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== Disease ==
== Disease ==
[https://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN] Defects in GBA are the cause of Gaucher disease (GD) [MIM:[https://omim.org/entry/230800 230800]; also known as glucocerebrosidase deficiency. GD is the most prevalent lysosomal storage disease, characterized by accumulation of glucosylceramide in the reticulo-endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset.<ref>PMID:8294033</ref> [:]<ref>PMID:19286695</ref> <ref>PMID:16293621</ref> <ref>PMID:1974409</ref> <ref>PMID:1972019</ref> <ref>PMID:8432537</ref> <ref>PMID:7916532</ref> <ref>PMID:8112750</ref> <ref>PMID:8076951</ref> <ref>PMID:8790604</ref> <ref>PMID:7627184</ref> <ref>PMID:7627192</ref> <ref>PMID:8937765</ref> <ref>PMID:8829654</ref> <ref>PMID:8829663</ref> <ref>PMID:8889591</ref> <ref>PMID:8780099</ref> <ref>PMID:9182788</ref> <ref>PMID:9217217</ref> <ref>PMID:9279145</ref> <ref>PMID:9153297</ref> <ref>PMID:9061570</ref> <ref>PMID:9554454</ref> <ref>PMID:9683600</ref> <ref>PMID:9637431</ref> <ref>PMID:9516376</ref> <ref>PMID:9851895</ref> <ref>PMID:9650766</ref> <ref>PMID:9554746</ref> <ref>PMID:10206680</ref> <ref>PMID:10340647</ref> <ref>PMID:10360404</ref> <ref>PMID:10744424</ref> <ref>PMID:10352942</ref> <ref>PMID:10447266</ref> <ref>PMID:10796875</ref> <ref>PMID:11992489</ref> <ref>PMID:11933202</ref> <ref>PMID:12204005</ref> <ref>PMID:12847165</ref> <ref>PMID:15292921</ref> <ref>PMID:15826241</ref> <ref>PMID:15605411</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Defects in GBA are the cause of Gaucher disease type 1 (GD1) [MIM:[https://omim.org/entry/230800 230800]; also known as adult non-neuronopathic Gaucher disease. GD1 is characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved.[:]<ref>PMID:19286695</ref> <ref>PMID:8889591</ref> <ref>PMID:10206680</ref> <ref>PMID:10340647</ref> <ref>PMID:12847165</ref> <ref>PMID:15605411</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Defects in GBA are the cause of Gaucher disease type 2 (GD2) [MIM:[https://omim.org/entry/230900 230900]; also known as acute neuronopathic Gaucher disease. GD2 is the most severe form and is universally progressive and fatal. It manifests soon after birth, with death generally occurring before patients reach two years of age.<ref>PMID:19286695</ref> <ref>PMID:9637431</ref> <ref>PMID:9851895</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Defects in GBA are the cause of Gaucher disease type 3 (GD3) [MIM:[https://omim.org/entry/231000 231000]; also known as subacute neuronopathic Gaucher disease. GD3 has central nervous manifestations.<ref>PMID:19286695</ref> <ref>PMID:8780099</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Defects in GBA are the cause of Gaucher disease type 3C (GD3C) [MIM:[https://omim.org/entry/231005 231005]; also known as pseudo-Gaucher disease or Gaucher-like disease.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Defects in GBA are the cause of Gaucher disease perinatal lethal (GDPL) [MIM:[https://omim.org/entry/608013 608013]. It is a distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Note=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.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>  Defects in GBA contribute to susceptibility to Parkinson disease (PARK) [MIM:[https://omim.org/entry/168600 168600]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.<ref>PMID:19286695</ref> <ref>PMID:12847165</ref> <ref>PMID:16148263</ref> <ref>PMID:17620502</ref> <ref>PMID:18332251</ref> <ref>PMID:19846850</ref>
[https://www.uniprot.org/uniprot/GBA1_HUMAN 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.<ref>PMID:10352942</ref>  Disease susceptibility may be associated with variants affecting the gene represented in this entry.
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/GLCM_HUMAN GLCM_HUMAN]  
[https://www.uniprot.org/uniprot/GBA1_HUMAN 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).<ref>PMID:15916907</ref> <ref>PMID:19279011</ref> <ref>PMID:24211208</ref> <ref>PMID:26724485</ref> <ref>PMID:27378698</ref> <ref>PMID:32144204</ref> <ref>PMID:33361282</ref> <ref>PMID:9201993</ref> <ref>PMID:32144204</ref>
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f6/2f61_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f6/2f61_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>

Latest revision as of 10:58, 30 October 2024

Crystal structure of partially deglycosylated acid beta-glucosidaseCrystal structure of partially deglycosylated acid beta-glucosidase

Structural highlights

2f61 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 2.5Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Acid beta-glucosidase (GCase) is a 497-amino acid, membrane-associated lysosomal exo-beta-glucosidase whose defective activity leads to the Gaucher disease phenotypes. To move toward a structure/function map for disease mutations, 52 selected single amino acid substitutions were introduced into GCase, expressed in an insect cell system, purified, and characterized for basic kinetic, stability, and activator response properties. The variant GCases from Gaucher disease patients and selected variant GCases from the mouse had decreased relative k(cat) and differential effects on active site binding and/or attachment of mechanism-based covalent (conduritol B epoxide) or reversible (deoxynojirimycin derivatives) inhibitors. A defect in negatively charged phospholipid activation was present in the majority of variant GCases but was increased in two, N370S and V394L. Deficits in saposin C enhancement of k(cat) were present in variant GCases involving residues 48-122, whereas approximately 2-fold increases were obtained with the L264I GCase. About 50% of variant GCases each had wild-type or increased sensitivity to in vitro cathepsin D digestion. Mapping of these properties onto the crystal structures of GCase indicated wide dispersion of functional properties that can affect catalytic function and stability. Site-directed mutagenesis of cysteine residues showed that the disulfide bonds, Cys(4)-Cys(16) and Cys(18)-Cys(23), and a free Cys(342) were essential for activity; the free Cys(126) and Cys(248) were not. Relative k(cat) was highly sensitive to a His substitution at Arg(496) but not at Arg(495). These studies and high phylogenetic conservation indicate localized and general structural effects of Gaucher disease mutations that were not obvious from the nature of the amino acid substitution, including those predicted to be nondisruptive (e.g. Val --> Leu). These results provide initial studies for the engineering of variant GCases and, potentially, molecular chaperones for therapeutic use.

Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.,Liou B, Kazimierczuk A, Zhang M, Scott CR, Hegde RS, Grabowski GA J Biol Chem. 2006 Feb 17;281(7):4242-53. Epub 2005 Nov 17. PMID:16293621[11]

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

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. ↑ Liou B, Kazimierczuk A, Zhang M, Scott CR, Hegde RS, Grabowski GA. Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. J Biol Chem. 2006 Feb 17;281(7):4242-53. Epub 2005 Nov 17. PMID:16293621 doi:10.1074/jbc.M511110200

2f61, resolution 2.50Å

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