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[PMID]:28388360
[Au] Autor:Tsujita N; Kuwahara H; Koyama H; Yanaka N; Arakawa K; Kuniyoshi H
[Ad] Endereço:a Graduate School of Biosphere Science , Hiroshima University , Higashi-Hiroshima , Japan.
[Ti] Título:Molecular characterization of aspartylglucosaminidase, a lysosomal hydrolase upregulated during strobilation in the moon jellyfish, Aurelia aurita.
[So] Source:Biosci Biotechnol Biochem;81(5):938-950, 2017 May.
[Is] ISSN:1347-6947
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The life cycle of the moon jellyfish, Aurelia aurita, alternates between a benthic asexual polyp stage and a planktonic sexual medusa (jellyfish) stage. Transition from polyp to medusa is called strobilation. To investigate the molecular mechanisms of strobilation, we screened for genes that are upregulated during strobilation using the differential display method and we identified aspartylglucosaminidase (AGA), which encodes a lysosomal hydrolase. Similar to AGAs from other species, Aurelia AGA possessed an N-terminal signal peptide and potential N-glycosylation sites. The genomic region of Aurelia AGA was approximately 9.8 kb in length and contained 12 exons and 11 introns. Quantitative RT-PCR analysis revealed that AGA expression increased during strobilation, and was then decreased in medusae. To inhibit AGA function, we administered the lysosomal acidification inhibitors, chloroquine or bafilomycin A1, to animals during strobilation. Both inhibitors disturbed medusa morphogenesis at the oral end, suggesting involvement of lysosomal hydrolases in strobilation.
[Mh] Termos MeSH primário: Aspartilglucosilaminase/genética
Aspartilglucosilaminase/metabolismo
Lisossomos/enzimologia
Reprodução Assexuada
Cifozoários/enzimologia
Cifozoários/fisiologia
Regulação para Cima
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Aspartilglucosilaminase/química
Sequência de Bases
Clonagem Molecular
Loci Gênicos/genética
Morfogênese
Cifozoários/genética
Cifozoários/crescimento & desenvolvimento
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170419
[Lr] Data última revisão:
170419
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE
[do] DOI:10.1080/09168451.2017.1285686


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[PMID]:28346360
[Au] Autor:Banning A; König JF; Gray SJ; Tikkanen R
[Ad] Endereço:Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany. Antje.Banning@biochemie.med.uni-giessen.de.
[Ti] Título:Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production.
[So] Source:Int J Mol Sci;18(4), 2017 Mar 26.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options.
[Mh] Termos MeSH primário: Aspartilglucosilaminase/metabolismo
[Mh] Termos MeSH secundário: Aspartilglucosilaminase/química
Aspartilglucosilaminase/genética
Células Cultivadas
Fibroblastos/citologia
Fibroblastos/metabolismo
Fibroblastos/patologia
Frequência do Gene
Genótipo
Células HEK293
Células HeLa
Seres Humanos
Doenças por Armazenamento dos Lisossomos/enzimologia
Doenças por Armazenamento dos Lisossomos/genética
Doenças por Armazenamento dos Lisossomos/patologia
Lisossomos/química
Lisossomos/metabolismo
Plasmídeos/genética
Plasmídeos/metabolismo
Polimorfismo de Nucleotídeo Único
Subunidades Proteicas/química
Subunidades Proteicas/genética
Subunidades Proteicas/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Subunits); EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170507
[Lr] Data última revisão:
170507
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170328
[St] Status:MEDLINE


