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Enzyme Nomenclature
Information on EC 5.1.3.14 - UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)
for references in articles please use BRENDA:EC5.1.3.14
Word Map on EC 5.1.3.14
- 5.1.3.14
-
sialic
- myopathy
- hereditary
-
rimmed
-
sialylation
-
quadriceps
- sialuria
-
glycoconjugates
-
hyposialylation
- udp-n-acetylmannosamine
-
cmp-sialic
- cmp-neu5ac
-
nonaka
-
cmp-n-acetylneuraminic
-
inclusion-body
-
udp-mannac
- neu5ac
- synthesis
- drug development
- medicine
- biotechnology
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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
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EC NUMBER 
COMMENTARY 
5.1.3.14
-
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RECOMMENDED NAME
GeneOntology No.
UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
products: UDP + N-acetyl-D-mannosamine; UDP-N-acetyl-D-mannosamine is not an intermediate
-
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
products: UDP + N-acetyl-D-mannosamine
-
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
ordered mechanism, where UDP is the first product released followed by irreversible formation of N-acetyl-mannosamine. A two step mechanism is proposed which involves the elimination of UDP from UDP-N-acetylglucosamine to give a 2-acetamidoglucal intermediate which is subsequently converted to N-acetylmannosamine; products: UDP + N-acetyl-D-mannosamine
-
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
during epimerization, tritium from tritium-enriched water is incorporated into both UDP-N-acetyl-D-glucosamine and UDP-N-acetyl-D-mannosamine
-
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
the mechanism involves a trans-elimination of monoprotic UDP to form 2-acetamidoglucal. Followed by a syn-addition, in the direction of UDP-N-acetyl-D-mannosamine formation
-
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
mechanism proceeds via cleavage of the anomeric C-O bond, with 2-acetamidoglucal and UDP as enzyme-bound intermediates. It is likely that E1-eliminations via oxocarbenium intermediates are involved in the reaction
-
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
2-epimerase-catalyzed elimination and readdition of UDP to the glycal intermediate may proceed through a transition state with significant oxocarbenium ion-like character
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
2-epimerase-catalyzed elimination and readdition of UDP to the glycal intermediate may proceed through a transition state with significant oxocarbenium ion-like character
UDP-N-acetyl-alpha-D-glucosamine = UDP-N-acetyl-alpha-D-mannosamine
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
epimerization
-
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
poly(3-O-beta-D-glucopyranosyl-N-acetylgalactosamine 1-phosphate) wall teichoic acid biosynthesis
-
-
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SYSTEMATIC NAME
IUBMB Comments
UDP-N-acetyl-alpha-D-glucosamine 2-epimerase
This bacterial enzyme catalyses the reversible interconversion of UDP-GlcNAc and UDP-ManNAc. The latter is used in a variety of bacterial polysaccharide biosyntheses.
cf. EC 3.2.1.183, UDP-N-acetylglucosamine 2-epimerase (hydrolysing).
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CAS REGISTRY NUMBER
COMMENTARY
9037-71-2
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, splice variant hGNE2
-
-
mutations in patients with hereditary inclusion body myopathy: G135V/R246W (GNE/GNE domain mutation), UDP-N-acetylglucosamine 2-epimerase activity is 38% of wild-type, N-acetylmannosamine kinase activity is 72% of wild-type. V216A/A631V (GNE/MNK domain mutation), UDP-N-acetylglucosamine 2-epimerase activity is 48% of wild-type, N-acetylmannosamine kinase activity is 63% of wild-type. M712T/M712T (MNK/MNK domain mutation), UDP-N-acetylglucosamine 2-epimerase activity is 83% of wild-type, N-acetylmannosamine kinase activity is 55% of wild-type
-
-
three different isozymes, hGNE1, hGNE2, and hGNE3, from the two splice variants including exon A1, The N-terminus of hGNE2 is prolonged by 31 additional amino acids. The lack of exon 2 in the cDNA encoding for hGNE3 leads to loss of the first 55 amino acids of hGNE1
-
-
bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, splice variant hGNE2
-
-
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
evolution
the bacterial UDP-GlcNAc-binding site is conserved and probably unique to the nonhydrolyzing bacterial 2-epimerases. Conservation of the allosteric site residues in the nonhydrolyzing bacterial 2-epimerases indicates that the allosteric regulatory mechanism, which involves direct interaction between one substrate molecule in the active site and another in the allosteric site, is used exclusively by this class of bacterial enzymes
evolution
the bacterial UDP-GlcNAc-binding site is conserved and probably unique to the nonhydrolyzing bacterial 2-epimerases. Conservation of the allosteric site residues in the nonhydrolyzing bacterial 2-epimerases indicates that the allosteric regulatory mechanism, which involves direct interaction between one substrate molecule in the active site and another in the allosteric site, is used exclusively by this class of bacterial enzymes
malfunction
-
