Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) is an autosomal recessive disorder caused by lysosomal acid alpha-glucosidase (AalphaGlu) deficiency and manifests predominantly as skeletal muscle weakness. Defects in post-translational modification and transport of mutant AalphaGlu species are frequently encountered and may potentially be corrected with chaperone-mediated therapy. In the present study, we have tested this hypothesis by using deoxynojirimycin and derivatives as chemical chaperones to correct the AalphaGlu deficiency in cultured fibroblasts from patients with GSDII. Four mutant phenotypes were chosen: Y455F/Y455F, P545L/P545L, 525del/R600C and D645E/R854X. In case of Y455F/Y455F and P545L/P545L, N-(n-butyl)deoxynojirimycin (NB-DNJ) restored the transport, maturation and activity of AalphaGlu in a dose dependent manner, while it had no effect on the reference enzyme beta-hexosaminidase. NB-DNJ promoted export from the endoplasmic reticulum (ER) to the lysosomes and stabilized the activity of mutant AalphaGlu species, Y455F and P545L, inside the lysosomes. In long-term culture, the AalphaGlu activity in the fibroblasts from the patients with mutant phenotypes, Y455F/Y455F and P545L/P545L, increased up to 14.0- and 7.9-fold, respectively, in the presence of 10mumol/L NB-DNJ. However, the effect of NB-DNJ on Y455F/Y455F subsided quickly after removal of the compound. We conclude that NB-DNJ acts in low concentration as chemical chaperone for certain mutant forms of AalphaGlu that are trapped in the ER, poorly transported or labile in the lysosomal environment. Chemical chaperone therapy could create new perspectives for therapeutic intervention in GSDII.
Mol Genet Metab 2007 Jan
PMID:Chemical chaperones improve transport and enhance stability of mutant alpha-glucosidases in glycogen storage disease type II. 1709 74

Using a combinatorial chemistry approach, we identified a tetrameric tripeptide, denoted Protein A Mimetic (PAM) or TG19318, able to bind to immunoglobulins of different classes and species. The inverso variant, with the tripeptide in the all-D configuration (D-PAM or TG19320), is described as retaining binding properties to Ig. This peptide has now been assayed as a binder for E class immunoglobulins, in linear and competitive ELISA experiments, dot-blot and surface plasmon resonance (SPR) analyses. We show that D-PAM binds IgE with high specificity and selectivity, the interaction being sufficient to inhibit anaphylactic release of beta-hexosaminidase from RBL 2H3 cells, with an IC50 value of 10 microg/mL. Intradermal administration of D-PAM suppresses PCA in the rat, with an IC50 of 1.25 microg/kg dose of peptide, while its intraperitoneal injection inhibits mouse PCA with an IC50 of about 7 mg/kg and an efficacy comparable to that of ketotifen. Similarly, D-PAM inhibits ACA in the mouse, with 50% suppression at 10 mg/kg. The results presented here show that the peptide is active on the studied models, with effective doses below toxicity level, hence the molecule is a promising candidate for development of a new class of anti-allergic drugs.
Mol Immunol 2008 Jan
PMID:Anti-allergic properties of a new all-D synthetic immunoglobulin-binding peptide. 1754 50

Human promyelocytic leukemia HL-60 cells represent an in vitro model of acute promyelocytic leukemia (APL), and are inducible to terminally differentiate into morphologically mature granulocytes by incubation with all trans retinoic acid (ATRA). Lysosomal glycohydrolases are involved in the changes of the membrane surface proteins' glycosylation, linked to the metastatic progression potential of neoplastic cells. In particular, it has been demonstrated that the Asn-linked glucidic residues were directly responsible for the metastatic potential, and it is known that the glycohydrolase alpha-D-mannosidase specifically hydrolyze the Asn-linked oligosaccharides. In this report, we present an in vitro study on the ATRA effects on lysosomal glycohydrolases expression and the eventual relationship with the retinoic acid-induced differentiation of HL-60 cells. We have investigated two highly expressed lysosomal glycohydrolases, namely beta-D-hexosaminidase and alpha-D-mannosidase, and showed that they were differently affected by ATRA differentiating action. In particular, due to the specific action on Asn-linked oligosaccharides, we tested alpha-D: -mannosidase enzymatic activity and observed that it was dramatically decreased after ATRA incubation, indicating a relationship with the differentiation state of the cells. These observations may directly be linked with the loss of metastatic progession of differentiated HL-60.
Mol Cell Biochem 2008 Jan
PMID:Effect of all trans retinoic acid on lysosomal alpha-D-mannosidase activity in HL-60 cell: correlation with HL-60 cells differentiation. 1789 19

