the α-amylase family of enzymes, which include α-amylases, pullulanas/isoamylase, cyclodextrin glucanotransferase (CGT), and branching enzyme.¹⁴¹⁵ Shown by x-ray crystallography, glycogen branching enzyme has four marginally asymmetric units each that are organized into three domains: an amino-terminal domain, involved in determining the length of the chain transfer, a carboxyl-terminal domain, involved in substrate preference and catalytic capacity, and a central (α/β) barrel catalytic domain.^16171819 The amino-terminal domain consists of 128 residues arranged in seven β-strands, the carboxyl-terminal domain with 116 residues also organized in seven β-strands, and the (α/β) barrel domain with 372 residues. While the central (α/β) barrel domain is common in members of the α-amylase family, numerous variations exist between the various barrel domains. Additionally, there are striking differences between the loops connecting elements of the secondary structure among these various α-amylase members, especially around the active site. In comparison to the other family members, glycogen binding enzyme has shorter loops, which result in a more open cavity, favorable to the binding of a bulkier substrate such as branched sugar. Through primary structure analysis and the x-ray crystallographic structures of the members of the α-amylase family, seven residue were conserved, Asp335, His340, Arg403, Asp 405, Glu458, His525, and Asp526 (E coli. numbering). These residues are implicated in catalysis and substrate binding.²⁰

Glycogen binding enzymes in other organisms have also been crystallized and structurally determined, demonstrating both similarity and variation to GBE found in Escherichia coli.^21222324

Function

In glycogen, every 10 to 14 glucose units, a side branch with an additional chain of glucose units occurs. The side chain attaches at carbon atom 6 of a glucose unit, an α-1,6-glycosidic bond. This connection is catalyzed by a branching enzyme, generally given the name α-glucan branching enzyme. A branching enzyme attaches a string of seven glucose units (with some minor variation to this number) to the carbon at the C-6 position on the glucose unit, forming the α-1,6-glycosidic bond. The specific nature of this enzyme means that this chain of 7 carbons is usually attached to a glucose molecule that is in position three from the non-reducing end of another chain. Because the enzyme works with such specificity regarding the number of glucose units transferred and the position to which they are transferred, the enzyme creates the very characteristic, highly branched glycogen molecule.²⁵

Clinical significance

Mutations in this gene are associated with glycogen storage disease type IV (also known as Andersen's disease) in newborns and with adult polyglucosan body disease.²⁶²⁷

Approximately 40 mutations in the GBE1 gene, most resulting in a point mutation in the glycogen branching enzyme, have led to the early childhood disorder, glycogen storage disease type IV (GSD IV).²⁸ This disease is characterized by a severe depletion or complete absence of GBE, resulting in the accumulation of abnormally structured glycogen, known as polyglucosan bodies.²⁹ Glycogen buildup leads to increased osmotic pressure resulting in cellular swelling and death.³⁰ The tissues most affected by this disease are the liver, heart, and neuromuscular system, areas with the greatest levels of glycogen accumulation.³¹³² Abnormal glycogen buildup in the liver interferes with liver functioning and can result in an enlarged liver and liver disease.³³³⁴ In muscles, the inability of cells to efficiently breakdown glycogen due to the severe reduction or absence of branching can lead to muscle weakness and atrophy.³⁵ At least three mutations in the GBE1 gene have been found to cause another disease called adult polyglucosan body disease (APBD).³⁶³⁷ While in GSD IV GBE activity is undetectable or minimally detectable, APBD is characterized by reduced or even normal GBE activity.³⁸ In this disease, abnormal glycogen can build up in neurons leading to a spectrum of problems. Specifically, some disease characteristics are gait difficulties from mixed upper and lower motor neuron involvement sensory loss in lower extremities, and neurogenic bladder, a problem in which a person lacks bladder control due to a brain, spinal cord, or nerve condition.³⁹⁴⁰

