Glucocerebrosidase: Difference between revisions

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{{Infobox gene}}
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'''β-Glucocerebrosidase''' (also called '''acid β-glucosidase''', '''D-glucosyl-N-acylsphingosine glucohydrolase''', or '''GCase''') is an [[enzyme]] with [[glucosylceramidase]] activity ({{EC number|3.2.1.45}}) that is needed to cleave, by [[hydrolysis]], the [[glycosidic bond|beta-glucosidic linkage]] of the chemical [[glucocerebroside]], an intermediate in [[glycolipid]] metabolism. It is localized in the [[lysosome]] and has a molecular weight of 59700 [[atomic mass unit|Daltons]].
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== Clinical significance ==
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[[Mutation]]s in the glucocerebrosidase [[gene]] cause [[Gaucher's disease]], a [[lysosomal storage disease]] characterized by an accumulation of glucocerebrosides. A related [[pseudogene]] is approximately 12 kb downstream of this gene on [[chromosome 1]]. [[Alternative splicing]] results in multiple transcript variants encoding the same protein.<ref>{{cite web | title = Entrez Gene: GBA glucosidase, beta; acid (includes glucosylceramidase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2629| accessdate = }}</ref>
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Mutations in the glucocerebrosidase gene are also associated with [[Parkinson's disease]].<ref>{{Cite web | title = PDGene | url = http://www.pdgene.org/ | date = 2008-11-12 | accessdate = 2008-11-13 | publisher = [[Alzheimer Research Forum]] | deadurl = yes | archiveurl = https://web.archive.org/web/20081220041909/http://www.pdgene.org/ | archivedate = 20 December 2008 | df = dmy-all }}</ref><ref name="pmid14728994">{{cite journal | vauthors = Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E | title = Glucocerebrosidase mutations in subjects with parkinsonism | journal = Molecular Genetics and Metabolism | volume = 81 | issue = 1 | pages = 70–3 | date = January 2004 | pmid = 14728994 | doi = 10.1016/j.ymgme.2003.11.004 }}</ref>


