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Frontiers in Pediatrics 2015Cronobacter is a class of Enterobacteriaceae that cause infections in neonates, especially those born prematurely. Over 90% of these infections have been linked... (Review)
Review
Cronobacter is a class of Enterobacteriaceae that cause infections in neonates, especially those born prematurely. Over 90% of these infections have been linked epidemiologically to powdered infant formula (PIF). Contamination of PIF can occur at manufacture, reconstitution, or storage of reconstituted product. Intrinsic properties that enable Cronobacter to cause disease include resistance to heat, ultraviolet radiation, oxygen radicals, stomach acids, and pasteurization; an ability to utilize sialic acid (a nutrition additive to PIF that facilitates the organism's growth and survival), and an exceptional affinity for biofilms in enteral feeding tubes. As part of ongoing endeavors to reduce the incidence of neonatal PIF-associated Cronobacter infections, the World Health Organization and the US Food and Drug Administration have established guidelines for PIF production, preparation for infant feeding, and storage of reconstituted product.
PubMed: 26191519
DOI: 10.3389/fped.2015.00056 -
FEBS Letters Sep 2005Sialic acids are expressed as terminal sugars in many glycoconjugates and play an important role during development and regeneration, as they are involved as polysialic...
Sialic acids are expressed as terminal sugars in many glycoconjugates and play an important role during development and regeneration, as they are involved as polysialic acid in a variety of cell-cell interactions mediated by the neural cell adhesion molecule NCAM. The key enzyme for the biosynthesis of sialic acid is the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine-kinase (GNE). Mutations in the binding site of the feedback inhibitor CMP-sialic acid of the GNE leads to sialuria, a disease in which patients produce sialic acid in gram scale. Here, we report on the consequences after expression of a sialuria-mutated GNE. Expression of the sialuria-mutated GNE leads to a dramatic increase of both cellular sialic acid and polysialic acid on NCAM. This could also be achieved by application of the sialic acid precursor N-acetylmannosamine. Our data suggest that biosynthesis of sialic acid regulates and limits the synthesis of polysialic acid.
Topics: Animals; CHO Cells; Cricetinae; Humans; Multienzyme Complexes; N-Acetylneuraminic Acid; Neural Cell Adhesion Molecules; Sialic Acid Storage Disease; Sialyltransferases
PubMed: 16137682
DOI: 10.1016/j.febslet.2005.08.013 -
American Journal of Human Genetics Jun 1999Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic acid (NeuAc, sialic...
Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic acid (NeuAc, sialic acid). Overproduction of NeuAc is believed to result from loss of feedback inhibition of uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). We report the cloning and characterization of human UDP-GlcNAc 2-epimerase cDNA, with mutation analysis of three patients with sialuria. Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266. The heterozygous nature of the mutant allele in all three patients reveals a dominant mechanism of inheritance for sialuria.
Topics: Allosteric Site; Amino Acid Sequence; Base Sequence; Carbohydrate Epimerases; Carrier Proteins; Child, Preschool; DNA, Complementary; Female; Humans; Male; Metabolism, Inborn Errors; Molecular Sequence Data; Mutation; N-Acetylneuraminic Acid
PubMed: 10330343
DOI: 10.1086/302411 -
Orphanet Journal of Rare Diseases Feb 2017Sialic acid storage diseases are neurodegenerative disorders characterized by accumulation of sialic acid in the lysosome. These disorders are caused by mutations in...
BACKGROUND
Sialic acid storage diseases are neurodegenerative disorders characterized by accumulation of sialic acid in the lysosome. These disorders are caused by mutations in SLC17A5, the gene encoding sialin, a sialic acid transporter located in the lysosomal membrane. The most common form of sialic acid storage disease is the slowly progressive Salla disease, presenting with hypotonia, ataxia, epilepsy, nystagmus and findings of cerebral and cerebellar atrophy. Hypomyelination and corpus callosum hypoplasia are typical as well. We report a 16 year-old boy with an atypically mild clinical phenotype of sialic acid storage disease characterized by psychomotor retardation and a mixture of spasticity and rigidity but no ataxia, and only weak features of hypomyelination and thinning of corpus callosum on MRI of the brain.
RESULTS
The thiobarbituric acid method showed elevated levels of free sialic acid in urine and fibroblasts, indicating sialic acid storage disease. Initial Sanger sequencing of SLC17A5 coding regions did not show any pathogenic variants, although exon 9 could not be sequenced. Whole exome sequencing followed by RNA and genomic DNA analysis identified a homozygous 6040 bp insertion in intron 9 of SLC17A5 corresponding to a long interspersed element-1 retrotransposon (KF425758.1). This insertion adds two splice sites, both resulting in a frameshift which in turn creates a premature stop codon 4 bp into intron 9.
