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Hiroshi Mizuno - One of the best experts on this subject based on the ideXlab platform.
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Crystallization and preliminary X-ray crystallographic studies of Alpha-Galactosidase I from Mortierella vinacea.
Acta crystallographica. Section D Biological crystallography, 2003Co-Authors: Zui Fujimoto, Mitsuru Momma, Satoshi Kaneko, Hideyuki Kobayashi, Gwi Gun Park, Wook-dong Kim, Hiroshi MizunoAbstract:Alpha-Galactosidases catalyze the hydrolysis of a galactosyl residue from galactooligosaccharides and galactopolysaccharides. Alpha-Galactosidase I from Mortierella vinacea was crystallized in two crystal forms using the hanging-drop vapour-diffusion method. Type 1 crystals belonged to space group I422, with unit-cell parameters a = b = 142.4, c = 131.5 A, and diffracted to beyond 2.1 A resolution, while type 2 crystals belonged to space group P4, with unit-cell parameters a = b = 100.9, c = 102.7 A, and diffracted to beyond 1.6 A resolution. This enzyme crystallized as a glycoprotein tetramer and the tetrameric structure was located around the crystallographic fourfold axis.
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crystal structure of rice alpha galactosidase complexed with d galactose
Journal of Biological Chemistry, 2003Co-Authors: Zui Fujimoto, Mitsuru Momma, Satoshi Kaneko, Hideyuki Kobayashi, Hiroshi MizunoAbstract:Alpha-Galactosidases catalyze the hydrolysis of alpha-1,6-linked galactosyl residues from galacto-oligosaccharides and polymeric galacto-(gluco)mannans. The crystal structure of rice Alpha-Galactosidase has been determined at 1.5A resolution using the multiple isomorphous replacement method. The structure consisted of a catalytic domain and a C-terminal domain and was essentially the same as that of alpha-N-acetylgalactosaminidase, which is the same member of glycosyl hydrolase family 27. The catalytic domain had a (beta/alpha)8-barrel structure, and the C-terminal domain was made up of eight beta-strands containing a Greek key motif. The structure was solved as a complex with d-galactose, providing a mode of substrate binding in detail. The d-galactose molecule was found bound in the active site pocket on the C-terminal side of the central beta-barrel of the catalytic domain. The d-galactose molecule consisted of a mixture of two anomers present in a ratio equal to their natural abundance. Structural comparisons of rice Alpha-Galactosidase with chicken alpha-N-acetylgalactosaminidase provided further understanding of the substrate recognition mechanism in these enzymes.
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Crystallization and preliminary X-ray crystallographic studies of rice Alpha-Galactosidase.
Acta crystallographica. Section D Biological crystallography, 2002Co-Authors: Zui Fujimoto, Mitsuru Momma, Satoshi Kaneko, Hideyuki Kobayashi, Osamu Kobayashi, Hiroshi MizunoAbstract:Alpha-Galactosidases catalyze the hydrolysis of galactooligosaccharides and galactopolysaccharides to alpha-galactose residues and are widely distributed in microorganisms, plants and animals. Alpha-Galactosidase from rice (Oryza sativa L. ssp. japonica) was crystallized by the hanging-drop vapour-diffusion method. The crystals belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 63.1, b = 71.3, c = 85.6 A, and diffract beyond 1.9 A resolution.
Zui Fujimoto - One of the best experts on this subject based on the ideXlab platform.
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Crystallization and preliminary X-ray crystallographic studies of Alpha-Galactosidase I from Mortierella vinacea.
Acta crystallographica. Section D Biological crystallography, 2003Co-Authors: Zui Fujimoto, Mitsuru Momma, Satoshi Kaneko, Hideyuki Kobayashi, Gwi Gun Park, Wook-dong Kim, Hiroshi MizunoAbstract:Alpha-Galactosidases catalyze the hydrolysis of a galactosyl residue from galactooligosaccharides and galactopolysaccharides. Alpha-Galactosidase I from Mortierella vinacea was crystallized in two crystal forms using the hanging-drop vapour-diffusion method. Type 1 crystals belonged to space group I422, with unit-cell parameters a = b = 142.4, c = 131.5 A, and diffracted to beyond 2.1 A resolution, while type 2 crystals belonged to space group P4, with unit-cell parameters a = b = 100.9, c = 102.7 A, and diffracted to beyond 1.6 A resolution. This enzyme crystallized as a glycoprotein tetramer and the tetrameric structure was located around the crystallographic fourfold axis.
