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• W2895028012 abstract "Glycosyl hydrolases (GHs) are carbohydrate-active enzymes that hydrolyze a specific β-glycosidic bond in glycoconjugate substrates; β-glucosidases degrade glucosylceramide, a ubiquitous glycosphingolipid. GHs are grouped into structurally similar families that themselves can be grouped into clans. GH1, GH5, and GH30 glycosidases belong to clan A hydrolases with a catalytic (β/α)8 TIM barrel domain, whereas GH116 belongs to clan O with a catalytic (α/α)6 domain. In humans, GH abnormalities underlie metabolic diseases. The lysosomal enzyme glucocerebrosidase (family GH30), deficient in Gaucher disease and implicated in Parkinson disease etiology, and the cytosol-facing membrane-bound glucosylceramidase (family GH116) remove the terminal glucose from the ceramide lipid moiety. Here, we compare enzyme differences in fold, action, dynamics, and catalytic domain stabilization by binding site occupancy. We also explore other glycosidases with reported glycosylceramidase activity, including human cytosolic β-glucosidase, intestinal lactase-phlorizin hydrolase, and lysosomal galactosylceramidase. Last, we describe the successful translation of research to practice: recombinant glycosidases and glucosylceramide metabolism modulators are approved drug products (enzyme replacement therapies). Activity-based probes now facilitate the diagnosis of enzyme deficiency and screening for compounds that interact with the catalytic pocket of glycosidases. Future research may deepen the understanding of the functional variety of these enzymes and their therapeutic potential. Glycosyl hydrolases (GHs) are carbohydrate-active enzymes that hydrolyze a specific β-glycosidic bond in glycoconjugate substrates; β-glucosidases degrade glucosylceramide, a ubiquitous glycosphingolipid. GHs are grouped into structurally similar families that themselves can be grouped into clans. GH1, GH5, and GH30 glycosidases belong to clan A hydrolases with a catalytic (β/α)8 TIM barrel domain, whereas GH116 belongs to clan O with a catalytic (α/α)6 domain. In humans, GH abnormalities underlie metabolic diseases. The lysosomal enzyme glucocerebrosidase (family GH30), deficient in Gaucher disease and implicated in Parkinson disease etiology, and the cytosol-facing membrane-bound glucosylceramidase (family GH116) remove the terminal glucose from the ceramide lipid moiety. Here, we compare enzyme differences in fold, action, dynamics, and catalytic domain stabilization by binding site occupancy. We also explore other glycosidases with reported glycosylceramidase activity, including human cytosolic β-glucosidase, intestinal lactase-phlorizin hydrolase, and lysosomal galactosylceramidase. Last, we describe the successful translation of research to practice: recombinant glycosidases and glucosylceramide metabolism modulators are approved drug products (enzyme replacement therapies). Activity-based probes now facilitate the diagnosis of enzyme deficiency and screening for compounds that interact with the catalytic pocket of glycosidases. Future research may deepen the understanding of the functional variety of these enzymes and their therapeutic potential. Glycoconjugates play essential roles in diverse biological processes and abnormalities and have been linked to multiple pathologies. The staggering structural diversity of glycoconjugates stems from the almost infinite possible combinations by which multiple monosaccharide building blocks may be linked with each other (1.Laine R.A. A calculation of all possible oligosaccharide isomers both branched and linear yields 1.05x10(12) structures for a reducing hexasaccharide–the isomer-barrier to development of single-method saccharide sequencing or synthesis systems.Glycobiology. 