Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The primary genetic defect underlying Krabbe disease or globoid cell leukodystrophy is considered to be a deficiency of galactosylceramide-beta-galactosidase. In the present study of the brains from 18 patients who had died from Krabbe disease at 7-37 months of age, the concentration of galactosylceramide of cerebral and cerebellar white matter was severely reduced to 10-20% of that in age-matched controls. The lowest values were found in the most long-standing cases. Lactosylceramide was reduced to about 50% of normal, while globotriaosylceramide, blobotetraosylceramide and III3-alpha-fucosylneolactotetraosylceramide were increased 10 to 100-fold. Two glycosphingolipids, which have never before been isolated from normal human brains were now isolated and characterized: galactosylsphingosine (psychosine) and galactosyl beta 1 leads to 4 galactosylceramide. We were unable to identify galactosylsphingosine in normal human brains with certainty. We estimate its concentration in the cerebral white matter in Krabbe disease to be increased at least 100-fold (higher than normal). Psychosine was isolated also from the cerebral cortex in Psychosine was isolated also from the cerebral cortex in Krabbe disease after derivatization to the N-acetyl form. Its concentration there was 1 nmol/g tissue compared with 6-10 nmol/g in the white matter. All the neutral glycosphingolipids were isolated and their structure proved by the quantitative determination of their components, degradation by acid and specific glycohydrolases and permethylation and gas-liquid chromatographic-mass spectrometric assay of the methylated sugars. The paradoxical findings of a severely reduced concentration of galactosylceramide and a primary deficiency of cerebroside-beta-galactosidase can be explained by the present finding of the accumulation of galactosylsphingosine in the brains from patients who had died from Krabbe disease. The enzyme has a broad specificity and it normally also degrades galactosylsphingosine. Because of competitive inhibition by the accumulated galactosylceramide its lysosomal hydrolysis will be blocked. The concentration of psychosine will steadily increase and reach toxic levels and kill the oligodendroglial cells. This results in an arrest of the galactosylceramide biosynthesis. Therefore, we feel that galactosylsphingosine and not galactosylceramide is the primary storage substance in the brain in Krabbe disease that the disease is a psychosine lipidosis.
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PMID:Krabbe disease: a galactosylsphingosine (psychosine) lipidosis. 735 54

Cytotoxic capacity of psychosine (galactosylsphingosine) was evaluated in comparison with C6-ceramide in cultured fibroblasts and the glia-derived MOCH-1 cells that have characteristics of myelinating cells (1). Psychosine caused cytotoxic cell death and DNA fragmentation at concentrations similar to C6-ceramide and MOCH-1 cells were substantially more sensitive to their cytotoxic effects than fibroblasts. In this system, pretreatment with GM1-ganglioside failed to protect the cells from the deleterious effects of these compounds. These findings are consistent with the hypothesis that psychosine is the cytotoxic metabolite that causes apoptotic death of the oligodendrocyte in globoid cell leukodystrophy (Krabbe disease). They further suggest that the protective capacity of GM1-ganglioside is unlikely to be the explanation for the paradoxical improvement of the phenotype of globoid cell leukodystrophy in the mouse simultaneously deficient in two lysosomal beta-galactosidases, galactosylceramidase and GM1-ganglioside beta-galactosidase.
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PMID:Psychosine is as potent an inducer of cell death as C6-ceramide in cultured fibroblasts and in MOCH-1 cells. 1151 26

As previously shown for [(3)H-galactosyl]ceramide, the breakdown of [(3)H-galactosyl]sphingosine was reduced in prosaposin-deficient skin fibroblast homogenates. Galactosylsphingosine hydrolysis was also deficient in cell homogenates from Krabbe's disease (beta-galactocerebrosidase-deficient) patients, but not acid beta-galactosidase-deficient patients. Moreover, hydrolysis of galactosylsphingosine in the prosaposin-deficient cell homogenates could be partially restored by adding pure saposin A or C, thereby identifying these saposins as essential facilitators of galactosylsphingosine hydrolysis. By contrast, saposins B and D had little effect on galactosylsphingosine hydrolysis in the prosaposin-deficient cells. The reduced galactosylsphingosine turnover in prosaposin-deficiency suggests that there could be a pathogenetic cerebral accumulation of galactosylsphingosine in this disorder.
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PMID:Saposins (sap) A and C activate the degradation of galactosylsphingosine. 1170 78

Patients with Gaucher disease have been classified as type 1 nonneuronopathic, type 2 acute neuronopathic, and type 3 chronic neuronopathic phenotypes. Increased quantities of glucocerebroside and glucosylsphingosine (glucopsychosine) are present in the brain of type 2 and type 3 Gaucher patients. Galactosylsphingosine has previously been shown to be neurotoxic in globoid cell leukodystrophy (Krabbe disease). To determine whether glucosylsphingosine is also neurotoxic, we examined its effect on cultured cholinergic neuron-like LA-N-2 cells. When these cells were exposed to 1, 5, or 10 microM glucosylsphingosine for a period of 18 h, they became shriveled, neurite outgrowth was suppressed, and the activities of the lysosomal enzymes glucocerebrosidase, sphingomyelinase, and beta-galactosidase were reduced in a dose-dependent manner. Acetylcholine in cells exposed to glucosylsphingosine also declined. Cells switched to glucosylsphingosine-free medium partially recovered. The data suggest that accumulation of glucosylsphingosine contributes to neuronal dysfunction and destruction in patients with neuronopathic Gaucher disease.
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PMID:Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3. 1467 74