enzyme deficiency causes the disease sialuria in humans. Hereditary inclusion body myopathy, h-IBM, is also a disease caused by different mutations in the GNE gene, it is an autosomal recessive neuromuscular disorder characterized by adult onset, slowly progressive skeletal muscle weakness, and typical histological features as rimmed vacuoles and filamentous inclusions. Sialuria is caused by the loss of feedback control of UDP-GlcNAc 2-epimerase activity due to the mutation of only one of the two arginine residues 263 and 266. Sialuria leads to massive production of free Neu5Ac, which accumulates in the cytoplasm and results in mental retardation and hepatomegaly
malfunction
-
GNE deficiency can lead to hereditary inclusion body myopathy, HIBM, phenotypes, overview
malfunction
-
mutations in the GNE gene are associated with autosomal recessive hereditary inclusion body myopathy, i.e. HIBM or IBM2, a progressive adult onset muscle wasting disorder characterized by sparing of the quadriceps. IBM2 is also known as distal myopathy with rimmed vacuoles or nonaka myopathy
malfunction
GNE mutations can result in two human disorders, hereditary inclusion body myopathy, HIBM, and sialuria
malfunction
-
stable knock-down of GNE dramatically increases incorporation of N-acetylmannosamine analogues into glycoproteins of HEK-293 cells
metabolism
-
the enzyme catalyzes the first two steps in the sialic acid biosynthesis, required for sialylation of diverse glycoproteins and glycolipids e.g. in skeletal muscle
metabolism
-
GNE is the rate-limiting enzyme of N-acetylneuraminate, i.e. sialic acid, biosynthesis
metabolism
-
GNE catalyzes the first two steps of sialic acid biosynthesis in the cytosol
metabolism
GNE catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid, i.e. sialic acid
metabolism
the enzyme catalyzes the interconversion of UDP-N-acetyl-alpha-D-glucosamine to UDP-N-acetyl-alpha-D-mannosamine, which is used in the biosynthesis of cell surface polysaccharides in bacteria
metabolism
-
the enzyme catalyzes the interconversion of UDP-N-acetyl-alpha-D-glucosamine to UDP-N-acetyl-alpha-D-mannosamine, which is used in the biosynthesis of cell surface polysaccharides in bacteria
-
physiological function
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, GNE, is the key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed
physiological function
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, GNE, is the key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed
physiological function
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, GNE, is the key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed
physiological function
-
GNE is required for sialic acid biosynthesis, the sialic acid pathway and the respective sialic acid precursors such as ManNAc do regulate the MAP kinase signalling pathway, influencing processes like cell proliferation, overview
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
UDP-N-acetyl-alpha-D-glucosamine
UDP-N-acetyl-alpha-D-mannosamine
-
-
-
r
UDP-N-acetyl-alpha-D-glucosamine
UDP-N-acetyl-alpha-D-mannosamine
allosteric regulatory mechanism, which involves direct interaction between one substrate molecule in the active site and another in the allosteric site
-
-
r
UDP-N-acetyl-alpha-D-glucosamine
UDP-N-acetyl-alpha-D-mannosamine
-
-
-
r
UDP-N-acetyl-alpha-D-glucosamine
UDP-N-acetyl-alpha-D-mannosamine
allosteric regulatory mechanism, which involves direct interaction between one substrate molecule in the active site and another in the allosteric site
-
-
r
UDP-N-acetyl-D-glucosamine
?
-
UDP-N-acetyl-D-glucosamine 2-epimerase and UDP-N-acetyl-D-mannosamine dehydrogenase are responsible for the formation of UDP-N-acetyl-D-mannosaminuronic acid from UDP-N-acetyl-D-glucosamine
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
enzyme of the N-acetylneuraminic acid metabolic pathway
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
enzyme of biosynthesis of N-acetylneuraminic acid
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
initial enzyme responsible for the biosynthesis of CMP-N-acetylneuraminic acid
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
possible role in the biogenesis of N-acetylmannosamine-containing macromolecules
-
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
the reverse reaction with UDP-N-acetylmannosamine requires the presence of UDP-N-acetylglucosamine
-
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
the reverse reaction with UDP-N-acetylmannosamine requires the presence of UDP-N-acetylglucosamine
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
the reverse reaction with UDP-N-acetylmannosamine requires the presence of UDP-N-acetylglucosamine
-
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
the reverse reaction with UDP-N-acetylmannosamine requires the presence of UDP-N-acetylglucosamine
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
first step of sialic acid biosynthesis
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
mechanism involves an anti elimination of UDP to form 2-acetamidoglucal as an intermediate, followed by syn-addition of water
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
first step of sialic acid biosynthesis
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
mechanism involves an anti elimination of UDP to form 2-acetamidoglucal as an intermediate, followed by syn-addition of water
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
reversibility is not detected
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
reversibility is not detected
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
key enzyme of sialic acid biosynthesis
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
characterization of ligand binding to the bifunctional enzyme
-
-
?
UDP-N-acetyl-D-glucosamine
UDP-N-acetyl-D-mannosamine
-
non-hydrolizing
-
-
?