1994; 4: 759-767Crossref PubMed Google Scholar). For instance, 1,056 unique trisaccharides can be formed just from 3 different monosaccharides. Polysaccharides are very stable compounds: their spontaneous hydrolysis takes place at a rate of 10−15 s−1, corresponding to a half-life of 4.7 million years (2.Wolfenden R. Lu X.D. Young G. Spontaneous hydrolysis of glycosides.J. Am. Chem. Soc. 1998; 120: 6814-6815Crossref Scopus (186) Google Scholar). To allow for the efficient metabolism of glycoconjugates, enzymes have evolved as specialized catalysts. In most organisms, an estimated 1% to 3% of the genes encode carbohydrate-active enzymes (3.Davies G.J. Gloster T.M. Henrissat B. Recent structural insights into the expanding world of carbohydrate-active enzymes.Curr. Opin. Struct. Biol. 2005; 15: 637-645Crossref PubMed Scopus (216) Google Scholar). Among these are glycoside hydrolases (GHs) that can enhance the rate of hydrolysis of specific carbohydrate glycosidic bonds in glycoconjugates more than 1017 times (2.Wolfenden R. Lu X.D. Young G. Spontaneous hydrolysis of glycosides.J. Am. Chem. Soc. 1998; 120: 6814-6815Crossref Scopus (186) Google Scholar). These GH enzymes show marked specificity regarding number, position, and configuration of the hydroxyl groups in their substrate sugar. They are widely applied in biotechnology, for example, in biofuel production, paper pulp bleaching, and the food industry (4.Garg S. Xylanase: applications in biofuel production.Curr. Metabolomics. 2016; 4: 23-37Crossref Google Scholar, 5.Collins T. Hoyoux A. Dutron A. Georis J. Genot B. Dauvrin T. Arnaut F. Gerday C. Feller G. Use of glycoside hydrolase family 8 xylanases in baking.J. Cereal Sci. 2006; 43: 79-84Crossref Scopus (81) Google Scholar). Likewise, specific GH inhibitors are extensively used as agrochemicals and therapeutic agents (6.Asano N. Nash R.J. Molyneux R.J. Fleet G.W.J. Sugar-mimic glycosidase inhibitors: natural occurrence, biological activity and prospects for therapeutic application.Tetrahedron Asymmetry. 2000; 11: 1645-1680Crossref Scopus (1009) Google Scholar, 7.von Itzstein M. Colman P. Design and synthesis of carbohydrate-based inhibitors of protein-carbohydrate interactions.Curr. Opin. Struct. Biol. 1996; 6: 703-709Crossref PubMed Scopus (41) Google Scholar, 8.Asano N. Glycosidase inhibitors: update and perspectives on practical use.Glycobiology. 2003; 13: 93R-104RCrossref PubMed Scopus (623) Google Scholar). Abnormalities in GHs underlie metabolic disorders in humans, for instance, inherited lysosomal storage disorders and lactose intolerance (9.Neufeld E.F. Lysosomal storage diseases.Annu. Rev. Biochem. 1991; 60: 257-280Crossref PubMed Google Scholar, 10.Sibley E. Carbohydrate intolerance.Curr. Opin. Gastroenterol. 2004; 20: 162-167Crossref PubMed Scopus (13) Google Scholar). GH enzymes differ in substrate specificity, mode of enzymatic attack (exo- vs. endoenzymes), and stereochemical mechanism and outcome (retaining vs. inverting enzymes) (11.Davies G.J. Williams S.J. Carbohydrate-active enzymes: sequences, shapes, contortions and cells.Biochem. Soc. Trans. 2016; 44: 79-87Crossref PubMed Scopus (25) Google Scholar). Over the last 20 years, the Carbohydrate-Active Enzymes database (http://www.cazy.org) has been developed. It distinguishes families of structurally related catalytic enzymes that degrade, modify, or create glycosidic bonds and identifies evolutionarily related families of GHs using the classification introduced by Bernard Henrissat (12.Henrissat B. A classification of glycosyl hydrolases based on amino-acid-sequence similarities.Biochem. J. 1991; 280: 309-316Crossref PubMed Google Scholar, 13.Henrissat B. Davies G. Structural and sequence-based classification of glycoside hydrolases.Curr. Opin. Struct. Biol. 1997; 7: 637-644Crossref PubMed Scopus (1312) Google Scholar). At present, >140 discrete GH families are known (11.Davies G.J. Williams S.J. Carbohydrate-active enzymes: sequences, shapes, contortions and cells.Biochem. Soc. Trans. 2016; 44: 79-87Crossref PubMed Scopus (25) Google Scholar). All eukaryote cells contain the glycosphingolipid β-glucosylceramide (GlcCer). In humans, the metabolism of GlcCer implies the removal of the terminal glucose from the ceramide lipid backbone by the lysosomal enzyme glucocerebrosidase (GBA1; family GH30), the cytosol-facing membrane-bound glucosylceramidase (GBA2; family GH116), and cytosolic GBA3 (family GH1) (14.Aerts J.M. Hollak C. Boot R. Groener A. Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 905-914Crossref PubMed Scopus (66) Google Scholar). Endoglycosylceramidases (family GH5) from lower organisms cleave the same linkage in complex glycosphingolipids, releasing the oligosaccharide in the process. A relatively common inherited lysosomal storage disorder, Gaucher disease, results from mutations in the GBA gene (15.Gaucher P.C.E. De l'épithélioma primitif de la rate. Hyper­trophie idiopathique de la rate sans leucémie.PhD Dissertation. University of Paris, Paris, France. French. 1882; Google Scholar, 16.Brady R.O. Kanfer J. Bradley R. Shapiro D. Demon­stration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease.J. Clin. Invest. 1966; 45: 1112-1115Crossref PubMed Google Scholar). Most common are mutations that result in impaired folding and lysosomal stability of GBA1 (14.Aerts J.M. Hollak C. Boot R. Groener A. Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 905-914Crossref PubMed Scopus (66) Google Scholar, 17.Zimmer K.P. le Coutre P. Aerts H.M. Harzer K. Fukuda M. O'Brien J.S. Naim H.Y. Intracellular transport of acid β-glucosidase and lysosome-associated membrane proteins is affected in Gaucher's disease (G202R mutation).J. Pathol. 1999; 188: 407-414Crossref PubMed Scopus (0) Google Scholar). Moreover, deficiency of this enzyme has been implicated in the etiology of Parkinson disease (18.Sidransky E. Nalls M.A. Aasly J.O. Aharon-Peretz J. Annesi G. Barbosa E.R. Bar-Shira A. Berg D. Bras J. Brice A. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.N. Engl. J. Med. 2009; 361: 1651-1661Crossref PubMed Scopus (1109) Google Scholar, 19.Siebert M. Sidransky E. Westbroek W. Glucocere­brosidase is shaking up the synucleinopathies.Brain. 2014; 137: 1304-1322Crossref PubMed Google Scholar). Inherited deficiency of GBA2 results in spastic paraplegia and cerebellar ataxia (20.van Weely S. Brandsma M. Strijland A. Tager J.M. Aerts J.M. Demonstration of the existence of a second, non-lysosomal glucocerebrosidase that is not deficient in Gaucher disease.Biochim. Biophys. Acta. 1993; 1181: 55-62Crossref PubMed Scopus (102) Google Scholar, 21.Hammer M.B. Eleuch-Fayache G. Schottlaender L.V. Nehdi H. Gibbs J.R. Arepalli S.K. Chong S.B. Hernandez D.G. Sailer A. Liu G. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.Am. J. Hum. Genet. 2013; 92: 245-251Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 22.Martin E. Schüle R. Smets K. Rastetter A. Boukhris A. Loureiro J.L. Gonzalez M.A. Mundwiller E. Deconinck T. Wessner M. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia.Am. J. Hum. Genet. 2013; 92: 238-244Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 23.Kancheva D. Atkinson D. De Rijk P. Zimon M. Chamova T. Mitev V. Yaramis A. Fabrizi G.M. Topaloglu H. Tournev I. Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing.Genet. Med. 2016; 18: 600-607Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 24.Sultana S. Reichbauer J. Schüle R. Mochel F. Synofzik M. van der Spoel A.C. Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46).Biochem. Biophys. Res. Commun. 2015; 465: 35-40Crossref PubMed Scopus (23) Google Scholar). This review focuses on the retaining β-glucosidases involved in the metabolism of GlcCer and complex glycosphingolipids. Table 1 presents an overview of the discussed β-glycosylceramidases and their GH families. Addressed are their fold topology, dynamics, mode of action, and catalytic domain stabilization by binding site occupancy. The more recent translation of fundamental knowledge on these glycosidases and their selective inhibitors to applications in industry and the clinic are discussed.TABLE 1β-GlycosylceramidasesFoldClanGH Familyβ-Glycosylceramidase Members(β/α)8AGH1LPH; GBA3GH5EGCII; EGCI; endogalactosylceramidase EGALC; glucocerebrosidase EGCrP1; steryl-β-glucosidase EGCrP2; steryl-β-glucosidase EGH1GH30GBA1GH59GALC(α/α)6OGH116GBA2 Open table in a new tab Retaining β-glycosidases generally employ the Koshland double-displacement mechanism with a catalytic nucleophile and acid/base for catalysis (25.Rye C.S. Withers S.G. Glycosidase mechanisms.Curr. Opin. Chem. Biol. 2000; 4: 573-580Crossref PubMed