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[PMID]:28063748
[Au] Autor:Yamamoto T; Shimojima K; Matsufuji M; Mashima R; Sakai E; Okuyama T
[Ad] Endereço:Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan; Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan. Electronic address: yamamoto.toshiyuki@twmu.ac.jp.
[Ti] Título:Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan.
[So] Source:Brain Dev;39(5):422-425, 2017 May.
[Is] ISSN:1872-7131
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, aspartylglucosaminidase (AGA). This disorder is rare in the general population except in Finland. Since the most characteristic feature of this disorder is a progressive developmental regression, patients often show no specific symptoms in the initial stages, and thus early diagnosis is often challenging. CASE REPORT: We encountered a 16-year-old boy who began to show difficulties in his speech at the age of 6years. Due to a mild regression in his development, he gradually lost common daily abilities. His diagnosis was first obtained through exome sequencing that identified a novel homozygous mutation in the AGA gene. This result was reasonable because of parental consanguinity. Reduced enzymatic activity of AGA was then confirmed. His urine was retrospectively screened by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and a specific pattern of abnormal metabolites was identified. CONCLUSIONS: Because both exome sequencing and MALDI-TOF-MS screening are adaptable and comprehensive, future combinatory use of these methods would be useful for diagnosis of rare inborn errors of metabolism such as AGU.
[Mh] Termos MeSH primário: Aspartilglucosaminúria/genética
Aspartilglucosilaminase/genética
Mutação/genética
[Mh] Termos MeSH secundário: Adolescente
Aspartilglucosaminúria/diagnóstico por imagem
Aspartilglucosilaminase/metabolismo
Exoma/genética
Seres Humanos
Japão
Imagem por Ressonância Magnética
Masculino
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
Tálamo/diagnóstico por imagem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170417
[Lr] Data última revisão:
170417
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170109
[St] Status:MEDLINE


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[PMID]:27906067
[Au] Autor:Arvio M; Mononen I
[Ad] Endereço:Päijät-Häme Social Welfare & Healthcare Joint Municipal Board, Lahti, Finland. maria.arvio@phsotey.fi.
[Ti] Título:Aspartylglycosaminuria: a review.
[So] Source:Orphanet J Rare Dis;11(1):162, 2016 12 01.
[Is] ISSN:1750-1172
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the Finnish population. It is a lifelong condition affecting on the patient's appearance, cognition, adaptive skills, physical growth, personality, body structure, and health. An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU. Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50 years.The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA), which leads to a disorder in the degradation of glycoasparagines - aspartylglucosamine or other glycoconjugates with an aspartylglucosamine moiety at their reducing end - and accumulation of these undegraded glycoasparagines in tissues and body fluids. A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population. Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population. A mouse strain, which completely lacks the Aga activity has been generated through targeted disruption of the Aga gene in embryonic stem cells. These Aga-deficient mice share most of the clinical, histopathologic and biochemical characteristics of human AGU disease. Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals. The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol. Enzyme replacement trials on human AGU patients have not been reported so far. Allogenic stem cell transplantation has not proved effective in curing AGU.
[Mh] Termos MeSH primário: Aspartilglucosaminúria/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/análogos & derivados
Acetilglucosamina/metabolismo
Animais
Aspartilglucosaminúria/enzimologia
Aspartilglucosaminúria/genética
Aspartilglucosilaminase/genética
Aspartilglucosilaminase/metabolismo
Glicoproteínas/metabolismo
Seres Humanos
Doenças por Armazenamento dos Lisossomos/enzimologia
Doenças por Armazenamento dos Lisossomos/genética
Doenças por Armazenamento dos Lisossomos/metabolismo
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Glycoproteins); 2776-93-4 (N-acetylglucosaminylasparagine); EC 3.5.1.26 (Aspartylglucosylaminase); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161202
[St] Status:MEDLINE


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[PMID]:25456816
[Au] Autor:Sui L; Lakshminarasimhan D; Pande S; Guo HC
[Ad] Endereço:Department of Biological Sciences, University of Massachusetts Lowell, 1 University Avenue, Lowell, MA 01854, USA.
[Ti] Título:Structural basis of a point mutation that causes the genetic disease aspartylglucosaminuria.
[So] Source:Structure;22(12):1855-61, 2014 Dec 02.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by a metabolic disorder of lysosomes to digest Asn-linked glycoproteins. The specific enzyme linked to AGU is a lysosomal hydrolase called glycosylasparaginase. Crystallographic studies revealed that a surface loop blocks the catalytic center of the mature hydrolase. Autoproteolysis is therefore required to remove this P loop and open up the hydrolase center. Nonetheless, AGU mutations result in misprocessing of their precursors and are deficient in hydrolyzing glycoasparagines. To understand the catalytic and structural consequences of AGU mutations, we have characterized two AGU models, one corresponding to a Finnish allele and the other found in a Canadian family. We also report a 2.1 Å resolution structure of the latter AGU model. The current crystallographic study provides a high-resolution structure of an AGU mutant. It reveals substantial conformation changes at the defective autocleavage site of the AGU mutant, which is trapped as an inactive precursor.
[Mh] Termos MeSH primário: Aspartilglucosaminúria/genética
Aspartilglucosilaminase/genética
Mutação Puntual
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Modelos Moleculares
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE


