1ogs

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human acid-beta-glucosidase

Structural highlights

1ogs is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:NAG, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT, TOPSAN

Disease

GBA1_HUMAN Gaucher disease type 3;Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;Gaucher disease type 1;Hereditary late-onset Parkinson disease;Gaucher disease type 2;Fetal Gaucher disease;NON RARE IN EUROPE: Dementia with Lewy body;NON RARE IN EUROPE: Parkinson disease. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.[1] Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Function

GBA1_HUMAN Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose (PubMed:15916907, PubMed:24211208, PubMed:32144204, PubMed:9201993). Plays a central role in the degradation of complex lipids and the turnover of cellular membranes (PubMed:27378698). Through the production of ceramides, participates in the PKC-activated salvage pathway of ceramide formation (PubMed:19279011). Catalyzes the glucosylation of cholesterol, through a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol (PubMed:24211208, PubMed:26724485, PubMed:32144204). GlcCer containing mono-unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose donors for cholesterol glucosylation when compared with GlcCer containing same chain length of saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-enine) (PubMed:24211208). Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide (Probable) (PubMed:26724485). Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol (PubMed:24211208, PubMed:26724485). Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the transfer of galactose between GalCers and cholesterol in vitro, but with lower activity than with GlcCers (PubMed:32144204). Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4-enine) is not a good substrate for hydrolysis, however it is a good xylose donor for transxylosylation activity to form cholesteryl 3-beta-D-xyloside (PubMed:33361282).[2] [3] [4] [5] [6] [7] [8] [9] [10]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the approximately 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non- neuronopathic and neuronopathic disease, respectively. We report the X-ray structure of GlcCerase at 2.0 A resolution. The catalytic domain consists of a (beta/alpha)(8) TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest alpha-helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase.

X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease.,Dvir H, Harel M, McCarthy AA, Toker L, Silman I, Futerman AH, Sussman JL EMBO Rep. 2003 Jul;4(7):704-9. PMID:12792654[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
46 reviews cite this structure
Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function.
Saftig et al. (2009)
45 more
101 other articles
No citations found

See Also

References

  1. ↑ Stone DL, van Diggelen OP, de Klerk JB, Gaillard JL, Niermeijer MF, Willemsen R, Tayebi N, Sidransky E. Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease? Eur J Hum Genet. 1999 May-Jun;7(4):505-9. PMID:10352942 doi:10.1038/sj.ejhg.5200315
  2. ↑ Ron I, Dagan A, Gatt S, Pasmanik-Chor M, Horowitz M. Use of fluorescent substrates for characterization of Gaucher disease mutations. Blood Cells Mol Dis. 2005 Jul-Aug;35(1):57-65. PMID:15916907 doi:10.1016/j.bcmd.2005.03.006
  3. ↑ Kitatani K, Sheldon K, Rajagopalan V, Anelli V, Jenkins RW, Sun Y, Grabowski GA, Obeid LM, Hannun YA. Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide formation. J Biol Chem. 2009 May 8;284(19):12972-8. PMID:19279011 doi:10.1074/jbc.M802790200
  4. ↑ Akiyama H, Kobayashi S, Hirabayashi Y, Murakami-Murofushi K. Cholesterol glucosylation is catalyzed by transglucosylation reaction of β-glucosidase 1. Biochem Biophys Res Commun. 2013 Nov 29;441(4):838-43. PMID:24211208 doi:10.1016/j.bbrc.2013.10.145
  5. ↑ Marques AR, Mirzaian M, Akiyama H, Wisse P, Ferraz MJ, Gaspar P, Ghauharali-van der Vlugt K, Meijer R, Giraldo P, Alfonso P, Irún P, Dahl M, Karlsson S, Pavlova EV, Cox TM, Scheij S, Verhoek M, Ottenhoff R, van Roomen CP, Pannu NS, van Eijk M, Dekker N, Boot RG, Overkleeft HS, Blommaart E, Hirabayashi Y, Aerts JM. Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases. J Lipid Res. 2016 Mar;57(3):451-63. PMID:26724485 doi:10.1194/jlr.M064923
  6. ↑ Magalhaes J, Gegg ME, Migdalska-Richards A, Doherty MK, Whitfield PD, Schapira AH. Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease. Hum Mol Genet. 2016 Aug 15;25(16):3432-3445. PMID:27378698 doi:10.1093/hmg/ddw185
  7. ↑ Akiyama H, Ide M, Nagatsuka Y, Sayano T, Nakanishi E, Uemura N, Yuyama K, Yamaguchi Y, Kamiguchi H, Takahashi R, Aerts JMFG, Greimel P, Hirabayashi Y. Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol. J Biol Chem. 2020 Apr 17;295(16):5257-5277. PMID:32144204 doi:10.1074/jbc.RA119.012502
  8. ↑ Boer DE, Mirzaian M, Ferraz MJ, Zwiers KC, Baks MV, Hazeu MD, Ottenhoff R, Marques ARA, Meijer R, Roos JCP, Cox TM, Boot RG, Pannu N, Overkleeft HS, Artola M, Aerts JM. Human glucocerebrosidase mediates formation of xylosyl-cholesterol by β-xylosidase and transxylosidase reactions. J Lipid Res. 2021;62:100018. PMID:33361282 doi:10.1194/jlr.RA120001043
  9. ↑ Vaccaro AM, Tatti M, Ciaffoni F, Salvioli R, Barca A, Scerch C. Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide. J Biol Chem. 1997 Jul 4;272(27):16862-7. PMID:9201993 doi:10.1074/jbc.272.27.16862
  10. ↑ Akiyama H, Ide M, Nagatsuka Y, Sayano T, Nakanishi E, Uemura N, Yuyama K, Yamaguchi Y, Kamiguchi H, Takahashi R, Aerts JMFG, Greimel P, Hirabayashi Y. Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol. J Biol Chem. 2020 Apr 17;295(16):5257-5277. PMID:32144204 doi:10.1074/jbc.RA119.012502
  11. ↑ Dvir H, Harel M, McCarthy AA, Toker L, Silman I, Futerman AH, Sussman JL. X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 2003 Jul;4(7):704-9. PMID:12792654 doi:10.1038/sj.embor.embor873

Contents


PDB ID 1ogs

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