Scopus (396) Google Scholar). The first step is a nucleophilic attack by the catalytic amino acid to the anomeric carbon of the glycosidic substrate. Concomitantly with the nucleophilic attack, a proton transfer from the acid/base residue followed by departure of the leaving group from the aglycon site occurs during the first transition state, from which an enzyme-glycoside covalent intermediate emerges. In the second step, an activated water molecule acts as a nucleophile with the assistance of the general acid/base to deglycosylate the nucleophile residue. The product is released from the enzymatic pocket through a second oxocarbenium ion transition state, and a new catalytic cycle can take place (Fig. 1). Thus, the reaction involves two transient oxocarbenium ion-like states, and the sugar substrate adopts different itineraries depending on its pyranose ring configuration (25.Rye C.S. Withers S.G. Glycosidase mechanisms.Curr. Opin. Chem. Biol. 2000; 4: 573-580Crossref PubMed Scopus (396) Google Scholar). In the case of GH1, GH5, and GH30 enzymes, the substrate itinerary is supposed to follow the 1S3 → 4H3 → 4C1 → 4H3 → 4C1 pathway for the Michaelis complex → transition state → covalent intermediate → transition state → product trajectory (26.Speciale G. Thompson A.J. Davies G.J. Williams S.J. Dissecting conformational contributions to glycosidase catalysis and inhibition.Curr. Opin. Struct. Biol. 2014; 28: 1-13Crossref PubMed Scopus (88) Google Scholar, 27.Ardèvol A. Rovira C. Reaction mechanisms in carbohydrate-active enzymes: glycoside hydrolases and glycosyltransferases. Insights from ab initio quantum mechanics/molecular mechanics dynamic simulations.J. Am. Chem. Soc. 2015; 137: 7528-7547Crossref PubMed Scopus (0) Google Scholar). Several retaining β-glycosidases are reported to also be able to transglycosylate when provided with a suitable aglycon acceptor (Fig. 1) (28.Danby P.M. Withers S.G. Advances in enzymatic glycoside synthesis.ACS Chem. Biol. 2016; 11: 1784-1794Crossref PubMed Scopus (79) Google Scholar). Transglycosylation capacity has been found to be influenced by temperature, pH, and the presence of organic solvent (29.Ribeirão M. Pereira-Chioccola V.L. Eichinger D. Rodrigues M.M. Schenkman S. Temperature differences for trans-glycosylation and hydrolysis reaction reveal an acceptor binding site in the catalytic mechanism of Trypanosoma cruzi trans-sialidase.Glycobiology. 1997; 7: 1237-1246Crossref PubMed Scopus (66) Google Scholar, 30.Eneyskaya E.V. Brumer H. Backinowsky L.V. Ivanen D.R. Kulminskaya A.A. Shabalin K.A. Neustroev K.N. Enzymatic synthesis of β-xylanase substrates: transglycosylation reactions of the β-xylosidase from Aspergillus sp.Carbohydr. Res. 2003; 338: 313-325Crossref PubMed Scopus (0) Google Scholar, 31.Akaike E. Tsutsumida M. Osumi K. Fujita M. Yamanoi T. Yamamoto K. Fujita K. High efficiency of transferring a native sugar chain from a glycopeptide by a microbial endoglycosidase in organic solvents.Carbohydr. Res. 2004; 339: 719-722Crossref PubMed Scopus (34) Google Scholar). This reaction has been successfully applied to synthesize oligosaccharides and glycoconjugates. The transglycosylation capacity of (mutant) β-glycosidases, in combination with their high regio- and stereospecificity, makes them an attractive instrument for synthesizing complex carbohydrates. All GH5 and GH30 glycosidases have an (α/β)8 TIM barrel catalytic domain with two conserved carboxylic acid residues between β-strands 4 and 7, serving as the nucleophile and acid/base catalytic dyad. The distance between these two catalytic residues is highly conserved, often between 5 and 5.5 Å between the Oε1 and Oε2 atoms of the nucleophile and acid/base glutamic acid residues, respectively (32.Davies G. Henrissat B. Structures and mechanisms of glycosyl hydrolases.Structure. 