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

---

Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe the clinical findings over the first 18 years of a patient with a novel phenotype for galactosialidosis, the storage disease produced by the combined deficiency of beta-galactosidase and neuraminidase. Clinical findings in the first few months included somewhat unusual appearance and hepatosplenomegaly. Dysostosis multiplex was evident by age 2 1/2 years. Mitral and aortic valvular disease appeared over the next few years and cardiac disease has become the most important clinical problem. Foam cells were present in the bone marrow, and vacuolated lymphocytes were present in the peripheral blood smear. The patient had no neurological symptoms, cherry red spots, or intellectual deterioration during the first 18 years. Evidence presented elsewhere indicates that the basic defect in this late infantile form of galactosialidosis (as is thought to be true for the other forms of galactosialidosis) is a reduced amount of the 32 kDa phosphoglycoprotein which associates with beta-galactosidase and alpha-neuraminidase in lysosomes.
...
PMID:Combined deficiency of beta-galactosidase and neuraminidase: natural history of the disease in the first 18 years of an American patient with late infantile onset form. 214 53

Three male siblings in a Japanese family were affected with beta-galactosidase-neuraminidase deficiency (galactosialidosis). One patient died at 45 years of age, and postmortem liver and brain tissues were studied enzymatically. The residual activity of neuraminidase was relatively high in these tissues. Neuraminidase activity did not change in the tissues after repeated freezing and thawing of the homogenates, whereas this enzyme in control tissues lost 30 to 60% of its activity. There was a profound deficiency of beta-galactosidase in the tissues of the patient. Michaelis constant, pH profiles, and cryostability were identical for the patient and control patients. Cathepsin B was moderately increased in activity in the patient's tissues.
...
PMID:beta-Galactosidase-neuraminidase deficiency (galactosialidosis): clinical, pathological, and enzymatic studies in a postmortem case. 640 77

Lysosomal protective protein/cathepsin A is a serine carboxypeptidase that forms a complex with beta-galactosidase and neuraminidase. The enzyme is synthesized as a 54-kDa precursor/zymogen and processed into a catalytically active 32- and 20-kDa two-chain form. We have expressed in baculovirus-infected insect cells the human one-chain precursor as well as the two separate subunits in order to establish the mode of catalytic activation of the zymogen and the assembly and activation of the two subunits. Infected insect cells synthesize large quantities of the exogenous proteins, which are glycosylated and secreted but not processed. Co-expression of the two subunits results in their assembly into a two-chain form of 34- and 20-kDa with negligible enzymatic activity. Limited proteolysis with trypsin of the 54-kDa precursor and the reconstituted 34- and 20-kDa form gives rise to a fully active 32- and 20-kDa product. These results enabled us to map the sites of proteolytic cleavage needed for full activation of the cathepsin A zymogen. They further indicate that the 34- and 20-kDa form is a transient processing intermediate that is converted into a mature and active enzyme by removal of a 2-kDa "linker" peptide from the COOH terminus of the 34-kDa subunit.
...
PMID:Lysosomal protective protein/cathepsin A. Role of the "linker" domain in catalytic activation. 759 59

An enzyme hydrolyzing the carboxyl terminus of endothelin-1 was detected in control human tissues but was deficient in tissues from a patient with galactosialidosis, a metabolic disease caused by the protective protein gene mutation. It was proportional to the amount of immunologically estimated mature protective protein. An antibody against the lysosomal protective protein/beta-galactosidase complex precipitated the enzyme activity almost completely. Transfection of the human cDNA for protective protein resulted in high expression of the enzyme activity in transformed fibroblasts from a galactosialidosis patient. These results indicated that the mature protective protein is a major soluble endogenous endothelin degradation enzyme in human tissues.
...
PMID:Protective protein as an endogenous endothelin degradation enzyme in human tissues. 782 72

