Inhibition of glucocerebrosidase and induction of neural abnormality by cyclophellitol in mice

Atsumi, Saoko; Nosaka, Chisato; Iinuma, Hisae; Umezawa, Kazuo

doi:10.1016/0003-9861(92)90685-p

Cited by 20 publications

(11 citation statements)

References 12 publications

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“…The amount and pattern of gangliosides, however, remained essentially the same as in control cells not incubated with the inhibitor. This result is in accordance with a lipid analysis of nerve tissue from Gaucher's patients and that of a mouse model with induced Gaucher's disease (Nilsson and Svennerholm, 1982;Atsumi et al, 1992) and rules out the possibility that the neuropathological symptoms developed in Gaucher's disease result from an aberrant ganglioside composition. The reversal of GC elevation was achieved by postincubation of CBE-treated NG108-15 cells with two inhibitors of GT, d,l-PDMP and NB-DNJ.…”

Section: Figsupporting

confidence: 86%

Differential Effects of Glycolipid Biosynthesis Inhibitors on Ceramide‐Induced Cell Death in Neuroblastoma Cells

Bieberich

Freischütz

Suzuki

et al. 1999

Journal of Neurochemistry

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An in vitro model of Gaucher's disease in murine neuroblastoma ϫ rat glioma NG108-15 cells was used to investigate the physiological effects of two specific inhibitors of glucosylceramide synthase, d,l-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (d,l-PDMP) and N-butyldeoxynojirimycin (NB-DNJ), which have been suggested as agents for treatment of glycolipid storage disorders. Incubation of NG108-15 cells with conduritol-B-epoxide, a covalent inhibitor of glucosylceramidase, raised the intracellular concentration of glucosylceramide (GC) by more than fourfold, indicating a glycolipid composition equivalent to that of Gaucher's cells. The level of GC was decreased, and the cells were depleted of gangliosides by postincubation with d,l-PDMP or NB-DNJ. Treatment with d,l-PDMP, but not with NB-DNJ, resulted in a dose-dependent reduction of the growth rate and eventually caused cell death in NG108-15 cells on reaching confluency. An in situ detection assay using terminal nucleotidyltransferase indicated that cell degeneration was accompanied by apoptosis. Lipid analysis by high-performance TLC revealed that on incubation with d,l-PDMP, but not with NB-DNJ, the concentration of endogenous ceramide was elevated by threefold. Ceramide elevation and apoptosis were also observed when NG108-15 cells were incubated with daunorubicin, which was previously reported to induce programmed cell death by stimulation of ceramide synthesis. Structural characterization by HPLC and subsequent laser desorption mass spectrometry revealed that the endogenous ceramide contained fatty acids with chain lengths ranging from C14:0 to C24:0. The results indicate that elevation of levels of these ceramide species by incubation with d,l-PDMP or daunorubicin induces programmed cell death in NG108-15 cells. Because ceramide accumulation and cell death were not observed on incubation with NB-DNJ, its use is suggested to be less toxic than that of d,l-PDMP for treatment of Gaucher's disease and other sphingolipid storage disorders. Key Words: Apoptosis-Gaucher's disease-Neuroblastoma cells-Cell death-Glycolipids. J. Neurochem. 72, 1040Neurochem. 72, -1049Neurochem. 72, (1999.Sphingolipids are known to be involved in various biological functions, including modulation of cell proliferation, differentiation, and apoptosis (Schwarz et al., 1995;Ariga et al., 1998). The main active compounds are ceramide and its glycosylated, e.g., glycosphingolipids, or phosphorylated, e.g., sphingomyelins, derivatives (Schwarz et al., 1995;Ballou et al., 1996). Ceramide, mainly generated from signal-induced cleavage of sphingomyelin by sphingomyelinase, has been shown to arrest cell cycle and to stimulate apoptosis (Jarvis et al., 1994;Ji et al., 1995;Obeid and Hannun, 1995;Witty et al., 1996;Ariga et al., 1998). Recent studies have demonstrated that induction of apoptosis can also be achieved by activation of de novo synthesis of ceramide (Bose et al., 1995). Hydrolysis of ceramide by ceramidase releases sphingosine, which has been found to be ...

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Section: Figsupporting

confidence: 86%

Differential Effects of Glycolipid Biosynthesis Inhibitors on Ceramide‐Induced Cell Death in Neuroblastoma Cells

Bieberich

Freischütz

Suzuki

et al. 1999

Journal of Neurochemistry

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“…) revealed that this inactivator does indeed label the same active site residue as that identified as the nucleophile by other methods (Withers et al, 1990). Cyclophellitol has also been used to inactivate glucocerebrosidases in vivo, thereby creating an animal model for Gaucher disease (Atsumi et al, 1992).…”

Section: Identification Of Active Site Amino Acids By Derivatization mentioning

confidence: 84%

Approaches to labeling and identification of active site residues in glycosidases

1995

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Glycosidases play a key role in a number of biological processes and, as such, are of considerable clinical and biotechnological importance. Knowledge of the identities of catalytically important active site residues is essential for understanding the catalytic mechanism, for enzyme classification, and for targeted bioengineering of glycosidases with altered characteristics. Here we review and discuss traditional strategies and novel approaches based on tandem mass spectrometry for the identification of the key active site residues in glycosidases.

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“…A recent publication, based on cyclophellitol, a newly discovered inhibitor of GlcCer glucosidase, did not report increases in organ weights (18). Here, the new inhibitor, which is somewhat more effective than conduritol B epoxide, was injected at 17 mg/kg for 5 days and the animals were evaluated 2 days later.…”

Section: Glucosylceramide As a Growth Factormentioning

confidence: 91%

Glucosylceramide in the nervous system - A mini-review

Radin

1994

Neurochem Res

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Inhibition of glucocerebrosidase and induction of neural abnormality by cyclophellitol in mice

Cited by 20 publications

References 12 publications

Differential Effects of Glycolipid Biosynthesis Inhibitors on Ceramide‐Induced Cell Death in Neuroblastoma Cells

Differential Effects of Glycolipid Biosynthesis Inhibitors on Ceramide‐Induced Cell Death in Neuroblastoma Cells

Approaches to labeling and identification of active site residues in glycosidases

Glucosylceramide in the nervous system - A mini-review

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