1995; 3: 853-859Abstract Full Text Full Text PDF PubMed Google Scholar). GH5 and GH30 glycosidases comprise fungal, bacterial, and eukaryotic β-1-4 glucanases, β-1-4 mannases, β-1-4 xylanases, cellulases, and glucosylceramidases (33.St John F.J. Gonzalez J.M. Pozharski E. Consolidation of glycosyl hydrolase family 30: a dual domain 4/7 hydrolase family consisting of two structurally distinct groups.FEBS Lett. 2010; 584: 4435-4441Crossref PubMed Scopus (85) Google Scholar, 34.Aspeborg H. Coutinho P.M. Wang Y. Brumer H. Henrissat B. Evolution, substrate specificity and subfamily classification of glycoside hydrolase family 5 (GH5).BMC Evol. Biol. 2012; 12: 186Crossref PubMed Scopus (264) Google Scholar). GH5 glycosidases have been further classified into 53 subfamilies, providing a more accurate prediction of function of yet uncharacterized proteins (34.Aspeborg H. Coutinho P.M. Wang Y. Brumer H. Henrissat B. Evolution, substrate specificity and subfamily classification of glycoside hydrolase family 5 (GH5).BMC Evol. Biol. 2012; 12: 186Crossref PubMed Scopus (264) Google Scholar). A new classification approach has led to the transfer of five GH5 protein subgroups to GH30 group 2, including the lysosomal enzyme GBA1 (Fig. 2C). The GH5 and GH30 glycosidases resemble each other regarding protein structure and substrate specificities but show differences in topology (33.St John F.J. Gonzalez J.M. Pozharski E. Consolidation of glycosyl hydrolase family 30: a dual domain 4/7 hydrolase family consisting of two structurally distinct groups.FEBS Lett. 2010; 584: 4435-4441Crossref PubMed Scopus (85) Google Scholar, 35.Durand P. Lehn P. Callebaut I. Fabrega S. Henrissat B. Mornon J-P. Active-site motifs of lysosomal acid hydrolases: invariant features of clan GH-A glycosyl hydrolases deduced from hydrophobic cluster analysis.Glycobiology. 1997; 7: 277-284Crossref PubMed Scopus (0) Google Scholar). For instance, one characteristic of the GH30 enzymes is the fusion of the (α/β)8 barrel catalytic domain with a β-structure consisting of an immunoglobulin-like fold (Fig. 2F). This β-structure, poorly conserved in GH30 glycosidases, is absent in GH5 enzymes (Fig. 2D). Characteristically, the TIM barrel of most GH5 enzymes is sealed with a cap-like structure that does not occur in GH30 enzymes. A special case stands for endoglycoceramidase II (EGCII) from Rhodococcus sp. that removes the entire oligosaccharide from gangliosides such as GM3 and GM1 (Fig. 2B) (36.Ito M. Yamagata T. A novel glycosphingolipid-degrading enzyme cleaves the linkage between the oligosaccharide and ceramide of neutral and acidic glycosphingolipids.J. Biol. Chem. 1986; 261: 14278-14282Abstract Full Text PDF PubMed Google Scholar). EGCII has two fold domains, a catalytic TIM barrel adjoined to a β-sandwich domain, as in GH30 members. However, the β-structure domain differs from the ones observed in most GH30 enzymes in that it is composed of only eight β-strands in a barrel geometry (Fig. 2E). The TIM barrel of EGCII is not capped by the small β-strand sheet observed in most other GH5 family members (37.Caines M.E. Vaughan M.D. Tarling C.A. Hancock S.M. Warren R.A.J. Withers S.G. Strynadka N.C. Structural and mechanistic analyses of endo-glycoceramidase II, a membrane-associated family 5 glycosidase in the Apo and GM3 ganglioside-bound forms.J. Biol. Chem. 2007; 282: 14300-14308Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Unlike EGCII, endoglycoceramidase I (EGCI) (another endoglycoceramidase from R. equi with broader substrate specificity than EGCII) displays a typical GH5 TIM barrel fold sealed with two β-strands at the noncatalytic face of the domain. However, in addition, the TIM barrel of this enzyme is also fused to a β-sandwich structure (38.Han Y-B. Chen L-Q. Li Z. Tan Y-M. Feng Y. Yang G-Y. Structural insights into the broad substrate specificity of a novel endoglycoceramidase I belonging to a new subfamily of GH5 glycosidases.J. Biol. Chem. 2017; 292: 4789-4800Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) (Fig. 2A). Thus, EGCI is a typical GH5 enzyme, while EGCII shows structural features of members of both GH5 and GH30 families. The evolutionary relationship between these enzymes remains unclear. Of note, the existence and characterization of an animal endoglycoceramidase in the animal kingdom was first described for leeches by Li et al. (39.Li S-C. Degasperi R. Muldrey J.E. Li Y-T. A unique glycosphingolipid-splitting enzyme (ceramide-glycanase from leech) cleaves the linkage between the oligosaccharide and the ceramide.Biochem. Biophys. Res. Commun. 