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[PMID]:25190167
[Au] Autor:Liu Y; Zou L; Meng Y; Zhang Y; Shi X; Ju J; Yang G; Hu L; Chen X
[Ad] Endereço:Department of Pediatrics, Chinese People's Liberation Army General Hospital, Beijing 100853, China.
[Ti] Título:[A family with two children diagnosed with aspartylglucosaminuria-case report and literature review].
[So] Source:Zhonghua Er Ke Za Zhi;52(6):455-9, 2014 Jun.
[Is] ISSN:0578-1310
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: The authors sought to investigate the clinical features and characteristics of genetic mutation in patients with aspartylglucosaminuria. METHOD: Clinical data of two pediatric siblings in a family were analyzed retrospectively and relative literature was reviewed in order to study the clinical features, imaging and enzymatic characteristics and genetic mutations. RESULT: Case 1, the proband, male, he was hospitalized at 20 months of age because of fever and hepatosplenomegaly for nine days. This child was of moderate nutritional status and normal development. Blood tests showed hemoglobin 78.0 g/L, RBC3.18 × 10¹²/L, WBC 4.06 × 109/L, neutrophils 0.236, lymphocytes 0.631, platelets 34 × 109/L, C-reactive protein 17 mg/L. Blood biochemistry showed alanine aminotransferase 67.1 U/L, aspartate aminotransferase 74.1 U/L, serum albumin 32.8 g/L, direct bilirubin 10.5 µmol/L, lactate dehydrogenase 301.7 U/L. Bone marrow cytology showed reactive morphological changes in bone marrow cells. Atypical lymphocytes could be seen in both peripheral blood and bone marrow smears. Cranial MRI showed poor myelination. Aspartylglucosaminidase activity in peripheral leucocytes of the proband 5.7 nmol/(g × min) vs. normal control>26.6 nmol/(g × min). On his AGA gene and that of his parents, a heterozygous mutation site located in exon 3, c.392C>T (p.S131L), was identified as a novel mutation inherited from his father. The mutation from his mother has not been detected. The proband was not responsive to the anti-infectious medication, nutritional intervention and symptomatic treatment.He died one month after diagnosis.His elder brother, Case 2, showed fever, recurrent respiratory tract infection and progressive psychomotor regression with hepatosplenomegaly from the age of four years. Cranial MRI revealed extensive symmetrical leukodystrophy in bilateral cerebra, cerebellum and brainstem.He died at the age of six years.Related literature was summarized, and no Chinese AGU cases had been reported; 221 foreign cases were collected. The clinical and imaging characteristics were summarized. Delay in language development was one of the clinical symptoms that the majority of parents of AGU children first noted. CONCLUSION: Patients with aspartylglucosaminuria lack of specific symptoms.For children with unexplained delayed speech and progressive mental retardation, the possibility of AGU should be considered, and efforts be made for enzymatic and genetic diagnosis. c.392C> T (p.S131L) was identified as a novel mutation of AGA gene.
[Mh] Termos MeSH primário: Aspartilglucosaminúria/diagnóstico
Aspartilglucosaminúria/genética
Aspartilglucosilaminase/genética
Mutação
[Mh] Termos MeSH secundário: Aspartilglucosaminúria/patologia
Aspartilglucosilaminase/metabolismo
Biomarcadores/sangue
Encéfalo/patologia
Pré-Escolar
Análise Mutacional de DNA
Heterozigoto
Seres Humanos
Lactente
Doenças por Armazenamento dos Lisossomos/diagnóstico
Doenças por Armazenamento dos Lisossomos/genética
Doenças por Armazenamento dos Lisossomos/patologia
Imagem por Ressonância Magnética
Masculino
Linhagem
Reação em Cadeia da Polimerase
[Pt] Tipo de publicação:CASE REPORTS; ENGLISH ABSTRACT; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Biomarkers); EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:160607
[Lr] Data última revisão:
160607
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140906
[St] Status:MEDLINE