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== Drugs ==
{{GNF_Protein_box
[[Alglucerase]] (Ceredase) was a version of glucocerebrosidase that was harvested from human [[placental]] [[biological tissue|tissue]] and then modified with enzymes.<ref name=Deegan>{{cite journal | vauthors = Deegan PB, Cox TM | title = Imiglucerase in the treatment of Gaucher disease: a history and perspective | journal = Drug Design, Development and Therapy | volume = 6 | issue =  | pages = 81–106 | year = 2012 | pmid = 22563238 | pmc = 3340106 | doi = 10.2147/DDDT.S14395 }}</ref> It was approved by the FDA in 1991<ref name="urlwhqlibdoc.who.int">{{cite journal | url = http://whqlibdoc.who.int/druginfo/DRUG_INFO_5_3_1991_p122-125.pdf | title = Regulatory Matters | journal = WHO Drug Information | year = 1991 | volume = 5 | issue = 3 | pages = 123–4 }}</ref> and has been withdrawn from the market<ref name="urlEnzyme-replacement Therapy for Lysosomal Storage Disorders">{{cite web | url = http://www.aetna.com/cpb/medical/data/400_499/0442.html | title = Enzyme-replacement Therapy for Lysosomal Storage Disorders | series = Clinical Policy Bulletin Number: 0442 | publisher = Aetna | date = 2014-08-08 }}</ref><ref name="urlwww.fda.gov">{{cite web | url = http://www.fda.gov/downloads/drugs/informationondrugs/ucm300963.pdf | title = FDA Prescription and Over-the-Counter Drug Product List | publisher = U.S. Food and Drug Administration | series = Additions/Deletions for Prescription Drug Product List | date = March 2012 }}</ref> due to the approval of similar drugs made with [[recombinant DNA]] technology instead of being harvested from tissue; drugs made recombinantly, since there is no concern about diseases being transmitted from the tissue used in harvesting, and are less expensive to manufacture.<ref name=Deegan/>
| image = PBB_Protein_GBA_image.jpg
| image_source = Acid &beta;-glucosidase, drawn from {{PDB|1OGS}}.
| PDB = {{PDB2|1ogs}}, {{PDB2|1y7v}}, {{PDB2|2f61}}, {{PDB2|2j25}}, {{PDB2|2nsx}}, {{PDB2|2nt0}}, {{PDB2|2nt1}}
| Name = Glucosidase, beta; acid (includes glucosylceramidase)
| HGNCid = 4177
| Symbol = GBA
  | AltSymbols =; GBA1; GCB; GLUC
| OMIM = 606463
| ECnumber =
| Homologene = 68040
| MGIid = 95665
  | GeneAtlas_image1 = PBB_GE_GBA_209093_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_GBA_210589_s_at_tn.png
| Function = {{GNF_GO|id=GO:0003824 |text = catalytic activity}} {{GNF_GO|id=GO:0004348 |text = glucosylceramidase activity}} {{GNF_GO|id=GO:0016798 |text = hydrolase activity, acting on glycosyl bonds}} {{GNF_GO|id=GO:0043169 |text = cation binding}}  
| Component = {{GNF_GO|id=GO:0005764 |text = lysosome}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0005975 |text = carbohydrate metabolic process}} {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006665 |text = sphingolipid metabolic process}} {{GNF_GO|id=GO:0007040 |text = lysosome organization and biogenesis}} {{GNF_GO|id=GO:0008152 |text = metabolic process}}  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2629
    | Hs_Ensembl = ENSG00000177628
    | Hs_RefseqProtein = NP_000148
    | Hs_RefseqmRNA = NM_000157
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 153470867
    | Hs_GenLoc_end = 153481112
    | Hs_Uniprot = P04062
    | Mm_EntrezGene = 14466
    | Mm_Ensembl = ENSMUSG00000028048
    | Mm_RefseqmRNA = NM_001077411
    | Mm_RefseqProtein = NP_001070879
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 3
    | Mm_GenLoc_start = 89288855
    | Mm_GenLoc_end = 89294608
    | Mm_Uniprot = Q78NR7
  }}
}}
__NOTOC__
'''Glucocerebrosidase''' (also called glucosylceramidase, β-glucosidase, or D-glucosyl-N-acylsphingosine glucohydrolase) is an [[enzyme]] ({{EC number|3.2.1.45}}) that is needed to cleave, by [[hydrolysis]], the beta-glucosidic linkage of the chemical [[glucocerebroside]], an intermediate in glycolipid metabolism. It is localized in the [[lysosome]] and has a molecular weight of 59700 Daltons.  


Mutations in the gene cause [[Gaucher disease]], a [[lysosomal storage disease]] characterized by an accumulation of glucocerebrosides. A related [[pseudogene]] is approximately 12 kb downstream of this gene on [[chromosome 1]]. [[Alternative splicing]] results in multiple transcript variants encoding the same protein.<ref>{{cite web | title = Entrez Gene: GBA glucosidase, beta; acid (includes glucosylceramidase)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2629| accessdate = }}</ref>
Recombinant glucocerebrosidases used as drugs include:<ref name="pmid23233555">{{cite journal | vauthors = Grabowski GA | title = Gaucher disease and other storage disorders | journal = Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | volume = 2012 | issue =  | pages = 13–8 | year = 2012 | pmid = 23233555 | url=http://asheducationbook.hematologylibrary.org/content/2012/1/13.long| doi = 10.1182/asheducation-2012.1.13 | doi-broken-date = 2017-08-14 }}</ref>
* [[Imiglucerase]] (Cerezyme)<ref name=Deegan/>
* [[Velaglucerase]] (Vpriv)<ref name=Deegan/>
* [[Taliglucerase alfa]] (Elelyso)<ref>{{cite news|last=Yukhananov|first=Anna|title=U.S. FDA approves Pfizer/Protalix drug for Gaucher|url=http://www.chicagotribune.com/health/sns-rt-us-fda-gaucherbre8401jz-20120501,0,5155428.story|accessdate=2 May 2012|newspaper=[[Chicago Tribune]]|date=1 May 2012|agency=[[Reuters]]}}{{dead link|date=October 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>


==See also==
== See also ==
* [[Imiglucerase]]
* Closely related enzymes
* [[Beta-glucosidase]]
** [[GBA2]]: acid β-glucosidase (bile acid), also {{EC number|3.2.1.45}}
** [[GBA3]]: acid β-glucosidase (cytosolic), {{EC number|3.2.1.21}}


