Abstract
The hydrolytic cleavage of a β-glucoside has to follow a multi-step pathway because the activation energy for a direct nucleophilic displacement of the aglycon by an SN2 - like mechanism would be so high as to make this route impossible. This does also hold for enzyme catalyzed reactions which appear to have evolved to effect mechanisms that have many features in common. The first detailed picture of the active site of a glycoside hydrolase was proposed 20 years ago by D.C. Phillips and his group at Oxford (1). It was based on the X-ray structure analysis of an enzyme inhibitor complex of the endo-β-N-acetylglucosaminidase lysozyme. Parallel and subsequent studies with covalent and non-covalent inhibitors have shown that the general principles proposed by Phillips are also valid for the majority of other β-glucosidases (2). A model (Fig. 1) for the transition state for the bond cleavage step leading to the formation of a glycosyl enyzme intermediate was derived from these studies (3).
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References
C.C.F. Blake, D.F. Koenig, G.A. Mair, A.C.T. North, D.C. Phillips, and V.R. Sarma, Structure of Hen Egg-White Lysozyme: A Three-Dimensional Fouries Synthesis at 2 Å Resolution, Nature 206:757–763 (1965)
P. Lalegerie, G. Legier, and J.M. Yon, The Use of Inhibitors in the Study of Glycosidases, Biochimie 64:977–1000 (1982)
G. Legier, M.L. Sinnott, and S.G. Withers, Catalysis by β-Glucosidase A3 of Aspergillus wentii, J. Chem. Soc. Perkin II, 1376–1383 (1980)
G. Legier, Struktur des aktiven Zentrums glykosidspaltender Enzyme, Forschungsber. Land Nordrhein-Westfalen, Nr. 2846 (1979), Westdeutscher Verlag, Opladen, FRG
T. Dinur, K.M. Osiecki, G. Legier, S. Gatt, R.J. Desnick, and G.A. Grabowski, Human Acid β-Glucosidase: Isolation and Amino Acid Sequence of a Peptide Containing the Catalytic Site, Proc. Natl. Acad. Sci. USA 83:1660–1664 (1986)
M.C. Stephens, A. Bernatsky, H. Singh, J.N. Kanfer, and G. Legier, Distribution of Conduritol B epoxide in the Animal Model for Gaucher’s Disease, Biochim. Biophys. Acta 672:29–32 (1981)
G.A. Grabowski, K. Osiecki-Newman, T. Dinur, D. Fabbro, G. Legier, S. Gatt, and R.J. Desnick, Human Acid β-Glucosidase: Use of Coduritol B epoxide Derivatives to Investigate the Catalytically Active Normal and Gaucher Disease Enzymes, J. Biol. Chem. 261:8263–8269 (1986)
H. Liedtke, Charakterisierung der lysosomalen β-Glucosidase und eines cytosolischen Aktivatorproteins aus Kalbsmilz, Thesis, University of Cologne (1987)
G. Legier and E. Bieberich, unpublished data
H. Liedtke and G. Legier, Bromoconduritol B, a New Active Site Directed Inhibitor of Acid β-Glucosidase (Glucocerebrosidase), Abstr. Gentner Symposium on the Biology of Complex Carbohydrates, p. 79, F. Cramer and N. Sharon ed., Rehovot and Eilat, Israel (1987)
G. Legier and W. Lötz, Glykosidspaltende Enzyme VII: Funktionelle Gruppen am aktiven Zentrum einer cx-Glucosidase aus Saccharomyces cerevisiae, Hoppe-Seyler’s Z. physiol. Chem. 354:243–254 (1973)
W. Fürst, A. Vogel, M. Lee-Vaupel, E. Conzelmann, and K. Sandhoff, Glycosphingolipid Activator Proteins, in: “Enzymes of Lipid Metabolism II”, p. 315–338, L. Freys, H. Dreyfus, R. Massarelli, and S. Gatt, ed. Plenum Publishing Corporation, New York (1986)
R. Glew, A. Basu, E. Prence, K. Garett, and R. Cooper, The Effects of Acidic Lipids and Heat-Stable Factor on the Physico-Chemical and Kinetic Properties of Glucocerebrosidase, in: “Enzymes of Lipid Metabolism II”, L. Freys, H. Dreyfus, R. Massarelli, and S. Gatt, ed., Plenum Publishing Corporation, New York (1986)
G.A. Levvy and S.M. Snaith, Inhibition of Glycoside Hydrolases by Hexonolactones, Adv. Enzymol. 36:151–181 (1972)
K. Osiecki-Newman, G. Legier, T. Dinur, S. Gatt. R.J. Desnick, and G.A. Grabowski, unpublished data
J.N. Kanfer, S.S. Raghavan, R.A. Mumford, G. Legier, R.S. Labow, D.G. Williamson, and D.S. Layne, Recent Observations on Gaucher’s Disease, in: “Current Trends in Sphingolipidoses and Allied Disorders” B.W. Volk and L. Schneck, ed., Plenum publishing Corporation, New York (1976)
G.A. Grabowski, J. Goldblatt, T. Dinur, J. Kruse, L. Svennerholm, S. Gatt, and R.J. Desnick, Genetic Heterogeneity in Gaucher Disease: Physicokinetic and Immunologic Studies of the Residual Enzyme in Cultured Fibroblasts from Non-Neuronopathic and Neuronopathic Patients Am. J. Hum. Genetics 21:529–549 (1985)
A. Fersht, “Enzyme Structure and Mechanism”, 2nd ed., p. 320, W.H. Freeman and Co., New York (1985)
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© 1988 Plenum Press, New York
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Legler, G. (1988). β-Glucocerebrosidase: Mechanistic Studies With Covalent and Non-Covalent Inhibitors. In: Salvayre, R., Douste-Blazy, L., Gatt, S. (eds) Lipid Storage Disorders. NATO ASI Series, vol 150. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-1029-7_7
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DOI: https://doi.org/10.1007/978-1-4613-1029-7_7
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