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[PMID]:23271757
[Au] Autor:Opladen T; Ebinger F; Zschocke J; Sengupta D; Ben-Omran T; Shahbeck N; Moog U; Fischer C; Bürger F; Haas D; Ruef P; Harting I; Al-Rifai H; Hoffmann GF
[Ad] Endereço:1Department of Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
[Ti] Título:Aspartylglucosaminuria: unusual neonatal presentation in Qatari twins with a novel aspartylglucosaminidase gene mutation and 3 new cases in a Turkish family.
[So] Source:J Child Neurol;29(1):36-42, 2014 Jan.
[Is] ISSN:1708-8283
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aspartylglucosaminuria is a rare autosomal recessive lysosomal storage disorder leading early to a progressive intellectual disability. Monozygous Qatari twins presented with an unusual perinatal manifestation characterized by severe muscular hypotonia, scarce spontaneous movements, multiple contractures, and respiratory insufficiency. Biochemical investigations suggested aspartylglucosaminuria, and a novel homozygous mutation c.439T>C (p.S147P) was found in the aspartylglucosaminidase gene. However, it cannot be excluded that the unusual neonatal presentation is due to an additional autosomal recessive disease in this multiply consanguineous family. The classical aspartylglucosaminuria phenotype (progressive speech delay, psychomotor retardation, and behavioral abnormalities) was observed in 3 Turkish siblings. Although aspartylglucosaminuria was suspected early, the definite diagnosis was not confirmed until the age of 18 years. A novel homozygous mutation c.346C>T (p.R116W) was found. These 5 cases emphasize that aspartylglucosaminuria is panethnic and may possibly present with prenatal manifestation. Screening for aspartylglucosaminuria should be done in all patients with unexplained psychomotor retardation.
[Mh] Termos MeSH primário: Aspartilglucosaminúria/genética
Aspartilglucosilaminase/genética
Mutação/genética
[Mh] Termos MeSH secundário: Adolescente
Encéfalo/patologia
Consanguinidade
Eletroencefalografia
Saúde da Família
Feminino
Seres Humanos
Lactente
Imagem por Ressonância Magnética
Catar
Turquia
Gêmeos/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:141015
[Lr] Data última revisão:
141015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121229
[St] Status:MEDLINE
[do] DOI:10.1177/0883073812469049


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[PMID]:21769371
[Au] Autor:Witte MD; van der Marel GA; Aerts JM; Overkleeft HS
[Ad] Endereço:Whitehead Institute For Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
[Ti] Título:Irreversible inhibitors and activity-based probes as research tools in chemical glycobiology.
[So] Source:Org Biomol Chem;9(17):5908-26, 2011 Sep 07.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In this review, we will discuss the enzymes that are involved in the synthesis and degradation of glycoconjugates and we will give an overview of the inhibitors and activity-based probes (ABPs) that have been used to study these. Following discussion of some general aspects of the biosynthesis and degradation of N-linked glycoproteins, attention is focused on the enzymes that hydrolyze the protein-carbohydrate linkage, peptide N-glycanase and glycosylasparaginase and their mechanism. We then focus on the biosynthesis of O-linked glycoproteins and glycolipids and in particular on the enzymes that hydrolyze the interglycosidic linkages in these, the glycosidases. Some important mechanism-based glycosidase inhibitors that form a covalent bond with the targeted enzyme(s), their corresponding ABPs and their application to study this class of enzymes are highlighted. Finally, alternative pathways for degradation of glycoconjugates and an ABP-based strategy to study these will be discussed.
[Mh] Termos MeSH primário: Glicoconjugados/metabolismo
Glicômica/métodos
[Mh] Termos MeSH secundário: Animais
Aspartilglucosilaminase/antagonistas & inibidores
Aspartilglucosilaminase/metabolismo
Inibidores Enzimáticos/farmacologia
Glicosídeo Hidrolases/antagonistas & inibidores
Glicosídeo Hidrolases/metabolismo
Seres Humanos
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/antagonistas & inibidores
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Glycoconjugates); EC 3.2.1.- (Glycoside Hydrolases); EC 3.5.1.26 (Aspartylglucosylaminase); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1112
[Cu] Atualização por classe:110811
[Lr] Data última revisão:
110811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110720
[St] Status:MEDLINE
[do] DOI:10.1039/c1ob05531c