The genomes of myonecrotic strains of Clostridium perfringens encode a large number of secreted glycoside hydrolases. The activities of these enzymes are consistent with degradation of the mucosal layer of the human gastrointestinal tract, glycosaminoglycans and other cellular glycans found throughout the body. In many cases this is thought to aid in the propagation of the major toxins produced by C. perfringens. One such example is the family 84 glycoside hydrolases, which contains five C. perfringens members (CpGH84A-E), each displaying a unique modular architecture. The smallest and most extensively studied member, CpGH84C, comprises an N-terminal catalytic domain with beta-N-acetylglucosaminidase activity, a family 32 carbohydrate-binding module, a family 82 X-module (X82) of unknown function, and a fibronectin type-III-like module. Here we present the structure of the X82 module from CpGH84C, determined by both NMR spectroscopy and X-ray crystallography. CpGH84C X82 adopts a jell-roll fold comprising two beta-sheets formed by nine beta-strands. CpGH84C X82 displays distant amino acid sequence identity yet close structural similarity to the cohesin modules of cellulolytic anaerobic bacteria. Cohesin modules are responsible for the assembly of numerous hydrolytic enzymes in a cellulose-degrading multi-enzyme complex, termed the cellulosome, through a high-affinity interaction with the calcium-binding dockerin module. A planar surface is located on the face of the CpGH84 X82 structure that corresponds to the dockerin-binding region of cellulolytic cohesin modules and has the approximate dimensions to accommodate a dockerin module. The presence of cohesin-like X82 modules in glycoside hydrolases of C. perfringens is an indication that the formation of novel X82-dockerin mediated multi-enzyme complexes, with potential roles in pathogenesis, is possible.
J Mol Biol 2008 Jan 04
PMID:Three-dimensional structure of a putative non-cellulosomal cohesin module from a Clostridium perfringens family 84 glycoside hydrolase. 1799 32

Mucopolysaccharidosis type IIIA (MPS IIIA) is a heritable glycosaminoglycan (GAG) storage disorder which is characterised by lysosomal accumulation of heparan sulphate, secondary to a deficiency of sulphamidase (heparan-N-sulphatase, N-sulphoglucosamine sulphohydrolase, EC No. 3.10.1.1.). There is currently no treatment for affected individuals who experience progressive CNS deterioration prior to an early death. As a first step towards developing gene therapy as a treatment for MPS IIIA, an MPS IIIA mouse model was used to examine the efficacy of intravenous lentiviral-mediated gene therapy. Five-week-old mice were injected with virus expressing murine sulphamidase and analysed 6 months after treatment. Transduction by the lentiviral vector was highest in the liver and spleen of treated animals, and sulphamidase activity in these tissues averaged 68% and 186% of normal, respectively. Storage was assessed using histochemical, chemical and mass spectrometric analyses. Storage in most somatic tissues was largely normalised, although chondrocytes were an obvious exception. Histologically, improvement of lysosomal storage within the brain was variable. However, beta-hexosaminidase activity, which is abnormally elevated in MPS IIIA, was significantly reduced in every treated tissue, including the brain. Total uronic acid was also significantly reduced in the brains of treated mice. The level of a disaccharide marker (hexosamine-N-sulphate[alpha-1,4]hexuronic acid; HNS-UA) of heparan sulphate storage was also decreased in the brains of treated mice, albeit non-significantly. These results suggest that lentiviral-mediated somatic gene transfer may affect not only the somatic, but possibly also the CNS pathology, found in MPS IIIA.
Mol Genet Metab 2008 Apr
PMID:Lentiviral-mediated gene therapy for murine mucopolysaccharidosis type IIIA. 1824 29

