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malfunction
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neuC is deleted from the chromosome of EV36, a K-12-K1 hybrid, by allelic exchange. Exogenously added sialic acid restores capsule expression to the deletion strain, confirming that NeuC is necessary for sialic acid synthesis. The NeuC homologue from serotype III Streptococcus agalactiae complements deletion mutant
malfunction
GNE myopathy is autosomal recessive inherited and characterized by adult onset, slowly progressive muscle weakness and atrophy
malfunction
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hereditary inclusion body myopathy (GNE myopathy) is a neuromuscular disorder due to mutation in key sialic acid biosynthetic enzyme gene, GNE, D176V and V572L. Mutation in GNE affects beta1-integrin-mediated cell adhesion process in GNE mutant cells
malfunction
isozymes hGNE3 and hGNE8 contain a 53-residue N-terminal deletion, epimerase enzymatic activity of isozymes GNE3 and GNE8 is likely absent, because the deleted fragment contains important substrate binding residues in homologous bacterial epimerases. Isozymes hGNE5-hGNE8 have a 53-residue deletion, which was assigned a role in substrate UDP-GlcNAc binding
malfunction
defective GNE inhibition by CMP-Neu5Ac causes cytoplasmic accumulation and increased excretion of free sialic acid. Sialuria is an autosomal dominant disorder which is related to GNE mutation in one of the two arginine residues 263 and 266 (R263L, R266Q or R266W), the mutations in Arg263 and Arg266 can cause sialuria by hindering the enzyme inhibition through CMP-Neu5Ac binding
malfunction
distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive genetic disease characterized by weakness of the anterior compartment of the lower limbs, sparing the quadriceps muscle, and rimmed vacuoles in muscle biopsies. The disease is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene located on chromosome 9p13.3. We present two cases of Chinese patients with progressive lower extremity weakness, phenotypes, overview
malfunction
hereditary inclusion body myopathy (GNE myopathy) is a neuromuscular disorder due to mutation in key sialic acid biosynthetic enzyme, GNE. The subcellular distribution of recombinant GNE and its mutant shows differential localization in the cell. The enzyme mutation leads to hyposialylation of cell membrane receptor, beta1-integrin. Hyposialylated beta1-integrin localized to internal vesicles that is restored upon supplementation with sialic acid. Fibronectin stimulation causes migration of hyposialylated beta1-integrin to the cell membrane and colocalization with focal adhesion kinase (FAK) leading to increased focal adhesion formation. This further activates FAK and Src, downstream signaling molecules and leads to increased cell adhesion. The mutation in GNE affects beta1-integrin-mediated cell adhesion process in GNE mutant cells. Activation of endoplasmic reticulum stress response due to accumulation of misfolded mutated GNE protein
malfunction
impaired feed-back inhibition of the enzyme by CMP-Neu5Ac to regulate the GNE activity can result in sialuria
malfunction
mutation M743T of enzyme GNE leads to GNE myopathy (i.e. hereditary inclusion body myopathy, HIBM), a unique muscle pathophysiology disorder
malfunction
phenotype-genotype analysis of GNE myopathy index patients of a kohort, overview
malfunction
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GNE myopathy is autosomal recessive inherited and characterized by adult onset, slowly progressive muscle weakness and atrophy
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malfunction
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neuC is deleted from the chromosome of EV36, a K-12-K1 hybrid, by allelic exchange. Exogenously added sialic acid restores capsule expression to the deletion strain, confirming that NeuC is necessary for sialic acid synthesis. The NeuC homologue from serotype III Streptococcus agalactiae complements deletion mutant
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metabolism
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key enzyme in the sialic acid biosynthetic pathway
metabolism
the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase, encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid. Two distinct human disorders, sialuria and hereditary inclusion body myopathy, are associated with predominantly missense mutations in GNE
metabolism
bifunctional UDP-N-acetylglucosamine2-epimerase/N-acetylmannosamine kinase, GNE, is key sialic acid biosynthetic enzyme
metabolism
sialic acid biosynthesis in mammals starts by converting UDP-GluNAc into UDP and ManNAc, followed by phosphorylation of ManNAc at the sixth position, catalysis of both reactions is carried out by the bifunctional enzyme GNE. Regulation of cell-surface sialyation level by binding to the downstream product CMP-Neu5Ac. The feedback inhibition is highly positively cooperative and it does not affect the ManNAc kinase activity
metabolism
the biosynthesis of sialic acids starts with hydrolytic epimerization of N-acetyl glucosamine (GlcNAc), catalyzed by UDP-GlcNAc 2-epimerase and producing N-acetyl mannosamine (ManNAc), which then reacts with phosphoenolpyruvate to form Neu5Ac. Whereas the substrate for non-hydrolyzing epimerase and hydrolyzing epimerase is the same, in this case, UDP-GlcNAc, the product of the former is UDP-ManNAc, and that of the latter is alpha-ManNAc plus UDP
physiological function
mGne2 encoding transcript may act as a tissue-specific regulator of sialylation
physiological function
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the enzyme is involved in sialic acid synthesis and other cellular functions, it plays a role in beta1-integrin-mediated cell adhesion, overview
physiological function
UDP-GlcNAc 2-epimerase/ManNAc kinase catalyzes the first two committed steps in sialic acid synthesis. Isozyme hGNE1 is the ubiquitously expressed major isoform, while the isozymes hGNE2-hGNE8 isoforms are differentially expressed and may act as tissue-specific regulators of sialylation
physiological function
biosynthesis of sialic acid is regulated by a 79-kDa bifunctional enzyme UDP-N-acetylglucosamine2-epimerase/N-acetylmannosamine kinase (GNE), consisting of N-terminal epimerase and C-terminal kinase domain. The epimerase domain converts UDP-GlcNAc to ManNAc and kinase domain phosphorylates ManNAc to ManNAc phosphate
physiological function
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 feedback inhibited by the downstream product CMP-Neu5Ac. Being a key enzyme that catalyzes the rate-limiting step of sialic acid biosynthesis, GNE plays an important role in regulation of cell-surface sialyation level by binding to the downstream product CMP-Neu5Ac. Regulation of cell-surface sialyation level by binding to the downstream product CMP-Neu5Ac. The feedback inhibition is highly positively cooperative and it does not affect the ManNAc kinase activity. By mediating cell-cell recognition, sialic acids are important in the development of nervous system. Structure and biosynthesis of sialic acid, overview
physiological function
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mGne2 encoding transcript may act as a tissue-specific regulator of sialylation
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additional information
in the dimeric state GNE possess only kinase activity, in the hexameric state it displays both the epimerase and kinase activities while no activity is observed when GNE is present as a monomer
additional information
the binding of UDP-GlcNAc to an allosteric site may stabilize the closed, active conformation of the enzyme, whereas the open form seems to be not active. Residue D143 is essential for catalytic activity
additional information
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the binding of UDP-GlcNAc to an allosteric site may stabilize the closed, active conformation of the enzyme, whereas the open form seems to be not active. Residue D143 is essential for catalytic activity
additional information
the comparison of the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases might explain the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. Full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme, possible epimerase-kinase channel