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crystal structure of rice alpha galactosidase complexed with d galactose
Journal of Biological Chemistry, 2003Co-Authors: Zui Fujimoto, Mitsuru Momma, Satoshi Kaneko, Hideyuki Kobayashi, Hiroshi MizunoAbstract:Alpha-Galactosidases catalyze the hydrolysis of alpha-1,6-linked galactosyl residues from galacto-oligosaccharides and polymeric galacto-(gluco)mannans. The crystal structure of rice Alpha-Galactosidase has been determined at 1.5A resolution using the multiple isomorphous replacement method. The structure consisted of a catalytic domain and a C-terminal domain and was essentially the same as that of alpha-N-acetylgalactosaminidase, which is the same member of glycosyl hydrolase family 27. The catalytic domain had a (beta/alpha)8-barrel structure, and the C-terminal domain was made up of eight beta-strands containing a Greek key motif. The structure was solved as a complex with d-galactose, providing a mode of substrate binding in detail. The d-galactose molecule was found bound in the active site pocket on the C-terminal side of the central beta-barrel of the catalytic domain. The d-galactose molecule consisted of a mixture of two anomers present in a ratio equal to their natural abundance. Structural comparisons of rice Alpha-Galactosidase with chicken alpha-N-acetylgalactosaminidase provided further understanding of the substrate recognition mechanism in these enzymes.
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Crystallization and preliminary X-ray crystallographic studies of rice Alpha-Galactosidase.
Acta crystallographica. Section D Biological crystallography, 2002Co-Authors: Zui Fujimoto, Mitsuru Momma, Satoshi Kaneko, Hideyuki Kobayashi, Osamu Kobayashi, Hiroshi MizunoAbstract:Alpha-Galactosidases catalyze the hydrolysis of galactooligosaccharides and galactopolysaccharides to alpha-galactose residues and are widely distributed in microorganisms, plants and animals. Alpha-Galactosidase from rice (Oryza sativa L. ssp. japonica) was crystallized by the hanging-drop vapour-diffusion method. The crystals belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 63.1, b = 71.3, c = 85.6 A, and diffract beyond 1.9 A resolution.
John J Shacka - One of the best experts on this subject based on the ideXlab platform.
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Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of Alpha-Galactosidase A-deficient mice
Acta Neuropathologica Communications, 2014Co-Authors: Michael P Nelson, Darrel B O’quinn, Tonia E Tse, Stefanie M Percival, Edgar A. Jaimes, David G Warnock, John J ShackaAbstract:BackgroundMutations in the gene for Alpha-Galactosidase A result in Fabry disease, a rare, X-linked lysosomal storage disorder characterized by a loss of Alpha-Galactosidase A enzymatic activity. The resultant accumulation of glycosphingolipids throughout the body leads to widespread vasculopathy with particular detriment to the kidneys, heart and nervous system. Disruption in the autophagy-lysosome pathway has been documented previously in Fabry disease but its relative contribution to nervous system pathology in Fabry disease is unknown. Using an experimental mouse model of Fabry disease, Alpha-Galactosidase A deficiency, we examined brain pathology in 20-24 month old mice with particular emphasis on the autophagy-lysosome pathway.ResultsAlpha-Galactosidase A-deficient mouse brains exhibited enhanced punctate perinuclear immunoreactivity for the autophagy marker microtubule-associated protein light-chain 3 (LC3) in the parenchyma of several brain regions, as well as enhanced parenchymal and vascular immunoreactivity for lysosome-associated membrane protein-1 (LAMP-1). Ultrastructural analysis revealed endothelial cell inclusions with electron densities and a pronounced accumulation of electron-dense lipopigment. The pons of Alpha-Galactosidase A-deficient mice in particular exhibited a striking neuropathological phenotype, including the presence of large, swollen axonal spheroids indicating axonal degeneration, in addition to large interstitial aggregates positive for phosphorylated alpha-synuclein that co-localized with the axonal spheroids. Double-label immunofluorescence revealed co-localization of phosphorylated alpha-synuclein aggregates with ubiquitin and LC3.ConclusionTogether these findings indicate widespread neuropathology and focused axonal neurodegeneration in Alpha-Galactosidase A-deficient mouse brain in association with disruption of the autophagy-lysosome pathway, and provide the basis for future mechanistic assessment of the contribution of the autophagy-lysosome pathway to this histologic phenotype.