Mammalian sialidase Neu4, ubiquitously expressed in human tissues, is located in the lysosomal and mitochondrial lumen and has broad substrate specificity against sialylated glycoconjugates. To investigate whether Neu4 is involved in ganglioside catabolism, we transfected beta-hexosaminidase-deficient neuroglia cells from a Tay-Sachs patient with a Neu4-expressing plasmid and demonstrated the correction of storage due to the clearance of accumulated GM2 ganglioside. To further clarify the biological role of Neu4, we have generated a stable loss-of-function phenotype in cultured HeLa cells and in mice with targeted disruption of the Neu4 gene. The silenced HeLa cells showed reduced activity against gangliosides and had large heterogeneous lysosomes containing lamellar structures. Neu4(-/-) mice were viable, fertile and lacked gross morphological abnormalities, but showed a marked vacuolization and lysosomal storage in lung and spleen cells. Lysosomal storage bodies were also present in cultured macrophages preloaded with gangliosides. Thin-layer chromatography showed increased relative level of GD1a ganglioside and a markedly decreased level of GM1 ganglioside in brain of Neu4(-/-) mice suggesting that Neu4 may be important for desialylation of brain gangliosides and consistent with the in situ hybridization data. Increased levels of cholesterol, ceramide and polyunsaturated fatty acids were also detected in the lungs and spleen of Neu4(-/-) mice by high-resolution NMR spectroscopy. Together, our data suggest that Neu4 is a functional component of the ganglioside-metabolizing system, contributing to the postnatal development of the brain and other vital organs.
Hum Mol Genet 2008 Jun 01
PMID:Mice deficient in Neu4 sialidase exhibit abnormal ganglioside catabolism and lysosomal storage. 1827 Feb 9

Effects of hyaluronic acid (HA) on allergic inflammation were investigated. HA exerted negative effects on beta-hexoaminidase secretion and histamine release in antigen-stimulated rat basophilic leukemia (RBL2H3) cells. HA inhibited interaction between IgE and FcepsilonRI and between FcepsilonRI and PKCdelta. HA inhibited CD44 interaction with PKCalpha, indicating that HA targets CD44. PKCalpha and -delta were responsible for increased Rac1 activity and expression of p47(phox), p67(phox). HA inhibited phosphorylation of PKCalpha and -delta. Rac1 was responsible for increased ROS, and NADPH oxidase was the main source for ROS. The inhibition of PKC prevented antigen from increasing phosphorylation of ERK and p38 MAPK. ERK, p38 MAPK, and ROS, were responsible for secretion of beta-hexosaminidase, histamine release, and induction of chemokines. HA suppressed induction of chemokines, such as MIP-2 and Sprr-2a. CD44 mediated effect of antigen on phosphorylation of ERK, p38MAPK, ROS production, secretion of beta-hexosaminidase, and histamine release. GPCR did not mediate allergic function of antigen or affect anti-allergic function of HA. In vivo anti-allergic effect of HA was investigated using Nc/Nga mice model of DNFB-induced atopic dermatitis. HA reduced skin lesions in Nc/Nga mice treated with DNFB, decreased expression levels of MIP-2, Sprr-2a, and serum IgE level. In conclusion, hyaluronic acid exerts negative effect on allergic inflammation by targeting CD44 and inhibiting FcepsilonRI signaling.
Mol Immunol 2008 May
PMID:Hyaluronic acid targets CD44 and inhibits FcepsilonRI signaling involving PKCdelta, Rac1, ROS, and MAPK to exert anti-allergic effect. 1828 79

