8ax3

Structural highlights

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]}

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