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autophagy lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha galactosidase a deficient mice
Acta neuropathologica communications, 2014Co-Authors: Michael P Nelso, Tonia E Tse, Darrel Oqui, Stefanie M Percival, Edgar A. Jaimes, David G Warnock, John J ShackaAbstract:Background Mutations in the gene for Alpha-Galactosidase A result in Fabry disease, a rare, X-linked lysosomal storage disorder characterized by a loss of Alpha-Galactosidase A enzymatic activity. The resultant accumulation of glycosphingolipids throughout the body leads to widespread vasculopathy with particular detriment to the kidneys, heart and nervous system. Disruption in the autophagy-lysosome pathway has been documented previously in Fabry disease but its relative contribution to nervous system pathology in Fabry disease is unknown. Using an experimental mouse model of Fabry disease, Alpha-Galactosidase A deficiency, we examined brain pathology in 20-24 month old mice with particular emphasis on the autophagy-lysosome pathway.
Gonzalo Duro - One of the best experts on this subject based on the ideXlab platform.
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Novel Alpha-Galactosidase A mutation in a female with recurrent strokes.
Clinical biochemistry, 2012Co-Authors: Antonino Tuttolomondo, Antonia Serio, Domenico Nuzzo, Gonzalo Duro, Domenico Raimondo, Giuseppe Albeggiani, Francesco Iemolo, Rosaria Pecoraro, Salvatore Miceli, Federica PizzoAbstract:Anderson-Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The complete genomic and cDNA sequences of the human Alpha-Galactosidase A gene have been determined and to date, several disease-causing Alpha-Galactosidase A mutations have been identified, including missense mutations, small deletions/insertions, splice mutations, and large gene rearrangements We report a case of a 56-year-old woman with recurrent cryptogenic strokes. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. She did not show other typical signs of Fabry disease such as acroparesthesias and angiokeratoma. The patient's Alpha-Galactosidase A activity was 4.13 nmol/mL/h in whole blood. Alpha-Galactosidase A gene sequence analysis revealed a heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4 in this woman, leading to the p.Tyr184Asn amino acid substitution.
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identification of a novel mutation in the alpha galactosidase a gene in patients with fabry disease
Clinical Biochemistry, 2012Co-Authors: Paolo Colomba, Antonia Nucera, Carmela Zizzo, Giuseppe Albeggiani, Daniele Francofonte, Francesco Iemolo, Antonino Tuttolomondo, Antonio Pinto, Gonzalo DuroAbstract:Abstract Objectives Mutation analysis of the Alpha-Galactosidase A (GLA) gene is a valuable tool for the diagnosis of affected families. In our work, we analyze about one thousand samples per year from patients suspected of having Fabry disease (FD). Design and methods We carried out high resolution melting analysis (HRM) and DNA sequencing of all the exons of the GLA gene. We also assayed the Alpha-Galactosidase A activity in patients' blood. Results In some members of one family, we identified a new mutation in the GLA gene, c.614delC. This is a deletion of a single nucleotide, a cytosine, in exon 4 of the gene which causes a frameshift mutation. Conclusions Patients with the c.614delC mutation show classical clinical manifestations of FD, and the male patient has no Alpha-Galactosidase A activity. These data suggest that c.614delC is a novel mutation associated with FD.
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Identification of a novel mutation in the Alpha-Galactosidase A gene in patients with Fabry disease.
Clinical biochemistry, 2012Co-Authors: Paolo Colomba, Antonia Nucera, Carmela Zizzo, Giuseppe Albeggiani, Daniele Francofonte, Francesco Iemolo, Antonino Tuttolomondo, Antonio Pinto, Gonzalo DuroAbstract:Mutation analysis of the Alpha-Galactosidase A (GLA) gene is a valuable tool for the diagnosis of affected families. In our work, we analyze about one thousand samples per year from patients suspected of having Fabry disease (FD). We carried out high resolution melting analysis (HRM) and DNA sequencing of all the exons of the GLA gene. We also assayed the Alpha-Galactosidase A activity in patients' blood. In some members of one family, we identified a new mutation in the GLA gene, c.614delC. This is a deletion of a single nucleotide, a cytosine, in exon 4 of the gene which causes a frameshift mutation. Patients with the c.614delC mutation show classical clinical manifestations of FD, and the male patient has no Alpha-Galactosidase A activity. These data suggest that c.614delC is a novel mutation associated with FD. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Russell J. Molyneux - One of the best experts on this subject based on the ideXlab platform.
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Specific Alpha-Galactosidase inhibitors, N-methylcalystegines--structure/activity relationships of calystegines from Lycium chinense.
