Glycogen branching enzyme

Glycogen branching enzyme
Identifiers
EC number 2.4.1.18
CAS number 9001-97-2
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
1,4-alpha-glucan branching enzyme
Identifiers
Symbol GBE1
Entrez 2632
HUGO 4180
OMIM 607839
RefSeq NM_000158
UniProt Q04446
Other data
EC number 2.4.1.18
Locus Chr. 3 p12

Glycogen branching enzyme is an enzyme that adds branches to the growing glycogen molecule during the synthesis of glycogen, a storage form of glucose. More specifically, during glycogen synthesis, a glucose 1-phosphate molecule reacts with uridine triphosphate (UTP) to become UDP-glucose, an activated form of glucose. The activated glucosyl unit of UDP-glucose is then transferred to the hydroxyl group at the C-4 of a terminal residue of glycogen to form an α-1,4-glycosidic linkage, a reaction catalyzed by glycogen synthase. Importantly, glycogen synthase can only catalyze the synthesis of α-1,4-glycosidic linkages. Since glycogen is a readily mobilized storage form of glucose, the extended glycogen polymer is branched by glycogen branching enzyme to provide glycogen breakdown enzymes, such as glycogen phosphorylase, with a large number of terminal residues for rapid degradation. Branching also importantly increases the solubility and decreases the osmotic strength of glycogen.[1]

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, 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.[2][3][4][5]

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.[3][4][5][6] The human GBE gene was also isolated by a function complementation of the Saccharomyces cerevisiae GBE deficiency.[6] From the isolated cDNA, the length of the gene was found to be approximately 3 kb.[6] 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.[6]

Structure

Structure of glycogen branching enzyme found in E. Coli

Glycogen branching enzyme belongs to the α-amylase family of enzymes, which include α-amylases, pullulanas/isoamylase, cyclodextrin glucanotransferase (CGT), and branching enzyme.[7][8] 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.[7][9][10][11] 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.[7]

Glycogen binding enzymes in other organisms have also been crystallized and structurally determined, demonstrating both similarity and variation to GBE found in Escherichia coli.[12][13][14][15]

Function

Scheme demonstrating the function of glycogen branching enzyme

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.[16]

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.[2][17]

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).[5] 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.[5] Glycogen buildup leads to increased osmotic pressure resulting in cellular swelling and death.[5] The tissues most affected by this disease are the liver, heart, and neuromuscular system, areas with the greatest levels of glycogen accumulation.[5][18] Abnormal glycogen buildup in the liver interferes with liver functioning and can result in an enlarged liver and liver disease.[5][19] 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.[5] At least three mutations in the GBE1 gene have been found to cause another disease called adult polyglucosan body disease (APBD).[5][20] While in GSD IV GBE activity is undetectable or minimally detectable, APBD is characterized by reduced or even normal GBE activity.[20] 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.[20][21]

Model organisms

Model organisms have been used in the study of GBE1 function. A conditional knockout mouse line, called Gbe1tm1a(KOMP)Wtsi[25][26] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[27][28][29]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[23][30] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[23] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[23]