1986; 141: 346-352Crossref PubMed Scopus (70) Google Scholar, 40.Zhou B. Li S. Laine R.A. Huang R. Li Y. Isolation and characterization of ceramide glycanase from the leech, Macrobdella decora.J. Biol. Chem. 1989; 264: 12272-12277Abstract Full Text PDF PubMed Google Scholar). The same researchers later reported on a similar enzyme in earthworms (41.Carter B.Z. Li S-C. Li Y-T. Ceramide glycanase from the earthworm, Lumbricus terrestris.Biochem. J. 1992; 285: 619-623Crossref PubMed Scopus (14) Google Scholar), clams (42.Basu S.S. Dastgheibhosseini S. Hoover G. Li Z. Basu S. Analysis of glycosphingolipids by fluorophore-assisted carbohydrate electrophoresis using ceramide glycanase from Mercenaria mercenaria.Anal. Biochem. 1994; 222: 270-274Crossref PubMed Scopus (30) Google Scholar), and oysters (43.Pavlova N.V. Li S-C. Li Y-T. Degradation of glycosphingolipids in oyster: ceramide glycanase and ceramidase in the hepatopancreas of oyster, Crassostrea virginica.Glycoconj. J. 2018; 35: 77-86Crossref PubMed Scopus (1) Google Scholar). In humans, no endoglycoceramidase is characterized yet, although an endohydrolysis activity toward gangliosides has been noted for human cancer cells and tissues of other mammals (44.Basu M. Kelly P. O'donnell P. Miguel M. Bradley M. Sonnino S. Banerjee S. Basu S. Ceramide glycanase activities in human cancer cells.Biosci. Rep. 1999; 19: 449-460Crossref PubMed Scopus (8) Google Scholar, 45.Basu M. Kelly P. Girzadas M. Li Z. Basu S. Properties of animal ceramide glycanases.Methods Enzymol. 2000; 311: 287-297Crossref PubMed Scopus (11) Google Scholar). In addition to its capacity to hydrolyze, GBA1 may act in vivo as transglucosidase, generating β-glucosylcholesterol (46.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; 441: 838-843Crossref PubMed Scopus (33) Google Scholar). The accumulation of cholesterol in lysosomes, as occurs in Niemann-Pick type C or experimentally induced with U18666A, promotes the formation of glucosylated sterols by GBA1 (47.Marques A.R. Mirzaian M. Akiyama H. Wisse P. Ferraz M.J. Gaspar P. Ghauharali-van der Vlugt K. Meijer R. Giraldo P. Alfonso P. Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.J. Lipid Res. 2016; 57: 451-463Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar) Moreover, GH5 EGCII has been engineered by mutagenesis into a highly efficient transglucosidase applicable for carbohydrate synthesis (48.Vaughan M.D. Johnson K. DeFrees S. Tang X. Warren R.A.J. Withers S.G. Glycosynthase-mediated synthesis of glycosphingolipids.J. Am. Chem. Soc. 2006; 128: 6300-6301Crossref PubMed Scopus (0) Google Scholar, 49.Rich J.R. Cunningham A-M. Gilbert M. Withers S.G. Glycosphingolipid synthesis employing a combination of recombinant glycosyltransferases and an endoglycoceramidase glycosynthase.Chem. Commun. (Camb.). 2011; 47: 10806-10808Crossref PubMed Scopus (27) Google Scholar). Other glycosylceramidases classified in family GH5 are bacterial (Rhodococcus sp.) endogalactosylceramidase, first named EGCIII (50.Ito M. Yamagata T. Purification and characterization of glycosphingolipid-specific endoglycosidases (endoglycoceramidases) from a mutant strain of Rhodococcus sp. Evidence for three molecular species of endoglycoceramidase with different specificities.J. Biol. Chem. 1989; 264: 9510-9519Abstract Full Text PDF PubMed Google Scholar, 51.Ishibashi Y. Nakasone T. Kiyohara M. Horibata Y. Sakaguchi K. Hijikata A. Ichinose S. Omori A. Yasui Y. Imamura A. A novel endoglycoceramidase hydrolyzes oligogalactosylceramides to produce galactooligosaccharides and ceramides.J. Biol. Chem. 2007; 282: 11386-11396Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar); Cryptococcus neoformans glucocerebrosidase EGCrP1 (52.Ishibashi Y. Ikeda K. Sakaguchi K. Okino N. Taguchi R. Ito M. Quality control of fungus-specific glucosylceramide in Cryptococcus neoformans by endoglycoceramidase-related protein 1 (EGCrP1).J. Biol. Chem. 2012; 287: 368-381Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar); steryl-β-glucosidase EGCrP2 (53.Watanabe T. Ito T. Goda H.M. Ishibashi Y. Miyamoto T. Ikeda K. Taguchi R. Okino N. Ito M. Sterylglucoside catabolism in Cryptococcus neoformans with endoglycoceramidase-related protein 2 (EGCrP2), the first steryl-β-glucosidase identified in fungi.J. Biol. Chem. 2015; 290: 1005-1019Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar); and Saccharomyces cerevisiae steryl-β-glucosidase EGH1 (54.Watanabe T. Tani M. Ishibashi Y. Endo I. Okino N. Ito M. Ergosteryl-β-glucosidase (Egh1) involved in sterylglucoside catabolism and vacuole formation in Saccharomyces cerevisiae.Glycobiology. 