European journal of biochemistry, 1997Co-Authors: Naoki Asano, Atsushi Kato, Miwa Miyauchi, Haruhisa Kizu, Tsuyoshi Tomimori, Katsuhiko Matsui, Robe J Nash, Russell J. MolyneuxAbstract:An examination of the roots of Lycium chinense (Solanaceae) has resulted in the discovery of 14 calystegines, a cycloheptane bearing an amino group and three hydroxyl groups, and two polyhydroxylated piperidine alkaloids. Calystegines A7 and B5, in addition to the previously known calystegines A3, A5, A6, B1, B2, B3, B4, C1, C2 and N1, were isolated and determined as 1alpha,2beta,4alpha-trihydroxy-nortropane and 1alpha,2alpha,4alpha,7alpha-tetrahydroxy-nort ropane, respectively. L. chinense also had two polyhydroxytropanes bearing a methyl group on the nitrogen atom, unlike the previously reported nortropane alkaloids. They were established as N-methylcalystegines B2 and C1, and their N-methyl groups were found to be axially oriented from NOE experiments. 1Beta-amino-3beta,4beta,5alpha-trihydroxycyclohepta ne was also present in L. chinense and may be a biosynthetic precursor of the calystegines that occur in this plant. Two polyhydroxypiperidine alkaloids, fagomine and 6-deoxyfagomine, were isolated. Calystegine B2 is a potent competitive inhibitor of almond beta-glucosidase (Ki = 1.9 microM) and coffee bean Alpha-Galactosidase (Ki = 0.86 microM), while N-methylcalystegine B2 was a more potent competitive inhibitor of the latter enzyme (Ki = 0.47 microM) than the parent compound but showed a marked lack of inhibitory activities towards most other glycosidases. Since this compound is a very specific inhibitor of Alpha-Galactosidase and inhibits rat liver lysosomal Alpha-Galactosidase with a Ki of 1.8 microM, it may provide a useful experimental model for the lysosomal storage disorder, Fabry's disease. The addition of a hydroxyl group at C6exo, as in calystegines B1 and C1, enhances the inhibitory potential towards beta-glucosidase and beta-galactosidase but markedly lowers or abolishes inhibition towards Alpha-Galactosidase. Hence, the N-methylation of calystegine C1 did not enhance its inhibition of Alpha-Galactosidase. The chemical N-methylation of calystegines A3 and B4 markedly enhanced inhibition of coffee bean Alpha-Galactosidase, with Ki values of 5.2 microM and 36 microM, respectively, but almost eliminated their inhibitory potential towards beta-glucosidase and trehalase, respectively. Thus, methylation of the nitrogen atom significantly altered the specificity of the inhibitors.
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Calystegins, a novel class of alkaloid glycosidase inhibitors.
Archives of Biochemistry and Biophysics, 1993Co-Authors: Russell J. Molyneux, Y. T. Pan, Arlette Goldmann, David Tepfer, Alan D. ElbeinAbstract:The alkaloid extract from roots of naturally growing Convolvulus arvensis, purified by ion-exchange chromatography, showed significant inhibitory activity toward beta-glucosidase and Alpha-Galactosidase. The demonstrated occurrence of polyhydroxy-nortropane alkaloids, the calystegins, in C. arvensis and their structural similarity to known polyhydroxy alkaloid glycosidase inhibitors, suggested that these might be responsible for the observed activity. Pure calystegins, isolated from transformed root cultures of the related plant species Calystegia sepium, were tested for glycosidase inhibitory activity. The purity of the alkaloids was established by gas chromatography and their identity confirmed by their mass spectrometric fragmentation patterns. The trihydroxy alkaloid, calystegin A3, was a moderately good inhibitor of beta-glucosidase (Ki = 4.3 x 10(-5) M) and a weak inhibitor of Alpha-Galactosidase (Ki = 1.9 x 10(-4) M). An increased level of hydroxylation, as in the tetrahydroxy calystegins B, consisting of 27% calystegin B1 and 73% calystegin B2, resulted in greatly enhanced inhibitory activity. The calystegins B were potent inhibitors of beta-glucosidase (Ki = 3 x 10(-6) M) and Alpha-Galactosidase (Ki = 7 x 10(-6) M). These levels of activity are comparable with those of the polyhydroxy indolizidine alkaloids castanospermine and swainsonine toward alpha-glucosidase and alpha-mannosidase, respectively, and of the polyhydroxy pyrrolizidine alkaloid australine toward alpha-glucosidase. The calystegins therefore compose a new structural class of polyhydroxy alkaloids, the nortropanes, possessing potent glycosidase inhibitory properties.