Enzymes belonging to the beta-N-acetylhexosaminidase family cleave chitin oligosaccharides produced by the action of chitinases on chitin into the constituent N-acetylglucosamine monomer. Four genes encoding putative chitooligosaccharidolytic beta-N-acetylhexosaminidases (hereafter referred to as N-acetylglucosaminidases (NAGs)) in the red flour beetle, Tribolium castaneum, namely TcNAG1, TcFDL, TcNAG2, and TcNAG3, and three other related hexosaminidases were identified by searching the recently completed genome [Tribolium Genome Sequencing Consortium, 2007. The first genome sequence of a beetle, Tribolium castaneum, a model for insect development and pest biology. Nature, submitted for publication]. Full-length cDNAs for all four NAGs were cloned and sequenced, and the exon-intron organization of the corresponding genes was determined. Analyses of their developmental expression patterns indicated that, although all four of the NAGs are transcribed during most developmental stages, each gene had a distinct spatial and temporal expression pattern. TcNAG1 transcripts are the most abundant, particularly at the late pupal stage, while TcNAG3 transcripts are the least abundant, even at their peak levels in the late larval stages. The function of each NAG during different developmental stages was assessed by observations of lethal phenotypes after gene-specific double-stranded RNA (dsRNA)-mediated transcript depletion as verified by real-time PCR. TcNAG1 dsRNA was most effective in interrupting all three types of molts: larval-larval, larval-pupal, and pupal-adult. Treated insects died after failing to completely shed their old cuticles. Knockdown of transcripts for the other three NAG genes resulted in phenotypes similar to those of TcNAG1 dsRNA-treated insects, but the effects were somewhat variable and less severe. Sequence comparisons with other enzymatically characterized insect homologs suggested that TcFDL, unlike the other NAGs, may have a role in N-glycan processing in addition to its apparent role in cuticular chitin turnover. These results support the hypothesis that TcNAGs participate in chitin turnover and/or N-glycan processing during insect development and that each NAG fulfills an essential and distinct function.
Insect Biochem Mol Biol 2008 Apr
PMID:Characterization and expression of the beta-N-acetylhexosaminidase gene family of Tribolium castaneum. 1834 52

Mast cell activation involves the rapid release of inflammatory mediators, including histamine, from intracellular granules. The cells are capable of regranulation and multiple rounds of activation. The goal of this study was to determine if there are changes in the content of pre-formed mast cell mediators after a round of activation. After 24 h, the histamine content of bone marrow-derived mast cells (BMMC), but not that of peritoneal mast cells, exceeded the amount in resting cells. Accumulation of histamine in BMMC peaked at 72 h of activation, and returned toward preactivation levels by 96 h. The increase in histamine content was accompanied by an increase in the gene expression of histidine decarboxylase. No increases in beta hexosaminidase or murine mast cell protease-6 were observed. These findings indicate that BMMC respond to activation by increasing total cell-associated histamine content. This increase may be important to the response of these cells upon subsequent exposure to antigens.
Cell Mol Life Sci 2008 May
PMID:Activation-induced cellular accumulation of histamine in immature but not mature murine mast cells. 1840 84

Tay-Sachs disease is an autosomal recessive storage disease caused by the impaired activity of the lysosomal enzyme hexosaminidase A. In this fatal disease, the sphingolipid GM2 ganglioside accumulates in the neurons. Due to high carrier rates and the severity of the disease, population screening and prenatal diagnosis of Tay-Sachs disease are routinely carried out in Israel. Laboratory diagnosis of Tay-Sachs is carried out with biochemical and DNA-based methods in peripheral and umbilical cord blood, amniotic fluid, and chorionic villi samples. The assay of hexosaminidase A (Hex A) activity is carried out with synthetic substrates, 4-methylumbelliferyl-6-sulfo-N-acetyl-beta-glucosaminide (4-MUGS) and 4-methylumbelliferil-N-acetyl-beta-glucosamine (4-MUG), and the DNA-based analysis involves testing for the presence of specific known mutations in the alpha-subunit gene of Hex A. Prenatal diagnosis of Tay-Sachs disease is accomplished within 24-48 h from sampling. The preferred strategy is to simultaneously carry out enzymatic analysis in the amniotic fluid supernatant or in chorionic villi and molecular DNA-based testing in an amniotic fluid cell-pellet or in chorionic villi.
Methods Mol Biol 2008
PMID:Rapid detection of fetal Mendelian disorders: Tay-Sachs disease. 1842 78


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