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GBA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1OGS, 1Y7V, 2F61, 2J25, 2NSX, 2NT0, 2NT1, 2V3D, 2V3E, 2V3F, 2VT0, 2WCG, 2WKL, 2XWD, 2XWE, 3GXD, 3GXF, 3GXI, 3GXM, 3KE0, 3KEH, 3RIK, 3RIL
Identifiers
Aliases	GBA, GBA1, GCB, GLUC, glucosylceramidase beta, Glucocerebrosidase
External IDs	OMIM: 606463; MGI: 95665; HomoloGene: 68040; GeneCards: GBA; OMA:GBA - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q22 Start 155,234,452 bp End 155,244,699 bp
Gene location (Mouse) Chr. Chromosome 3 (mouse) Band 3 F1|3 39.01 cM Start 89,110,235 bp End 89,116,273 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium islet of Langerhans placenta blood Pituitary Gland anterior pituitary bone marrow cells right adrenal gland right adrenal cortex left adrenal gland Top expressed in esophagus internal carotid artery external carotid artery lip stroma of bone marrow superior surface of tongue decidua fossa endothelial cell of lymphatic vessel motor neuron More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hydrolase activity, acting on glycosyl bonds protein binding hydrolase activity signaling receptor binding glucosylceramidase activity Cellular component membrane lysosome extracellular exosome lysosomal lumen lysosomal membrane extracellular space Biological process termination of signal transduction skin morphogenesis glycosphingolipid metabolic process positive regulation of protein dephosphorylation lipid metabolism response to testosterone cellular response to starvation negative regulation of interleukin-6 production response to thyroid hormone ceramide biosynthetic process cellular response to tumor necrosis factor sphingosine biosynthetic process positive regulation of proteolysis involved in cellular protein catabolic process regulation of water loss via skin response to estrogen glucosylceramide catabolic process negative regulation of MAP kinase activity response to pH metabolism negative regulation of inflammatory response regulation of macroautophagy sphingolipid metabolic process mitochondrion organization neuron projection development regulation of cellular protein metabolic process positive regulation of proteasomal ubiquitin-dependent protein catabolic process negative regulation of protein homooligomerization cell death in response to oxidative stress positive regulation of protein-containing complex disassembly regulation of protein metabolic process negative regulation of neuron death positive regulation of protein lipidation positive regulation of neuronal action potential positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization autophagosome organization regulation of lysosomal protein catabolic process beta-glucoside catabolic process response to dexamethasone Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2629 14466 Ensembl ENSG00000262446 ENSG00000177628 ENSMUSG00000028048 UniProt P04062 P17439 RefSeq (mRNA) NM_000157 NM_001005741 NM_001005742 NM_001005749 NM_001005750 NM_001171811 NM_001171812 NM_001077411 NM_008094 RefSeq (protein) NP_000148 NP_001005741 NP_001005742 NP_001165282 NP_001165283 NP_001070879 NP_032120 Location (UCSC) Chr 1: 155.23 – 155.24 Mb Chr 3: 89.11 – 89.12 Mb PubMed search
Wikidata
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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 3.2.1.45) that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism that is abundant in cell membranes (particularly skin cells). It is localized in the lysosome, where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.

Structure

β-Glucocerebrosidase is a member of the glycoside hydrolase family 30 and consists of three distinct domains (I-III).

• Three-dimensional PyMol rendering of glucocerebrosidase with three domains highlighted.
• Three-dimensional PyMol rendering of glucocerebrosidase with catalytic residues highlighted.

Domain I (residues 1–27 and 383–414) forms a three-stranded anti-parallel β-sheet. This domain contains two disulfide bridges that are necessary for correct folding, as well as a glycosylated residue (Asn19) that is required for catalytic activity in vivo. Domain II (residues 30–75 and 431–497) consists of two β-sheets that resemble an immunoglobulin fold. Domain III (residues 76–381 and 416–430) is homologous to a TIM barrel and is a highly conserved domain among glycoside hydrolases. Domain III harbors the active site, which binds the substrate glucocerebroside in close proximity to the catalytic residues E340 and E235. Domains I and III are tightly associated, while domains II and III are joined by a disordered linker.

Mechanism

Crystal structures indicate that β-glucocerebrosidase binds the glucose moiety and adjacent O-glycosydic bond of glucocerebroside. The two aliphatic chains of glucocerebroside may remain associated with the lysosomal bilayer or interact with the activating protein Saposin C.

Consistent with other glycoside hydrolases, the mechanism of glucocerebroside hydrolysis by β-glucocerebrosidase involves acid/base catalysis by two glutamic acid residues (E340 and E235) and precedes through a two-step mechanism. In the first step, E340 performs a nucleophilic attack at the carbon of the O-glycosidic linkage to displace the sphingosine moiety, which is simultaneously protonated by E235 as it is released from the active site. In the second step, glucose is hydrolyzed from the E340 residue to regenerate the active enzyme.