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[PMID]:20800597
[Au] Autor:Wang Y; Guo HC
[Ad] Endereço:Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118-2526, USA.
[Ti] Título:Crystallographic snapshot of glycosylasparaginase precursor poised for autoprocessing.
[So] Source:J Mol Biol;403(1):120-30, 2010 Oct 15.
[Is] ISSN:1089-8638
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glycosylasparaginase belongs to a family of N-terminal nucleophile hydrolases that autoproteolytically generate their mature enzymes from single-chain protein precursors. Previously, based on a precursor structure paused at pre-autoproteolysis stage by a reversible inhibitor (glycine), we proposed a mechanism of intramolecular autoproteolysis. A key structural feature, a highly strained conformation at the scissile peptide bond, had been identified and was hypothesized to be critical for driving autoproteolysis through an N-O acyl shift. To examine this "twist-and-break" hypothesis, we report here a 1. 9-Å-resolution structure of an autoproteolysis-active precursor (a T152C mutant) that is free of inhibitor or ligand and is poised to undergo autoproteolysis. The current crystallographic study has provided direct evidence for the natural conformation of the glycosylasparaginase autocatalytic site without influence from any inhibitor or ligand. This finding has confirmed our previous proposal that conformational strain is an intrinsic feature of an active precursor.
[Mh] Termos MeSH primário: Aspartilglucosilaminase/química
Proteínas de Bactérias/química
Flavobacterium/enzimologia
Precursores de Proteínas/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Modelos Moleculares
Proteínas Mutantes/química
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Mutant Proteins); 0 (Protein Precursors); EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1010
[Cu] Atualização por classe:101004
[Lr] Data última revisão:
101004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100831
[St] Status:MEDLINE
[do] DOI:10.1016/j.jmb.2010.08.038


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[PMID]:20655929
[Au] Autor:Masso M; Vaisman II
[Ad] Endereço:Laboratory for Structural Bioinformatics, Department of Bioinformatics and Computational Biology, George Mason University, 10900 University Blvd MS 5B3, Manassas, VA 20110, USA. mmasso@gmu.edu
[Ti] Título:Knowledge-based computational mutagenesis for predicting the disease potential of human non-synonymous single nucleotide polymorphisms.
[So] Source:J Theor Biol;266(4):560-8, 2010 Oct 21.
[Is] ISSN:1095-8541
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Certain genetic variations in the human population are associated with heritable diseases, and single nucleotide polymorphisms (SNPs) represent the most common form of such differences in DNA sequence. In particular, substantial interest exists in determining whether a non-synonymous SNP (nsSNP), leading to a single residue replacement in the translated protein product, is neutral or disease-related. The nature of protein structure-function relationships suggests that nsSNP effects, either benign or leading to aberrant protein function possibly associated with disease, are dependent on relative structural changes introduced upon mutation. In this study, we characterize a representative sampling of 1790 documented neutral and disease-related human nsSNPs mapped to 243 diverse human protein structures, by quantifying environmental perturbations in the associated proteins with the use of a computational mutagenesis methodology that relies on a four-body, knowledge-based, statistical contact potential. These structural change data are used as attributes to generate a vector representation for each nsSNP, in combination with additional features reflecting sequence and structure of the corresponding protein. A trained model based on the random forest supervised classification algorithm achieves 76% cross-validation accuracy. Our classifier performs at least as well as other methods that use significantly larger datasets of nsSNPs for model training, and the novelty of our attributes differentiates the model as an orthogonal approach that can be utilized in conjunction with other techniques. A dedicated server for obtaining predictions, as well as supporting datasets and documentation, is available at http://proteins.gmu.edu/automute.
[Mh] Termos MeSH primário: Biologia Computacional/métodos
Doença/genética
Bases de Conhecimento
Mutagênese/genética
Polimorfismo de Nucleotídeo Único/genética
[Mh] Termos MeSH secundário: Algoritmos
Aspartilglucosilaminase/química
Bases de Dados Genéticas
Seres Humanos
Aprendizagem
Modelos Moleculares
Estrutura Secundária de Proteína
Curva ROC
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.5.1.26 (Aspartylglucosylaminase)
[Em] Mês de entrada:1012
[Cu] Atualização por classe:100913
[Lr] Data última revisão:
100913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100727
[St] Status:MEDLINE
[do] DOI:10.1016/j.jtbi.2010.07.026



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