References

  1. ↑ Berg, Jeremey (2012). Biochemistry Seventh Edition. W.H. Freeman and Company. pp. 627–630.
  2. 1 2 "Entrez Gene: glucan (1,4-alpha-), branching enzyme 1". Retrieved 2011-08-30.
  3. 1 2 National Center for Biotechnology Information. "GBE1 glucan (1,4-alpha-), branching enzyme 1 [ Homo sapiens (human) ]". US. National Library of Medicine.
  4. 1 2 Online Mendelian Inheritance in Man. "Glycogen Branching Enzyme; GBE1". Johns Hopkins University.
  5. 1 2 3 4 5 6 7 8 9 Genetics Home Reference. "GBE1". U.S. National Library of Medicine.
  6. 1 2 3 4 Thon, Vicki; Khalil, Miriam; Cannon, John (1993). "Isolation of Human Glycogen Branching Enzyme cDNAs by Screening Complementation in Yeast" (PDF). The Journal of Biological Chemistry. 268 (10): 7509–7513.
  7. 1 2 3 Abad, Marta; Binderup, Kim; Rios-Steiner, Jorge; Arni, Raghuvir; Preiss, Jack; Geiger, James (August 23, 2002). "The X-ray Crystallographic Structure of Escherichia coli Branching Enzyme" (PDF). The Journal of Biological Chemistry. 44. 277 (44): 42164–42170. doi:10.1074/jbc.m205746200.
  8. ↑ Pal Kuntal; Kumar, Shiva; Sharma, Shikha; Saurabh Kumar; Alam, Mohammad Suhail; Xu, H. Eric; Agrawal, Pushpa; Swaminathan, Kunchithapadam (May 5, 2010). "Crystal Structure of Full-length Mycobacterium tuberculosis H37Rv Glycogen Branching Enzyme INSIGHTS OF N-TERMINAL β-SANDWICH IN SUBSTRATE SPECIFICITY AND ENZYMATIC ACTIVITY". The Journal of Biological Chemistry. 265: 20897–20903.
  9. ↑ Matsuura, Yoshiki; Kusunoki, Masami; Harada, Wakako; Kakudo, Masao (1984). "Structure and Possible Catalytic Residues of Taka-Amylase A". The Journal of Biochemistry. 95 (3): 697–702.
  10. ↑ Buisson, G; Duee, E; Haser, R; Payan, F (December 20, 1987). "Three dimensional structure of porcine pancreatic alpha-amylase at 2.9 A resolution. Role of calcium in structure and activity". The EMBO Journal. 6 (13): 3909–3916. PMC 553868 Freely accessible. PMID 3502087.
  11. ↑ Devillers, Claire; Piper, Mary; Ballicora, Miguel; Preiss, Jack (October 2003). "Characterization of the branching patterns of glycogen branching enzyme truncated on the N-terminus". Archives of Biochemistry and Biophysics. 418 (1): 34–38. doi:10.1016/S0003-9861(03)00341-2.
  12. ↑ Kuriki, Takashi; Stewart, Douglas; Preiss, Jack (1997). "Construction of Chimeric Enzyme out of Maize Endosperm Branching Enzyme I and II: Activity and Properties" (PDF). The Journal of Biological Chemistry. 46: 28999–29004.
  13. ↑ Palomo, Marta; Pijning, Tjaard; Booiman Thijs; Dobruchowska Justyna; Van der Vlist Jeroen; Kralj, Slavko; Planas, Antoni; Loos, Katja; Johannis P. Kamerling; Bauke W. Dijkstra; Marc J. E. C; van der Maarel; Lubbert Dijkhuizen; Hans Leemhuis (February 4, 2011). "Thermus thermophilus Glycoside Hydrolase Family 57 Branching Enzyme Crystal Structure, Mechanism of Action and Products Formed" (PDF). The Journal of Biological Chemistry. 286 (5): 3520–3530. PMC 3030357 Freely accessible. PMID 21097495. doi:10.1074/jbc.m110.179515.
  14. ↑ Santos, Camila; Tonoli, Celisa; Trindade, Daniel; Betzel, Christian; Takata, Hiroki; Kuriki, Takashi; Kanai, Tamotsu; Imanaka, Tadayuki; Arni, Raghuvir; Murakami, Mario (2011). "Structural basis for branching-enzyme activity of glycoside hydrolase family 57: Structure and stability studies of a novel branching enzyme from the hyperthermophilic archaeon Thermococcus Kodakaraensis KOD1" (PDF). Proteins. 79: 547–557. PMID 21104698. doi:10.1002/prot.22902.
  15. ↑ Nogushi, Junji; Chaen, Kimiko; Vu, Nhuan; Akasaka, Taiki; Shimada, Hiroaki; Nakashima, Takashi; Nishi, Aiko; Satoh, Hikaru; Omori, Toshiro; Kakuta, Yoshimuitsu; Makoto, Kimura (April 3, 2011). "Crystal structure of the branching enzyme I (BEI) from Oryza sativa L with implications for catalysis and substrate binding". Glycobiology. 21 (8): 1108–1116. PMID 21493662. doi:10.1093/glycob/cwr049.
  16. ↑ Rose, Steven (1999). The Chemistry of LIfe. Pelican Books. pp. 199–201.
  17. ↑ McKusick, Victor A.; Kniffin, Cassandra L. (May 2, 2016). "OMIM Entry 263570 - Polyglucosan body neuropathy, adult form". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 7 March 2017.
  18. ↑ Mingyi, Chen (2011). Glycogen Storages Diseases chapter of Molecular Pathology of Liver Diseases. Springer. pp. 677–682.
  19. ↑ Bruno C.; Van Diggelen, O.P.; Cassandrini, D.; Gimpelev, M.; Gluffre B.; Donati M.A.; Introvini, P.; Alegria, A.; Assereto, S.; Morandi, L.; Mora, M.; Tonoli, E.; Mascelli, S.; Traverso, M.; Pasquini, E.; Bado, M.; Vilarinho, L.; Van Noort, G.; Mosca, F.; DiMauro, S.; Zara, F.; Minetti, C. (September 28, 2004). "Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV)". Neurology. 63 (6): 1053–1058. PMID 15452297. doi:10.1212/01.wnl.0000138429.11433.0d.
  20. 1 2 3 Klein, Christopher. "Adult Polyglucosan Body Disease".
  21. ↑ Hussain, Abrar; Armistead, Joy; Gushulak, Lara; Kruck, Christa; Pind, Steven; Triggs-Raine, Barbara; Natowicz, Marvin (September 2002). "The adult polyglucosan body disease mutation GBE1 c.1076A>C occurs at high frequency in persons of Ashkenazi Jewish background". Biochemical and Biophysical Research Communications. 426: 286–288. PMID 22943850. doi:10.1016/j.bbrc.2012.08.089.
  22. ↑ "Citrobacter infection data for Gbe1". Wellcome Trust Sanger Institute.
  23. 1 2 3 4 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  24. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  25. ↑ "International Knockout Mouse Consortium".
  26. ↑ "Mouse Genome Informatics".
  27. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. PMC 3572410 Freely accessible. PMID 21677750. doi:10.1038/nature10163.
  28. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. PMID 21677718. doi:10.1038/474262a.
  29. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. PMID 17218247. doi:10.1016/j.cell.2006.12.018.
  30. ↑ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. PMC 3218837 Freely accessible. PMID 21722353. doi:10.1186/gb-2011-12-6-224.

Further reading

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