Human Acid β-Glucosidase: Primary Structure of the Active Site

Dinur, Tama; Osiecki-Newman, Karen; Fabbro, Diane; Legler, Günter; Gátt, Shimon; Desnick, Robert J.; Grabowski, Gregory A.

doi:10.1007/978-1-4684-5212-9_41

Cited by 4 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). The 50-fold lower value for BrCBE is consistent with published results (29). Moreover, a single topical application of BrCBE to intact murine epidermis resulted in a dose-and time-dependent inhibition of j-glucosidase activity.…”

Section: Resultssupporting

confidence: 91%

“…Repeated topical applications of BrCBE, a potent inhibitor of B-GlcCer'ase (28)(29)(30), to intact Br-CBE Figure 5. Effect of BrCBE on [3H]-H20 incorporation into sphingolipids.…”

Section: Resultsmentioning

confidence: 99%

“…In order to directly test the hypothesis that extracellular sphingolipid processing is necessary for barrier maintenance, we applied an inhibitor of f3-GlcCer'ase, bromoconduritol B epoxide (BrCBE; [28][29][30], topically to intact skin, and found that this agent caused a progressive, reversible alteration in barrier integrity. Abnormal barrier function was associated with enzyme inhibition, enhanced sphingolipid synthesis, and accumulation of GlcCer in the stratum corneum.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

Holleran¹,

Takagi²,

Menon³

et al. 1993

J. Clin. Invest.

245

201

View full text Add to dashboard Cite

The interstices of the mammalian stratum corneum contain lipids in a system of continuous membrane bilayers critical for the epidermal permeability barrier. During the transition from inner to outer stratum corneum, the content of polar lipids, including glucosylceramides, decreases while ceramide content increases. We investigated whether inhibition of glucosylceramide hydrolysis would alter epidermal permeability barrier function. Daily topical applications of bromoconduritol B epoxide (BrCBE) to intact murine skin selectively inhibited fl-glucocerebrosidase, increased glucosylceramide content of stratum corneum with ceramide content remaining largely unchanged, and caused a progressive, reversible decrease in barrier function. Histochemistry of inhibitor-treated epidermis revealed persistence of periodic acid-Schiff-positive staining in stratum corneum cell membranes, consistent with retention of hexose moieties. Electron microscopy of inhibitor-treated samples revealed no evidence of toxicity or changes in the epidermal lipid delivery system. However, immature membrane structures persisted in the intercellular spaces throughout the stratum corneum, with reappearance of mature membrane structures progressing outward from the lower stratum corneum upon termination of BrCBE. Finally, the induced barrier abnormality was not reversed by coapplications of ceramide. These data demonstrate that glucosylceramide hydrolysis is important in the formation of the epidermal permeability barrier, and suggest that accumulation of glucosylceramides in stratum corneum intercellular membrane domains leads to abnormal barrier function. (J. Clin. Invest. 1993.91:1656-1664

show abstract

Section: Resultssupporting

confidence: 91%

“…Repeated topical applications of BrCBE, a potent inhibitor of B-GlcCer'ase (28)(29)(30), to intact Br-CBE Figure 5. Effect of BrCBE on [3H]-H20 incorporation into sphingolipids.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

Holleran¹,

Takagi²,

Menon³

et al. 1993

J. Clin. Invest.

245

201

View full text Add to dashboard Cite

show abstract

“…Genetic defects in several of these hydrolytic enzymes cause various disorders with lysosomal accumulation of the substrate lipids, a group of disorders termed the sphingolipidoses [41,[90][91][92][93]. Particularly, some of the known sphingolipidoses might closely associate with aberrant metabolisms of ceramide because of defective activities of ceramide generating/degrading enzymes: Farber's disease, Gaucher disease, and Niemann-Pick type A and B diseases are caused by a deficiency of acid ceramidase [94,95], glucocerebrosidase (acid-β-glucosidase) [96][97][98], acid SMase [99,100], respectively. The salvage pathway is one of the routes for controlling cellular levels of ceramide.…”

Section: Sphingolipidosesmentioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

539

457

View full text Add to dashboard Cite

Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through re-acylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

show abstract

“…5). The data thus appear to reflect a greatly reduced intrinsic reactivity of the enzyme, because inactivation requires effective proton transfer to the oxirane ring by an acidic group of the active site [9] and correct orientation of the aspartate group [18] .…”

Section: Binding Of Nug To Serum Albuminmentioning

confidence: 91%

Intracellular Activity of Lysosomal Glucosylceramidase Measured with 4-Nonylumbelliferyl β-glucoside

Bieberich¹,

Legler²

1989

Biological Chemistry Hoppe-Seyler

View full text Add to dashboard Cite

Enzymatic activity of lysosomal glucosylceramidase was determined in intact murine hybridoma and macrophage cells with the synthetic substrate nonylumbelliferyl-ß-glucoside (NUG). The substrate was applied as complex with bovine serum albumin (two binding sites, K d 2.2 ± 0.3 ). The transport of the artificial substrate from medium to the enzyme was explored by measurements of substrate concentrations in cellular membranes and of endocytosis rate relative to substrate hydrolysis. The results indicated that, after enrichment in the plasma membrane, the substrate is mainly transported by simple diffusion. Release of nonylumbelliferone monitored fluorimetrically after disintegration of the cells in borate buffer containing Triton X-100 at pH 9.5 showed that 10

~~show abstract~~

Human Acid β-Glucosidase: Primary Structure of the Active Site

Cited by 4 publications

References 21 publications

Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

The sphingolipid salvage pathway in ceramide metabolism and signaling

Intracellular Activity of Lysosomal Glucosylceramidase Measured with 4-Nonylumbelliferyl β-glucoside

Contact Info

Product

Resources

About