Properties

β-Glucocerebrosidase is maximally active at pH 5.5, the pH of the lysosomal compartment. Within the lysosome it remains associated with the membrane, where it binds and degrades its substrate glucocerebroside (GluCer). It requires the activating protein Saposin C as well as negatively charged lipids for maximal catalytic activity. The role of Saposin C is not known; however, it is shown to bind both the lysosomal membrane and the lipid moieties of GluCer, and therefore may recruit GluCer to the active site of the enzyme.

β-Glucocerebrosidase is specifically and irreversibly inhibited by the glucose analog Conduritol B epoxide. Conduritol B epoxide binds to the GCase active site, where the enzyme cleaves its epoxide ring, forming a permanent covalent bond between the enzyme and the inhibitor.

Initially, GCase was thought to be one of the few lysosomal enzymes that does not follow the mannose-6-phosphate pathway for trafficking to the lysosome. A study in I-cell disease fibroblasts (in which the phosphotransferase that puts Mannose 6-phosphate on proteins to target them to the lysosome is defective) showed targeting of GCase to the lysosome independent of the M6P pathway. The lysosomal transporter and integral membrane protein LIMP-2 (Lysosomal Integral Membrane Protein 2) was shown to bind GCase and facilitate transport to the lysosome, demonstrating a mechanism for M6P-independent lysosomal trafficking. This conclusion was called into question when a crystal structure of GCase in complex with LIMP-2 showed a Mannose 6-phosphate moiety on LIMP-2, suggesting the complex can also follow the traditional mannose-6-phosphate pathway.

Clinical significance

Mutations in the glucocerebrosidase gene cause Gaucher's disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides in macrophages that infiltrate many vital organs.

Mutations in the glucocerebrosidase gene are also associated with Parkinson's disease.

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.

Drugs

Alglucerase (Ceredase) was a version of glucocerebrosidase that was harvested from human placental tissue and then modified with enzymes. It was approved by the FDA in 1991 but has been withdrawn from the market due to the approval of similar drugs made with recombinant DNA technology instead of being harvested from tissue. Drugs made recombinantly pose no risk of diseases being transmitted from the tissue used in harvesting, and are less expensive to manufacture.

Recombinant glucocerebrosidases used as drugs include:

• Imiglucerase (Cerezyme)
• Velaglucerase (Vpriv)
• Taliglucerase alfa (Elelyso)

See also

• Closely related enzymes
  • GBA2: acid β-glucosidase (bile acid), also EC 3.2.1.45
  • GBA3: acid β-glucosidase (cytosolic), EC 3.2.1.21

