Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

This study was designed to establish an in vitro model with biochemical and morphological similarities to the human neurodegenerative disease GM1 gangliosidosis. Utilizing a specific inactivator of the lysosomal enzyme GM1-ganglioside beta-galactosidase (beta-D-galactopyranosylmethyl-p-nitrophenyltriazene [beta-GalMNT]) and neuroblastoma X glioma hybrid cells (NG108-15), we suppressed beta-galactosidase activity for up to 72 hours. Coincidental with suppression of this enzyme to levels less than 1% of control, we found up to a nine-fold accumulation of its substrate, the GM1-ganglioside, and the ultrastructural appearance of membranous cytoplasmic bodies. beta-GalMNT treatment suppressed growth but had little effect on the specific activity of choline acetyltransferase, lactate dehydrogenase, or other lysosomal enzymes including galactosylceramidase. This model should permit studies of the neurophysiological effects of increased ganglioside accumulation and their reversibility.
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PMID:Inactivation of GM1-ganglioside beta-galactosidase by a specific inhibitor: a model for ganglioside storage disease. 303 98

Three adult patients in a single family showed severe myoclonus, ataxia, and pyramidal signs. Enzymatic analysis of lymphocytes, plasma, and cultured skin fibroblasts showed marked deficiency of beta-galactosidase activity, more profound with GM1 ganglioside than with another natural substrate, asialofetuin. Other lysosomal hydrolases were normal. Although the physical signs were similar to those of types 1 and 2 GM1 gangliosidosis, none had bony abnormalities.
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PMID:A family with beta-galactosidase deficiency: three adults with atypical clinical patterns. 307 94

Sphingolipid activator proteins (SAP) are relatively low-molecular-mass proteins that stimulate the hydrolysis of specific sphingolipids by the required lysosomal enzymes. SAP-1 or sulfatide/GM1 ganglioside activator protein has previously been demonstrated to stimulate the enzymatic hydrolysis of sulfatide, GM1 ganglioside and globotriaosylceramide. Using monospecific rabbit antibodies against human liver sulfatide/GM1 activator, the biosynthesis and processing of this activator were studied in cultured skin fibroblasts from controls and patients with GM1 gangliosidosis and a variant form of metachromatic leukodystrophy. When [35S]methionine was presented in the medium to control human fibroblasts for 4 h, the majority of the immunoprecipitable radiolabeling was confined to bands within three regions of apparent molecular mass 65-70, 35-52 and 8-13 kDa. The only immunoprecipitable radiolabeled species excreted into the medium when NH4Cl was present had an apparent molecular mass of 70 kDa. When the excretion products were given to fresh cells followed by incubation for up to 24 h there was production of the mature species. Treatment of the 70 kDa form with endoglycosidase F resulted in production of a 53 kDa molecular mass form. Pulse-chase experiments indicated that the initial immunoprecipitable translation product was 65 kDa which increased to 70 kDa over the next hour. The 65 kDa species must result from co-translational glycosylation of the polypeptide chain. Apparently, intralysosomal processing converts the 13 kDa form to the 8-11 kDa species. The cells from the patient with GM1 gangliosidosis could not process to the smallest species found in controls due to the deficiency of acid beta-galactosidase. Patients who have a variant form of metachromatic leukodystrophy do not make any immunoprecipitable radiolabeled products in the cells or in the media. This indicates a severe mutation in the gene coding for this activator protein. The production of such small mature species from a relatively large precursor form may regulate the production of this interesting protein.
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PMID:Biosynthesis of the sulfatide/GM1 activator protein (SAP-1) in control and mutant cultured skin fibroblasts. 308 Oct 38

Immunoelectron microscopy was performed to study the biosynthesis of lysosomal beta-galactosidase (beta-gal) in normal and mutant human fibroblasts. Using polyclonal and monoclonal antibodies we show in normal cells precursor forms of beta-gal in the rough endoplasmic reticulum (RER) and in the Golgi apparatus throughout the stack of cisternae. In the lysosomes virtually all beta-gal exists as a high molecular weight multimer of mature enzyme. In the autosomal recessive disease GM1-gangliosidosis caused by a beta-gal deficiency and in galactosialidosis, associated with a combined deficiency of lysosomal neuraminidase and beta-gal, precursor forms of the latter enzyme are found in RER, Golgi and some labeling is present at the cell surface. The lysosomes remain unlabeled, indicative for the absence of enzyme molecules in this organelle. In galactosialidosis fibroblasts also no mature beta-gal is found in the lysosomes but in these cells the presence of the monomeric form can be increased by leupeptin (inhibition of proteolysis) whereas addition of a partly purified 32 kDa "protective protein" results in the restoration of high molecular weight beta-gal multimers in the lysosomes.
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PMID:Immunoelectron microscopical localization of lysosomal beta-galactosidase and its precursor forms in normal and mutant human fibroblasts. 308 61

A highly sensitive microassay method and a microscale purification system were developed to isolate the residual acid beta-galactosidase in GM1-gangliosidosis fibroblasts. The sensitivity of the microassay system, composed of a 96-well microplate and a microplate fluorometer, was 100-fold higher than that of the conventional system and the response was linear in the pmole range. Acid beta-galactosidase was characterized as a thiol enzyme which was inactivated by a mercuric compound. This enzyme was completely adsorbed on an Hg-agarose column and was easily eluted from the column by 10 mM 2-mercaptoethanol. The microscale purification system using Con A-Sepharose, PAT-Sepharose, and Hg-agarose column chromatography achieved 565- and 7,970-fold purifications of acid beta-galactosidase with an overall yields of 44% and 45% from normal and GM1-gangliosidosis fibroblasts, respectively. The purified enzyme fractions did not contain any other lysosomal enzyme activities except for a small amount of beta-N-acetylhexosaminidase activity.
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PMID:Acid beta-galactosidase from human fibroblasts. A microscale purification method monitored by a highly sensitive enzyme assay. 308 62