Further reading

• Barker SA, Bourne E, Peat S (1949). "The enzymic synthesis and degradation of starch. Part IV. The purification and storage of the Q-enzyme of the potato". Journal of the Chemical Society (Resumed): 1705–1711. doi:10.1039/jr9490001705.
• Baum H, Gilbert GA (May 1953). "A simple method for the preparation of crystalline potato phosphorylase and Q-enzyme". Nature. 171 (4361): 983–984. Bibcode:1953Natur.171..983B. doi:10.1038/171983a0. PMID 13063502. S2CID 2243647.
• Hehre EJ (1951). "Enzymic Synthesis of Polysaccharides: A Biological type of Polymerization". Advances in Enzymology - and Related Areas of Molecular Biology. Vol. 11. pp. 297–337. doi:10.1002/9780470122563.ch6. ISBN 978-0-470-12256-3. PMID 24540594. {{cite book}}: ISBN / Date incompatibility (help); |journal= ignored (help)
• Allan CM, Wang Y, Jimenez M, Marshan B, Spaliviero J, Illingworth P, et al. (March 2006). "Follicle-stimulating hormone increases primordial follicle reserve in mature female hypogonadal mice". The Journal of Endocrinology. 188 (3): 549–557. doi:10.1677/joe.1.06614. PMID 16522734.
• Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, et al. (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–968. doi:10.1016/j.cell.2005.08.029. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070. S2CID 8235923.
• Massa R, Bruno C, Martorana A, de Stefano N, van Diggelen OP, Federico A (April 2008). "Adult polyglucosan body disease: proton magnetic resonance spectroscopy of the brain and novel mutation in the GBE1 gene". Muscle & Nerve. 37 (4): 530–536. doi:10.1002/mus.20916. PMID 17994551. S2CID 18749059.
• Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR (2010). "Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score". Molecular Medicine. 16 (7–8): 247–253. doi:10.2119/molmed.2009.00159. PMC 2896464. PMID 20379614.
• Hannula-Jouppi K, Kaminen-Ahola N, Taipale M, Eklund R, Nopola-Hemmi J, Kääriäinen H, et al. (October 2005). "The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia". PLOS Genetics. 1 (4): e50. doi:10.1371/journal.pgen.0010050. PMC 1270007. PMID 16254601.
• Konstantinidou AE, Anninos H, Dertinger S, Nonni A, Petersen M, Karadimas C, et al. (April 2008). "Placental involvement in glycogen storage disease type IV". Placenta. 29 (4): 378–381. doi:10.1016/j.placenta.2008.01.005. PMID 18289670.
• Melén E, Himes BE, Brehm JM, Boutaoui N, Klanderman BJ, Sylvia JS, et al. (September 2010). "Analyses of shared genetic factors between asthma and obesity in children". The Journal of Allergy and Clinical Immunology. 126 (3): 631–7.e1–8. doi:10.1016/j.jaci.2010.06.030. PMC 2941152. PMID 20816195.
• Bruno C, van Diggelen OP, Cassandrini D, Gimpelev M, Giuffrè B, Donati MA, et al. (September 2004). "Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV)". Neurology. 63 (6): 1053–1058. doi:10.1212/01.wnl.0000138429.11433.0d. PMID 15452297. S2CID 7874969.
• Ziemssen F, Sindern E, Schröder JM, Shin YS, Zange J, Kilimann MW, et al. (April 2000). "Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease". Annals of Neurology. 47 (4): 536–540. doi:10.1002/1531-8249(200004)47:4<536::AID-ANA22>3.0.CO;2-K. PMID 10762170. S2CID 42856760.
• McCarthy JJ, Meyer J, Moliterno DJ, Newby LK, Rogers WJ, Topol EJ (December 2003). "Evidence for substantial effect modification by gender in a large-scale genetic association study of the metabolic syndrome among coronary heart disease patients". Human Genetics. 114 (1): 87–98. doi:10.1007/s00439-003-1026-1. PMID 14557872. S2CID 2568593.
• Tay SK, Akman HO, Chung WK, Pike MG, Muntoni F, Hays AP, et al. (April 2004). "Fatal infantile neuromuscular presentation of glycogen storage disease type IV". Neuromuscular Disorders. 14 (4): 253–260. doi:10.1016/j.nmd.2003.12.006. PMID 15019703. S2CID 34056349.
• Pescador N, Villar D, Cifuentes D, Garcia-Rocha M, Ortiz-Barahona A, Vazquez S, et al. (March 2010). "Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1". PLOS ONE. 5 (3): e9644. Bibcode:2010PLoSO...5.9644P. doi:10.1371/journal.pone.0009644. PMC 2837373. PMID 20300197.
• Bruno C, Cassandrini D, Assereto S, Akman HO, Minetti C, Di Mauro S (July 2007). "Neuromuscular forms of glycogen branching enzyme deficiency". Acta Myologica. 26 (1): 75–78. PMC 2949312. PMID 17915577.
• Flachsbart F, Franke A, Kleindorp R, Caliebe A, Blanché H, Schreiber S, et al. (December 2010). "Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study". Mutation Research. 694 (1–2): 13–19. Bibcode:2010MRFMM.694...13F. doi:10.1016/j.mrfmmm.2010.08.006. PMID 20800603.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, et al. (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. S2CID 7200157.
• Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, et al. (October 2010). "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study". Diabetes Care. 33 (10): 2250–2253. doi:10.2337/dc10-0452. PMC 2945168. PMID 20628086.

External links

• Biology portal

• GeneReviews/NCBI/NIH/UW entry on Adult Polyglucosan Body Disease
• OMIM entries on Adult Polyglucosan Body Disease
• Overview of all the structural information available in the PDB for UniProt: Q04446 (1,4-alpha-glucan-branching enzyme) at the PDBe-KB.

References

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