The deficiency of the lysosomal protective protein/carboxypeptidase L (CARB L) causes the lysosomal storage disorder, galactosialidosis, characterized by neuraminidase and beta-galactosidase deficiencies in patients' cells. The three enzymes form a complex inside the lysosome, and the neuraminidase and beta-galactosidase deficiencies are secondary to CARB L deficiency. Sequence similarity and common enzymological properties suggest that the protomeric tertiary structure of CARB L is conserved within a family of serine carboxypeptidases which includes the yeast carboxypeptidase Y, killer expression I gene product and several plant carboxypeptidases. We used this homology to build a model of the CARB L structure based on the recently published X-ray atomic coordinates of the wheat carboxypeptidase II (CPDW-II) which shares 32% primary structure identity with CARB L. Small insertions and deletions were accommodated into the model structure by energy minimization using the DREIDING II force field. The C alpha atomic coordinates of the final CARB L model have a RMS shift of 1.01 A compared to the corresponding conserved residues in the CPDW-II template structure. The correct orientation of the homologous catalytic triad residues Ser150, His429 and Asp392, the potential energy calculations and the distribution of hydrophobic and hydrophillic residues in the structure all support the validity of the CARB L model. Most missense mutations identified in galactosialidosis patients were located in secondary structural elements except for the Tyr211-->Asn mutation which is in a loop. The other mutant residues have their side chains deeply buried in the central beta-sheet of the model structure except for the Phe412-->Val mutation which is located in the dimer interface. The predicted effects of specific mutations on CARB L structural stability correlates well with recently published transient expression studies of mutant CARB L (Shimmoto, M. et al., J. Clin. Invest., 91:2393-2399, 1993).
...
PMID:Homologous modeling of the lysosomal protective protein/carboxypeptidase L: structural and functional implications of mutations identified in galactosialidosis patients. 814 24

Chinese hamster ovary cells were transfected with a recombinant DNA containing the entire coding sequence of human lysosomal protective protein cDNA under the control of mouse metallothionein I promoter. Neomycin and methotrexate-resistant stably transformed cell lines expressing this protein were isolated. Immunoprecipitation of the product with antiserum against human placental protective protein-beta-galactosidase complex revealed a 52-kDa protective protein precursor, which was then processed to mature form, a heterodimer of 32- and 20-kDa polypeptides. The precursor secreted in the culture medium was taken up by the mannose 6-phosphate receptor system and restored acid carboxypeptidase, beta-galactosidase, and neuraminidase activities in galactosialidosis fibroblasts. The expressed protein showed a granular pattern in intracellular distribution, was fractionated at the density of lysosomes, and had serine esterase activities; acid carboxypeptidase at pH 5.6, esterase at pH 7.0, and carboxyl-terminal deamidase at pH 7.0. They were inhibited simultaneously by phenylmethylsulfonyl fluoride, N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone, or iodoacetamide. The acid carboxypeptidase activity of the purified monomeric mature protective protein was labile in vitro under the acidic condition. Saposins (sphingolipid activator proteins) stabilized the activity at micromolar level concentrations.
...
PMID:Purification and characterization of human lysosomal protective protein expressed in stably transformed Chinese hamster ovary cells. 841 22

The lysosome is an intracytoplasmic acidic vacuole containing more than 60 hydrolytic enzymes for digestion of macromolecules, such as nucleic acids, proteins, lipids and complex carbohydrates. Expression of lysosomal enzyme activities is regulated by various intracellular environmental factors. Mutation of a gene coding for a lysosomal enzyme results in a specific genetic disease, often involving the central nervous system in children. Three groups of functional proteins are known at present for regulation of the expressed enzyme activity in lysosomes. Targeting of a newly synthesized protein is achieved by the mannose 6-phosphate receptor system, which was revealed in the course of I -cell disease research. Many lysosomal enzymes are excessively secreted in the extracellular compartment in the absence of this regulatory system in patients with this disease. Intralysosomal stability of beta-galactosidase is regulated by a multifunctional protein that interacts with two lysosomal enzymes, beta-galactosidase and sialidase, and also exerts catalytic activities as carboxypeptidase, esterase and deamidase under various pH conditions. It is encoded by a gene on chromosome 20, and its mutation results in a neurodegenerative disease in children and adults (galactosialidosis). For digestion of lipid substrates, lysosomal enzymes need specific activator proteins as natural detergents for molecular interaction with these nonpolar compounds. Two different groups of proteins have been revealed. A protein encoded by a gene on chromosome 5 interacts with ganglioside GM2 and its asialo derivative, for their catalytic hydrolysis by beta-hexosaminidase A. Another protein encoded by a gene on chromosome 10 is expressed as a precursor (prosaposin) which is then processed to four small proteins (saposins) with heterogeneous functions. They are essential for hydrolysis of sphingolipid substrates, and genetic deficiency of each protein results in various lipid storage diseases.
...
PMID:[Lysosomal enzymes, sphingolipid activator proteins, and protective protein]. 857 30