2015; 25: 1079-1089Crossref PubMed Scopus (8) Google Scholar). The endoglycoceramidases and EGPr1 degrade only glycolipids with a ceramide moiety. In contrast, EGH1 and EGCPr2 are reported to hydrolyze both glucosylceramide and steryl-β-glucosides (53.Watanabe T. Ito T. Goda H.M. Ishibashi Y. Miyamoto T. Ikeda K. Taguchi R. Okino N. Ito M. Sterylglucoside catabolism in Cryptococcus neoformans with endoglycoceramidase-related protein 2 (EGCrP2), the first steryl-β-glucosidase identified in fungi.J. Biol. Chem. 2015; 290: 1005-1019Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). No crystal structure of these enzymes is available yet. The GH116 family comprises enzymes with diverse specificities and includes the glucosylceramidase GBA2 (55.Cobucci-Ponzano B. Aurilia V. Riccio G. Henrissat B. Coutinho P.M. Strazzulli A. Padula A. Corsaro M.M. Pieretti G. Pocsfalvi G. A new archaeal β-glycosidase from sulfolobus solfataricus seeding a novel retaining β-glycan-specific glycoside hydrolase family along with the human non-lysosomal glucosylceramidase GBA2.J. Biol. Chem. 2010; 285: 20691-20703Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). The partial homology with β-xylosidase/β-glucosidase SSO1353 of Sulfolobus solfataricus assisted the identification of E527 as the nucleophile and D677 as the acid/base in GBA2 (55.Cobucci-Ponzano B. Aurilia V. Riccio G. Henrissat B. Coutinho P.M. Strazzulli A. Padula A. Corsaro M.M. Pieretti G. Pocsfalvi G. A new archaeal β-glycosidase from sulfolobus solfataricus seeding a novel retaining β-glycan-specific glycoside hydrolase family along with the human non-lysosomal glucosylceramidase GBA2.J. Biol. Chem. 2010; 285: 20691-20703Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 56.Kallemeijn W.W. Witte M.D. Voorn-Brouwer T.M. Walvoort M.T. Li K-Y. Codée J.D. van der Marel G.A. Boot R.G. Overkleeft H.S. Aerts J.M. A sensitive gel-based method combining distinct cyclophellitol-based probes for the identification of acid/base residues in human retaining β-glucosidases.J. Biol. Chem. 2014; 289: 35351-35362Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). At present, no 3D structure of GBA2 is available, but recently such a structure was reported for a GH116 β-glucosidase of Thermoanaerobacterium xylanolyticum (TxGH116), alone and in complex with diverse ligands (57.Charoenwattanasatien R. Pengthaisong S. Breen I. Mutoh R. Sansenya S. Hua Y. Tankrathok A. Wu L. Songsiriritthigul C. Tanaka H. Bacterial β-glucosidase reveals the structural and functional basis of genetic defects in human glucocerebrosidase 2 (GBA2).ACS Chem. Biol. 2016; 11: 1891-1900Crossref PubMed Scopus (20) Google Scholar). The TxGH116 structure consists of an N-terminal domain, primarily formed by a two-sheet β-sandwich, and a catalytic C-terminal (α/α)6 solenoid domain (Fig. 3A). The putative catalytic nucleophile is at the end of a long loop between the first and second α-helix of the C-terminal domain, while the putative catalytic acid/base is in a long loop between the fifth and sixth helix of the solenoid, containing the binding site for a structural Ca2+ ion. The N-terminal β-sandwich is tightly associated with the catalytic domain and contributes to the substrate binding cleft and unusual orientation of the acid/base residue. The TxGH116 structures allowed the identification of the glucoside binding- and active-site residues, which are conserved with GBA2. Mutagenic analysis of TxGH116 and structural modeling of GBA2 (Fig. 3B) provided a rationale f" @default.