==References==
== References ==
{{reflist|2}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Horowitz M, Zimran A | title = Mutations causing Gaucher disease | journal = Human Mutation | volume = 3 | issue = 1 | pages = 1–11 | year = 1994 | pmid = 8118460 | doi = 10.1002/humu.1380030102 }}
| citations =
* {{cite journal | vauthors = Tayebi N, Stone DL, Sidransky E | title = Type 2 gaucher disease: an expanding phenotype | journal = Molecular Genetics and Metabolism | volume = 68 | issue = 2 | pages = 209–19 | date = October 1999 | pmid = 10527671 | doi = 10.1006/mgme.1999.2918 }}
*{{cite journal | author=Horowitz M, Zimran A |title=Mutations causing Gaucher disease. |journal=Hum. Mutat. |volume=3 |issue= 1 |pages= 1-11 |year= 1994 |pmid= 8118460 |doi= 10.1002/humu.1380030102 }}
* {{cite journal | vauthors = Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E | title = Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease | journal = Human Mutation | volume = 15 | issue = 2 | pages = 181–8 | year = 2000 | pmid = 10649495 | doi = 10.1002/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S }}
*{{cite journal | author=Tayebi N, Stone DL, Sidransky E |title=Type 2 gaucher disease: an expanding phenotype. |journal=Mol. Genet. Metab. |volume=68 |issue= 2 |pages= 209-19 |year= 2000 |pmid= 10527671 |doi= 10.1006/mgme.1999.2918 }}
* {{cite journal | vauthors = Caillaud C, Poenaru L | title = [Gaucher's and Fabry's diseases: biochemical and genetic aspects] | journal = Journal De La Société De Biologie | volume = 196 | issue = 2 | pages = 135–40 | year = 2002 | pmid = 12360742 | doi =  }}
*{{cite journal | author=Stone DL, Tayebi N, Orvisky E, ''et al.'' |title=Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. |journal=Hum. Mutat. |volume=15 |issue= 2 |pages= 181-8 |year= 2000 |pmid= 10649495 |doi= 10.1002/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S }}
* {{cite journal | vauthors = Fabrega S, Durand P, Mornon JP, Lehn P | title = [The active site of human glucocerebrosidase: structural predictions and experimental validations] | journal = Journal De La Société De Biologie | volume = 196 | issue = 2 | pages = 151–60 | year = 2002 | pmid = 12360744 | doi =  }}
*{{cite journal | author=Caillaud C, Poenaru L |title=[Gaucher's and Fabry's diseases: biochemical and genetic aspects] |journal=J. Soc. Biol. |volume=196 |issue= 2 |pages= 135-40 |year= 2002 |pmid= 12360742 |doi=  }}
* {{cite journal | vauthors = Alfonso P, Aznarez S, Giralt M, Pocovi M, Giraldo P | title = Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain | journal = Journal of Human Genetics | volume = 52 | issue = 5 | pages = 391–6 | year = 2007 | pmid = 17427031 | doi = 10.1007/s10038-007-0135-4 | author6 = Spanish Gaucher's Disease Registry }}
*{{cite journal | author=Fabrega S, Durand P, Mornon JP, Lehn P |title=[The active site of human glucocerebrosidase: structural predictions and experimental validations] |journal=J. Soc. Biol. |volume=196 |issue= 2 |pages= 151-60 |year= 2002 |pmid= 12360744 |doi=  }}
*{{cite journal | author=Alfonso P, Aznarez S, Giralt M, ''et al.'' |title=Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. |journal=J. Hum. Genet. |volume=52 |issue= 5 |pages= 391-6 |year= 2007 |pmid= 17427031 |doi= 10.1007/s10038-007-0135-4 }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=gaucher  GeneReviews/NCBI/UW/NIH entry on Gaucher disease]
* {{MeshName|Glucocerebrosidase}}
* {{MeshName|Glucocerebrosidase}}
* {{Proteopedia|Acid-beta-glucosidase}}
{{PDB Gallery|geneid=2629}}
{{Sphingolipid metabolism enzymes}}
{{Sugar hydrolases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
{{Use dmy dates|date=April 2017}}