Deficiency of lysosomal protective protein/cathepsin A in humans is the primary cause of galactosialidosis, a lysosomal storage disease characterized by combined deficiency of beta-galactosidase and neuraminidase. We have investigated 20 galactosialidosis patients and nine of their obligate heterozygous parents. A group of 12 patients with the early infantile type of the disease exhibited practically complete absence of cathepsin A activity, whereas eight patients with either the late infantile or the juvenile/adult type had 2-5% residual activity. Highest levels (5%) were present in two patients with milder clinical manifestations and later onset of the disease. In most fibroblast strains, beta-galactosidase activity was 10-15% of normal levels, whereas neuraminidase was reduced to less than 4%. Interestingly, a substantial residual activity (10%) of the latter enzyme was detected in the patient with the mildest phenotype and the highest cathepsin A activity. Heterozygous values for cathepsin A were reduced on average to half of normal levels. However, in two cell strains, the activity was far below control range, and in these cases, neuraminidase activity was severely depressed. Finally, we showed that cathepsin A had considerable activity in chorionic villi and amniocytes, but was deficient in amniocytes from a pregnancy with an affected fetus, indicating the relevance of cathepsin A assay for prenatal diagnosis of galactosialidosis.
...
PMID:Cathepsin A deficiency in galactosialidosis: studies of patients and carriers in 16 families. 872 71

N-Acetylgalactosamine-6-sulfate sulfatase (GALNS) catalyzes the first step of intralysosomal keratan sulfate (KS) catabolism. In Morquio type A syndrome GALNS deficiency causes the accumulation of KS in tissues and results in generalized skeletal dysplasia in affected patients. We show that in normal cells GALNS is in a 1.27-MDa complex with three other lysosomal hydrolases: beta-galactosidase, alpha-neuraminidase, and cathepsin A (protective protein). GALNS copurifies with the complex by different chromatography techniques: affinity chromatography on both cathepsin A-binding and beta-galactosidase-binding columns, gel filtration, and chromatofocusing. Anti-human cathepsin A rabbit antiserum coprecipitates GALNS together with cathepsin A, beta-galactosidase, and alpha-neuraminidase in both a purified preparation of the 1. 27-MDa complex and crude glycoprotein fraction from human placenta extract. Gel filtration analysis of fibroblast extracts of patients deficient in either beta-galactosidase (beta-galactosidosis) or cathepsin A (galactosialidosis), which accumulate KS, demonstrates that the 1.27-MDa complex is disrupted and that GALNS is present only in free homodimeric form. The GALNS activity and cross-reacting material are reduced in the fibroblasts of patients affected with galactosialidosis, indicating that the complex with cathepsin A may protect GALNS in the lysosome. We suggest that the 1.27-MDa complex of lysosomal hydrolases is essential for KS catabolism and that the disruption of this complex may be responsible for the KS accumulation in beta-galactosidosis and galactosialidosis patients.
...
PMID:Association of N-acetylgalactosamine-6-sulfate sulfatase with the multienzyme lysosomal complex of beta-galactosidase, cathepsin A, and neuraminidase. Possible implication for intralysosomal catabolism of keratan sulfate. 891 Apr 59

The molecular form and subcellular distribution of acid beta-galactosidase in cultured fibroblasts from patients with beta-galactosidase deficiency (GM1-gangliosidosis, Morquio B disease and galactosialidosis) were studied, using antibodies against three different forms of the human enzyme: a high-molecular-weight multienzymic complex, a recombinant 84-kDa precursor, and a 64-kDa tryptic product of the precursor. The mature enzyme from normal fibroblasts was immunoprecipitated by the anti-complex and anti-64-kDa protein antibodies, but not by the anti-84-kDa precursor one. immunofluorescence staining of normal fibroblasts revealed the granular (lysosomal) distribution with anti-64-kDa protein antibody and the perinuclear reticular distribution with anti-84-kDa precursor antibody, probably representing the Golgi apparatus. Both patterns were demonstrated in Morquio B disease, but the residual enzyme activity was exclusively due to the mature enzyme. In Type 1 galactosialidosis, most of the expressed enzyme was detected as the precursor form with a perinuclear reticular distribution. In type 2 galactosialidosis, more than half of the enzyme activity was due to the mature form with a lysosomal distribution. Fibroblasts from a patient with GM1 gangliosidosis, expressing no beta-galactosidase mRNA, did not react against either anti-64-kDa protein antibody or anti-84-kDa precursor antibody. The combined use of immunoprecipitation and immunostaining was useful for analysing the pathophysiology of the intracellular processing and transport of the mutant beta-galactosidase.
...
PMID:Molecular form and subcellular distribution of acid beta-galactosidase in fibroblasts from patients with GM1 gangliosidosis, Morquio B disease and galactosialidosis. 910 59


1 2 Next >>

---