CONCLUSIONS
This study describes a novel pathogenic variant in SLC17A5, namely an intronic transposal insertion, in a patient with mild biochemical and clinical phenotypes. The presence of a small fraction of normal transcript may explain the mild phenotype. This case illustrates the importance of including lysosomal sialic acid storage disease in the differential diagnosis of developmental delay with postnatal onset and hypomyelination, as well as intronic regions in the genetic investigation of inborn errors of metabolism.
Topics: DNA Transposable Elements; Exons; Fibroblasts; Humans; Introns; Male; N-Acetylneuraminic Acid; Organic Anion Transporters; Polymerase Chain Reaction; Sialic Acid Storage Disease; Skin; Symporters; Exome Sequencing
PubMed: 28187749
DOI: 10.1186/s13023-017-0584-6 -
European Journal of Biochemistry Aug 1975N-Acetylneuraminic acid preparations from the urine of a patient with sialuria contain 1--2% of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. This new human sialic acid...
N-Acetylneuraminic acid preparations from the urine of a patient with sialuria contain 1--2% of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. This new human sialic acid was isolated by ion-exchange and partition chromatography. The structure has been elucidated by mass spectrometry and confirmed by comparison with the synthetic compound. The properties of this unsaturated sialic acid in the orcinol/Fe3+/HCl and the periodic acid/thiobarbituric acid tests as well as in thin-layer and gas-liquid chromatography are described. It does not react with acylneuraminate pyruvatelyase. The origin of this new human sialic acid is discussed.
Topics: Carbohydrate Metabolism, Inborn Errors; Child; Chromatography, Gas; Chromatography, Thin Layer; Humans; Intellectual Disability; Male; Mass Spectrometry; Sialic Acids
PubMed: 1175622
DOI: 10.1111/j.1432-1033.1975.tb02228.x -
Zhongguo Dang Dai Er Ke Za Zhi =... May 2023A boy, aged 3 hours, was admitted due to a prenatal diagnosis of fetal hydrops at 3 hours after resuscitation for birth asphyxia. Prenatal examination at 5 months of...
A boy, aged 3 hours, was admitted due to a prenatal diagnosis of fetal hydrops at 3 hours after resuscitation for birth asphyxia. Prenatal examination at 5 months of gestation showed massive ascites in the fetus, and after birth, the boy had the manifestations of systemic hydroderma, massive ascites, coarse face, and hepatomegaly. Genetic testing revealed heterozygous mutations in the gene, and there was a significant increase in urinary free sialic acid. Placental pathology showed extensive vacuolization in villous stromal cells, Hofbauer cells, cytotrophoblast cells, and syncytiotrophoblast cells in human placental chorionic villi. The boy was finally diagnosed with free sialic acid storage disorders (FSASDs). This is the first case of FSASDs with the initial symptom of fetal hydrops reported in China. The possibility of FSASDs should be considered for cases with non-immune hydrops fetalis, and examinations such as placental pathology and urinary free sialic acid may help with early diagnosis and clinical decision making.
Topics: Infant, Newborn; Male; Humans; Female; Pregnancy; Hydrops Fetalis; N-Acetylneuraminic Acid; Placenta; Ascites
PubMed: 37272184
DOI: 10.7499/j.issn.1008-8830.2303041 -
Scientific Reports Mar 2016The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for...
The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme.
Topics: Allosteric Regulation; Amino Acid Sequence; Carbohydrate Epimerases; Catalytic Domain; Conserved Sequence; Crystallography, X-Ray; Cytidine Monophosphate; Enzyme Inhibitors; Humans; Hydrogen Bonding; Hydrolysis; Kinetics; Models, Molecular; N-Acetylneuraminic Acid; Protein Binding; Protein Structure, Quaternary; Sialic Acids; Uridine Diphosphate
PubMed: 26980148
DOI: 10.1038/srep23274 -
Case Reports in Neurological Medicine 2012Salla disease (SD) is a disorder caused by defective storage of free sialic acid and results from mutations in the SLC17A5 gene. Early developmental delay of motor...