[[Category:EC 3.2.1]]
[[Category:EC 3.2.1]]
{{hydrolase-stub}}
 
{{Sugar hydrolases}}
 
{{Sphingolipid metabolism enzymes}}
{{3.2-enzyme-stub}}
[[he:גלוקוצרברוזידאז]]
[[ja:グルコセレブロシダーゼ]]
[[pt:Glucocerebrosídeo]]
{{WikiDoc Sources}}

Revision as of 03:12, 20 October 2017

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Ensembl

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

β-Glucocerebrosidase (also called acid β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase) is an enzyme with glucosylceramidase activity (EC 3.2.1.45) that is needed to cleave, by hydrolysis, the beta-glucosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism. It is localized in the lysosome and has a molecular weight of 59700 Daltons.

Clinical significance

Mutations in the glucocerebrosidase gene cause Gaucher's disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants encoding the same protein.[1]

Mutations in the glucocerebrosidase gene are also associated with Parkinson's disease.[2][3]

Drugs

Alglucerase (Ceredase) was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes.[4] It was approved by the FDA in 1991[5] and has been withdrawn from the market[6][7] due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue; drugs made recombinantly, since there is no concern about diseases being transmitted from the tissue used in harvesting, and are less expensive to manufacture.[4]

Recombinant glucocerebrosidases used as drugs include:[8]

See also

References

  1. ↑ "Entrez Gene: GBA glucosidase, beta; acid (includes glucosylceramidase)".
  2. ↑ "PDGene". Alzheimer Research Forum. 12 November 2008. Archived from the original on 20 December 2008. Retrieved 13 November 2008.
  3. ↑ Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E (January 2004). "Glucocerebrosidase mutations in subjects with parkinsonism". Molecular Genetics and Metabolism. 81 (1): 70–3. doi:10.1016/j.ymgme.2003.11.004. PMID 14728994.
  4. ↑ 4.0 4.1 4.2 4.3 Deegan PB, Cox TM (2012). "Imiglucerase in the treatment of Gaucher disease: a history and perspective". Drug Design, Development and Therapy. 6: 81–106. doi:10.2147/DDDT.S14395. PMC 3340106. PMID 22563238.
  5. ↑ "Regulatory Matters" (PDF). WHO Drug Information. 5 (3): 123–4. 1991.
  6. ↑ "Enzyme-replacement Therapy for Lysosomal Storage Disorders". Clinical Policy Bulletin Number: 0442. Aetna. 2014-08-08.
  7. ↑ "FDA Prescription and Over-the-Counter Drug Product List" (PDF). Additions/Deletions for Prescription Drug Product List. U.S. Food and Drug Administration. March 2012.
  8. ↑ Grabowski GA (2012). "Gaucher disease and other storage disorders". Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2012: 13–8. doi:10.1182/asheducation-2012.1.13 (inactive 2017-08-14). PMID 23233555.
  9. ↑ Yukhananov, Anna (1 May 2012). "U.S. FDA approves Pfizer/Protalix drug for Gaucher". Chicago Tribune. Reuters. Retrieved 2 May 2012.[permanent dead link]

Further reading

  • Horowitz M, Zimran A (1994). "Mutations causing Gaucher disease". Human Mutation. 3 (1): 1–11. doi:10.1002/humu.1380030102. PMID 8118460.
  • Tayebi N, Stone DL, Sidransky E (October 1999). "Type 2 gaucher disease: an expanding phenotype". Molecular Genetics and Metabolism. 68 (2): 209–19. doi:10.1006/mgme.1999.2918. PMID 10527671.
  • Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E (2000). "Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease". Human Mutation. 15 (2): 181–8. doi:10.1002/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S. PMID 10649495.
  • Caillaud C, Poenaru L (2002). "[Gaucher's and Fabry's diseases: biochemical and genetic aspects]". Journal De La Société De Biologie. 196 (2): 135–40. PMID 12360742.
  • Fabrega S, Durand P, Mornon JP, Lehn P (2002). "[The active site of human glucocerebrosidase: structural predictions and experimental validations]". Journal De La Société De Biologie. 196 (2): 151–60. PMID 12360744.
  • Alfonso P, Aznarez S, Giralt M, Pocovi M, Giraldo P (2007). "Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain". Journal of Human Genetics. 52 (5): 391–6. doi:10.1007/s10038-007-0135-4. PMID 17427031.

External links


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