References

1. ^ ENSG00000177628 GRCh38: Ensembl release 89: ENSG00000262446, ENSG00000177628 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000028048 – Ensembl, May 2017
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5. Vielhaber G, Pfeiffer S, Brade L, Lindner B, Goldmann T, Vollmer E, Hintze U, Wittern KP, Wepf R (November 2001). "Localization of ceramide and glucosylceramide in human epidermis by immunogold electron microscopy". The Journal of Investigative Dermatology. 117 (5): 1126–36. doi:10.1046/j.0022-202x.2001.01527.x. PMID 11710923.
6. Rijnboutt S, Aerts HM, Geuze HJ, Tager JM, Strous GJ (March 1991). "Mannose 6-phosphate-independent membrane association of cathepsin D, glucocerebrosidase, and sphingolipid-activating protein in HepG2 cells". The Journal of Biological Chemistry. 266 (8): 4862–8. doi:10.1016/S0021-9258(19)67728-8. hdl:1887/50559. PMID 1848227.
7. ^ Lieberman RL (2011). "A Guided Tour of the Structural Biology of Gaucher Disease: Acid-β-Glucosidase and Saposin C". Enzyme Research. 2011: 973231. doi:10.4061/2011/973231. PMC 3226326. PMID 22145077.
8. Rigden DJ, Jedrzejas MJ, de Mello LV (June 2003). "Identification and analysis of catalytic TIM barrel domains in seven further glycoside hydrolase families". FEBS Letters. 544 (1–3): 103–11. doi:10.1016/S0014-5793(03)00481-2. PMID 12782298.
9. Vocadlo DJ, Davies GJ, Laine R, Withers SG (August 2001). "Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate" (PDF). Nature. 412 (6849): 835–8. Bibcode:2001Natur.412..835V. doi:10.1038/35090602. PMID 11518970. S2CID 205020153.
10. Sinclair G, Pfeifer TA, Grigliatti TA, Choy FY (April 2006). "Secretion of human glucocerebrosidase from stable transformed insect cells using native signal sequences". Biochemistry and Cell Biology. 84 (2): 148–56. doi:10.1139/o05-165. PMID 16609695.
11. Aerts JM, Sa Miranda MC, Brouwer-Kelder EM, Van Weely S, Barranger JA, Tager JM (October 1990). "Conditions affecting the activity of glucocerebrosidase purified from spleens of control subjects and patients with type 1 Gaucher disease". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1041 (1): 55–63. doi:10.1016/0167-4838(90)90122-V. PMID 2223847.
12. Weiler S, Kishimoto Y, O'Brien JS, Barranger JA, Tomich JM (April 1995). "Identification of the binding and activating sites of the sphingolipid activator protein, saposin C, with glucocerebrosidase". Protein Science. 4 (4): 756–64. doi:10.1002/pro.5560040415. PMC 2143096. PMID 7613473.
13. Alattia JR, Shaw JE, Yip CM, Privé GG (October 2006). "Direct visualization of saposin remodelling of lipid bilayers". Journal of Molecular Biology. 362 (5): 943–53. doi:10.1016/j.jmb.2006.08.009. PMID 16949605.
14. Tamargo RJ, Velayati A, Goldin E, Sidransky E (July 2012). "The role of saposin C in Gaucher disease". Molecular Genetics and Metabolism. 106 (3): 257–63. doi:10.1016/j.ymgme.2012.04.024. PMC 3534739. PMID 22652185.
15. Ogawa S, Uetsuki S, Tezuka Y, Morikawa T, Takahashi A, Sato K (June 1999). "Synthesis and evaluation of glucocerebrosidase inhibitory activity of anhydro deoxyinositols from (+)-epi- and (-)-vibo-quercitols". Bioorganic & Medicinal Chemistry Letters. 9 (11): 1493–8. doi:10.1016/S0960-894X(99)00223-1. PMID 10386923.
16. Reczek D, Schwake M, Schröder J, Hughes H, Blanz J, Jin X, Brondyk W, Van Patten S, Edmunds T, Saftig P (November 2007). "LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase". Cell. 131 (4): 770–83. doi:10.1016/j.cell.2007.10.018. PMID 18022370. S2CID 6771697.
17. Glickman JN, Kornfeld S (October 1993). "Mannose 6-phosphate-independent targeting of lysosomal enzymes in I-cell disease B lymphoblasts". The Journal of Cell Biology. 123 (1): 99–108. doi:10.1083/jcb.123.1.99. PMC 2119824. PMID 8408210.
18. Zhao Y, Ren J, Padilla-Parra S, Fry EE, Stuart DI (July 2014). "Lysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor". Nature Communications. 5: 4321. Bibcode:2014NatCo...5.4321Z. doi:10.1038/ncomms5321. PMC 4104448. PMID 25027712.
19. Mucci JM, Rozenfeld P (2015). "Pathogenesis of Bone Alterations in Gaucher Disease: The Role of Immune System". Journal of Immunology Research. 2015: 192761. doi:10.1155/2015/192761. PMC 4433682. PMID 26064996.
20. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A, Rose C, Billette de Villemeur T, Berger MG (February 2017). "A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments". International Journal of Molecular Sciences. 18 (2): 441. doi:10.3390/ijms18020441. PMC 5343975. PMID 28218669.
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23. "Entrez Gene: GBA glucosidase, beta; acid (includes glucosylceramidase)".
24. ^ 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.
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Further reading

• Horowitz M, Zimran A (1994). "Mutations causing Gaucher disease". Human Mutation. 3 (1): 1–11. doi:10.1002/humu.1380030102. PMID 8118460. S2CID 30605941.
• Tayebi N, Stone DL, Sidransky E (October 1999). "Type 2 gaucher disease: an expanding phenotype". Molecular Genetics and Metabolism (Submitted manuscript). 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 (Submitted manuscript). 15 (2): 181–8. doi:10.1002/(SICI)1098-1004(200002)15:2<181::AID-HUMU7>3.0.CO;2-S. PMID 10649495. S2CID 31438997.
• Caillaud C, Poenaru L (2002). "". Journal de la Société de Biologie. 196 (2): 135–40. doi:10.1051/jbio/2002196020135. PMID 12360742. S2CID 81257040.
• Fabrega S, Durand P, Mornon JP, Lehn P (2002). "". Journal de la Société de Biologie. 196 (2): 151–60. doi:10.1051/jbio/2002196020151. PMID 12360744. S2CID 81542873.
• 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

• GeneReviews/NCBI/UW/NIH entry on Gaucher disease
• Glucocerebrosidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Proteopedia Acid-beta-glucosidase

• Biology

• Genes on human chromosome 1
• EC 3.2.1
• Parkinson's disease