Salla disease (SD) is a disorder caused by defective storage of free sialic acid and results from mutations in the SLC17A5 gene. Early developmental delay of motor functions, and later cognitive skills, is typical. We describe a developmental profile of an unusual homozygous patient, who harboured the SallaFIN (p.R39C) mutation gene. The study involved neurological examination, neuropsychological investigation, and brain imaging. The neurocognitive findings were atypical in comparison with other patients with the SallaFIN mutation. Interestingly, there was no deterioration in the patient's neurological condition during adulthood. Her neurocognitive skills were remarkably higher than those of other patients with a conventional phenotype of SD. Our results suggest that the phenotype of SD is broad. Unidentified genetic or environmental variation might explain the unique SD type of this case.
PubMed: 23227378
DOI: 10.1155/2012/615721 -
The Journal of Biological Chemistry 2021Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic...
Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, the deficiency of which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care exhibits poor uptake in skeletal muscles, limiting its clinical efficacy. Furthermore, it is unclear how the specific cellular processing steps of GAA after delivery to lysosomes impact its efficacy. GAA undergoes both proteolytic cleavage and glycan trimming within the endolysosomal pathway, yielding an enzyme that is more efficient in hydrolyzing its natural substrate, glycogen. Here, we developed a tool kit of modified rhGAAs that allowed us to dissect the individual contributions of glycan trimming and proteolysis on maturation-associated increases in glycogen hydrolysis using in vitro and in cellulo enzyme processing, glycopeptide analysis by MS, and high-pH anion-exchange chromatography with pulsed amperometric detection for enzyme kinetics. Chemical modifications of terminal sialic acids on N-glycans blocked sialidase activity in vitro and in cellulo, thereby preventing downstream glycan trimming without affecting proteolysis. This sialidase-resistant rhGAA displayed only partial activation after endolysosomal processing, as evidenced by reduced catalytic efficiency. We also generated enzymatically deglycosylated rhGAA that was shown to be partially activated despite not undergoing proteolytic processing. Taken together, these data suggest that an optimal rhGAA ERT would require both N-glycan and proteolytic processing to attain the most efficient enzyme for glycogen hydrolysis and treatment of Pompe disease. Future studies should examine the amenability of next-generation ERTs to both types of cellular processing.
Topics: Endosomes; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Hydrolysis; Polysaccharides; Proteolysis; alpha-Glucosidases
PubMed: 33971197
DOI: 10.1016/j.jbc.2021.100769 -
PloS One 2012Sialidases are glycohydrolytic enzymes present from virus to mammals that remove sialic acid from oligosaccharide chains. Four different sialidase forms are known in...
Sialidases are glycohydrolytic enzymes present from virus to mammals that remove sialic acid from oligosaccharide chains. Four different sialidase forms are known in vertebrates: the lysosomal NEU1, the cytosolic NEU2 and the membrane-associated NEU3 and NEU4. These enzymes modulate the cell sialic acid content and are involved in several cellular processes and pathological conditions. Molecular defects in NEU1 are responsible for sialidosis, an inherited disease characterized by lysosomal storage disorder and neurodegeneration. The studies on the biology of sialic acids and sialyltransferases, the anabolic counterparts of sialidases, have revealed a complex picture with more than 50 sialic acid variants selectively present in the different branches of the tree of life. The gain/loss of specific sialoconjugates have been proposed as key events in the evolution of deuterostomes and Homo sapiens, as well as in the host-pathogen interactions. To date, less attention has been paid to the evolution of sialidases. Thus we have conducted a survey on the state of the sialidase family in metazoan. Using an in silico approach, we identified and characterized sialidase orthologs from 21 different organisms distributed among the evolutionary tree: Metazoa relative (Monosiga brevicollis), early Deuterostomia, precursor of Chordata and Vertebrata (teleost fishes, amphibians, reptiles, avians and early and recent mammals). We were able to reconstruct the evolution of the sialidase protein family from the ancestral sialidase NEU1 and identify a new form of the enzyme, NEU5, representing an intermediate step in the evolution leading to the modern NEU3, NEU4 and NEU2. Our study provides new insights on the mechanisms that shaped the substrate specificity and other peculiar properties of the modern mammalian sialidases. Moreover, we further confirm findings on the catalytic residues and identified enzyme loop portions that behave as rapidly diverging regions and may be involved in the evolution of specific properties of sialidases.
Topics: Amino Acid Sequence; Amino Acids; Animals; Base Sequence; Biocatalysis; Catalytic Domain; Computational Biology; Conserved Sequence; Evolution, Molecular; Exons; Humans; Models, Molecular; Molecular Sequence Data; Multigene Family; Mutagenesis, Insertional; Neuraminidase; Phosphorylation; Phylogeny; Protein Structure, Secondary; Sialyltransferases; Substrate Specificity; Synteny; Vertebrates
PubMed: 22952925
DOI: 10.1371/journal.pone.0044193