Cultured fibroblasts from different variants of GM1-gangliosidosis synthesize normal amounts of 88-kDa beta-galactosidase precursor. Yet the amount of the mature 64-kDa form is reduced to 5-15% of normal values. In this communication it is shown that the mutation in the infantile and adult form of GM1-gangliosidosis interferes with the phosphorylation of precursor beta-galactosidase. As a result the precursor is secreted instead of being compartmentalized into the lysosomes and further processed. The impaired phosphorylation might be due to conformational changes of the precursor molecule.
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PMID:GM1-gangliosidosis. Defective recognition site on beta-galactosidase precursor. 308 69

The uptake and catabolism of [3H-ceramide]-GM1 was followed in living fibroblasts from patient with different forms of beta-galactosidase deficiency. Gangliosides are identified according to the nomenclature of Svennerholm (1963). A total inability to metabolize the ingested substrate was found in infantile GM1-gangliosidosis whereas cells from an adult GM1-gangliosidosis variant showed a slower rate of degradation, compared with controls. Morquio B fibroblasts had a comparable catabolism of GM1 as controls. Fibroblasts from different types of galactosialidosis, a recessive disease associated with a coexistent beta-galactosidase/neuraminidase deficiency all showed degradation of ingested GM1. In view of the molecular defect in this disease, this catabolism must be due to the 10-20% of monomeric beta-galactosidase molecules present in the lysosomes. Unexpectedly, in these cells an impaired metabolism of GM3 was found. The same finding was observed when cells with an isolated neuraminidase deficiency (mucolipidosis I) were loaded with GM1. A hypothesis is presented to explain these results.
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PMID:Ganglioside GM1 metabolism in living human fibroblasts with beta-galactosidase deficiency. 308 9

Cerebral lipids of patients with GM1-gangliosidoses, infantile, juvenile, and chronic type which are caused by deficiency of beta-galactosidase, were examined and compared to each other. The infantile type demonstrated abnormal accumulation of GM1 and asialo-GM1 in contrast with marked decrease in such major cerebral lipids as cholesterol, phospholipids, cerebroside, and sulfatide. It was also noted that significant amounts of such unusual lipids as free fatty acids, GlcCer, LacCer, GbOse3Cer, and GbOse-4Cer plus nLcOse4Cer were found in the brain. These findings pointed out that this infantile type might accompany a severe cerebral dysgenesis with poor myelination. The juvenile type also showed marked increase in GM1 and asialo-GM1, but the decrease in cholesterol, phospholipids, cerebroside, and sulfatide was not so much as the infantile type. These findings along with the occurrence of cholesterol ester suggested that the brain caused progressive demyelination after the immature myelin appeared. An autopsized brain tissue of a male patient who was eventually diagnosed as a case of GM1-gangliosidosis chronic type after his death, showed some accumulation of GM1 and asialo-GM1 particularly in the caudate nucleus and putamen, whereas it showed moderate amounts of GM1 in apparently normal gray and white matters. It seemed that there are no abnormal cerebral lipids except for gangliosides and some neutral glycosphingolipids in the chronic type.
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PMID:Abnormalities of cerebral lipids in GM1-gangliosidoses, infantile, juvenile, and chronic type. 308 2

The multiplicity of bovine liver acid beta-galactosidase was investigated. Acid beta-galactosidase activity was measured in the presence of glucono-delta-lactone, which inhibited the neutral beta-galactosidase activity but not the acid beta-galactosidase activity in bovine liver. Three forms of acid beta-galactosidase were separated by Sephadex G-200 gel filtration and the elution pattern of the 4-methylumbelliferyl-beta-galactosidase activity coincided with that of the GM1-beta-galactosidase activity. These forms were relatively stable under acidic conditions (pH 4.5), but the two high molecular weight forms were inclined to dissociate into the low molecular weight form under neutral conditions (pH 7.0). The three forms of the enzyme showed similar pH-optima and apparent Michaelis constants for GM1 ganglioside.
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PMID:Multiplicity of bovine liver GM1 ganglioside beta-galactosidase. 309 71

The metabolism of galactosylceramide was investigated in normal and twitcher mice, an animal model for human globoid cell leukodystrophy. The findings were compared with data obtained on human tissues. In vitro studies demonstrated that there were two genetically distinct enzymes that hydrolyze galactosylceramide: galactosylceramidase I and II. The former was deficient in the twitcher, while the latter was intact. beta-Galactosidase preparations purified from normal mouse liver possessed the activity to hydrolyze galactosylceramide when the assay conditions for galactosylceramidase II was used. Therefore, galactosylceramidase II was considered to be identical to GM1 ganglioside beta-galactosidase. In contrast to the human enzyme, the murine beta-galactosidase had a relatively high Km value toward galactosylceramide. The galactosylceramide-loading test demonstrated that the twitcher fibroblasts hydrolyzed the lipid at lower rates than seen in cases of human globoid cell leukodystrophy fibroblasts. These differences in galactosylceramidase II between murine and human tissues suggest that galactosylceramide accumulates in twitcher mice but not in humans with globoid cell leukodystrophy, even though galactosylceramidase I is genetically deficient in both human and this mouse model.
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PMID:Metabolism of galactosylceramide in the twitcher mouse, an animal model of human globoid cell leukodystrophy. 309 85


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