• W2895028012 created "2018-10-12" @default.
• W2895028012 creator A5013935159 @default.
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• W2895028012 creator A5056673744 @default.
• W2895028012 date "2018-12-01" @default.
• W2895028012 modified "2023-10-12" @default.
• W2895028012 title "Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses" @default.
• W2895028012 cites W1010681756 @default.
• W2895028012 cites W103120206 @default.
• W2895028012 cites W124542690 @default.
• W2895028012 cites W1480588550 @default.
• W2895028012 cites W1483358522 @default.
• W2895028012 cites W1490806866 @default.
• W2895028012 cites W1526562091 @default.
• W2895028012 cites W1533651529 @default.
• W2895028012 cites W1551180853 @default.
• W2895028012 cites W1562852007 @default.
• W2895028012 cites W1568362377 @default.
• W2895028012 cites W1574672893 @default.
• W2895028012 cites W1579829228 @default.
• W2895028012 cites W1591335564 @default.
• W2895028012 cites W1605271364 @default.
• W2895028012 cites W1726358853 @default.
• W2895028012 cites W1758125525 @default.
• W2895028012 cites W1775418466 @default.
• W2895028012 cites W1853218132 @default.
• W2895028012 cites W1935024944 @default.
• W2895028012 cites W1958194992 @default.
• W2895028012 cites W1967567145 @default.
• W2895028012 cites W1969540976 @default.
• W2895028012 cites W1971437040 @default.
• W2895028012 cites W1971710874 @default.
• W2895028012 cites W1973606909 @default.
• W2895028012 cites W1974323705 @default.
• W2895028012 cites W1976006228 @default.
• W2895028012 cites W1978441989 @default.
• W2895028012 cites W1980522070 @default.
• W2895028012 cites W1982579849 @default.
• W2895028012 cites W1987152474 @default.
• W2895028012 cites W1987250042 @default.
• W2895028012 cites W1987657794 @default.
• W2895028012 cites W1988843643 @default.
• W2895028012 cites W1990520168 @default.
• W2895028012 cites W1991151936 @default.
• W2895028012 cites W1991968375 @default.
• W2895028012 cites W1993962769 @default.
• W2895028012 cites W2000203194 @default.
• W2895028012 cites W2000365602 @default.
• W2895028012 cites W2002311959 @default.
• W2895028012 cites W2002571030 @default.
• W2895028012 cites W2003525182 @default.
• W2895028012 cites W2003791843 @default.
• W2895028012 cites W2007089471 @default.
• W2895028012 cites W2008275156 @default.
• W2895028012 cites W2009428796 @default.
• W2895028012 cites W2010593593 @default.
• W2895028012 cites W2011709758 @default.
• W2895028012 cites W2013210164 @default.
• W2895028012 cites W2015557434 @default.
• W2895028012 cites W2016639982 @default.
• W2895028012 cites W2018849208 @default.
• W2895028012 cites W2020792117 @default.
• W2895028012 cites W2027055112 @default.
• W2895028012 cites W2027343008 @default.
• W2895028012 cites W2027547993 @default.
• W2895028012 cites W2028589353 @default.
• W2895028012 cites W2030480923 @default.
• W2895028012 cites W2031241813 @default.
• W2895028012 cites W2033393842 @default.
• W2895028012 cites W2034410656 @default.
• W2895028012 cites W2034697201 @default.
• W2895028012 cites W2035849215 @default.
• W2895028012 cites W2039687878 @default.
• W2895028012 cites W2041175508 @default.
• W2895028012 cites W2043466478 @default.
• W2895028012 cites W2044534774 @default.
• W2895028012 cites W2048822589 @default.
• W2895028012 cites W2050590069 @default.
• W2895028012 cites W2053455149 @default.
• W2895028012 cites W2055570767 @default.
• W2895028012 cites W2055783962 @default.
• W2895028012 cites W2056275131 @default.
• W2895028012 cites W2059054872 @default.
• W2895028012 cites W2059796456 @default.
• W2895028012 cites W2061076816 @default.
• W2895028012 cites W2065713555 @default.
• W2895028012 cites W2066088355 @default.
• W2895028012 cites W2066146676 @default.
• W2895028012 cites W2066647917 @default.
• W2895028012 cites W2067126519 @default.
• W2895028012 cites W2068613322 @default.
• W2895028012 cites W2069941361 @default.
• W2895028012 cites W2071884298 @default.
• W2895028012 cites W2072425060 @default.
• W2895028012 cites W2073351315 @default.

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