UDP-N-acetyl-D-glucosamine
UDP-N-acetyl-D-mannosamine
-
-
-
r
UDP-N-acetyl-D-glucosamine + H2O
UDP + N-acetylmannosamine
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + H2O
UDP + N-acetylmannosamine
epimerase active site amino acid residues D21, G111, H132, G136 and D144 are required for stabilization of the active site structure, residues R19, S301 and E307 are involved in binding of the UDP portion of the substrate. Amino acid residues K24, P27, M29, D112, E134, D143, D144, R147, S302 and R113 are located in vicinity of the active site, while residues G182 and D187 are part of the active site hinge region. The possible general catalyst is residue H220, and residues H45 and H132 are required for 2-epimerase activity
-
-
?
additional information
?
-
-
3'-deoxy-UDP-N-acetylglucosamine is not a substrate
-
-
-
additional information
?
-
key enzyme for biosynthesis of N-acetylneuraminate is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, catalyzing the first two steps of the biosynthesis in the cytosol
-
?
additional information
?
-
-
rate-limiting step in sialic acid biosynthesis pathway. The enzyme is the major determinant of cell surface sialylation in hematopoietic cell lines and is a critical regulator of the function of specific cell surface adhesion molecules
-
?
additional information
?
-
-
downregulation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase in hyposialylated HIV-infected T cells with consequential glycosylation modification (the deficiency can be entirely corrected by nutrient complementation with N-acetylmannosamine). The promoter of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is de novo hypermethylated in HIV-infected CEM cells
-
-
-
additional information
?
-
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is a rate-limiting enzyme of sialic acid biosynthesis
-
-
-
additional information
?
-
-
the homozygous M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities but not in altered overall cellular sialylation in hereditary inclusion body myopathy
-
-
-
additional information
?
-
-
role of splice variant GNE1 in basic supply of cells with sialic acids, whereas GNE2 and GNE3 may have a function in finetuning of the sialic acid pathway
-
-
-
additional information
?
-
-
GNE interacts with proteins involved in the regulation of development, e.g. the transcription factor promyelotic leukemia zinc finger protein, which might play a crucial role in the hereditary inclusion body myopathy. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. Multienzyme complexes of GNE with the other enzymes of the sialic acid biosynthesis pathway, either close to the Golgi CMP sialic acid transporter or in particular with the nuclear localized CMP-sialic acid synthetase, are possible
-
-
-
additional information
?
-
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
additional information
?
-
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
additional information
?
-
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
additional information
?
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
additional information
?
-
-
role of splice variant GNE1 in basic supply of cells with sialic acids, whereas GNE2 and GNE3 may have a function in finetuning of the sialic acid pathway. No significant differences in activities of splice variants mGNE 1 and mGNE2
-
-
-
additional information
?
-
-
GNE interacts with proteins involved in the regulation of development, e.g. the transcription factor promyelotic leukemia zinc finger protein, which might play a crucial role in the hereditary inclusion body myopathy. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac. Multienzyme complexes of GNE with the other enzymes of the sialic acid biosynthesis pathway, either close to the Golgi CMP sialic acid transporter or in particular with the nuclear localized CMP-sialic acid synthetase, are possible
-
-
-
additional information
?
-
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
additional information
?
-
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
additional information
?
-
-
bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase
-
?
additional information
?
-
-
enzyme catalyzes the first step in synthesis of sialic acids
-
?
additional information
?
-
-
reaction mechanism involving an anti-elimination of UDP to give 2-acetamidoglucal, followed by a syn-addition of water
-
?
additional information
?
-
-
key enzyme of N-acetylneuraminic acid biosynthesis
-
?
additional information
?
-
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/ManNAc kinase catalyzes the first two steps in the biosynthesis of the sialic acids
-
?
additional information
?
-
-
the enzyme catalyzes the first step of sialic acid biosynthesis
-
?
additional information
?
-
-
GNE interacts with proteins involved in the regulation of development, e.g. the transcription factor promyelotic leukemia zinc finger protein, which might play a crucial role in the hereditary inclusion body myopathy. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac. Multienzyme complexes of GNE with the other enzymes of the sialic acid biosynthesis pathway, either close to the Golgi CMP sialic acid transporter or in particular with the nuclear localized CMP-sialic acid synthetase, are possible
-
-
-
additional information
?
-
-
GNE is a bifunctional enzyme with UDP-GlcNAc 2-epimerase and ManNAc kinase activities
-
-
-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
UDP-N-acetyl-alpha-D-glucosamine
UDP-N-acetyl-alpha-D-mannosamine
Q81K32
allosteric regulatory mechanism, which involves direct interaction between one substrate molecule in the active site and another in the allosteric site
-
-
r
UDP-N-acetyl-alpha-D-glucosamine
UDP-N-acetyl-alpha-D-mannosamine
Q9REV4
allosteric regulatory mechanism, which involves direct interaction between one substrate molecule in the active site and another in the allosteric site
-
-
r
UDP-N-acetyl-D-glucosamine
?
-
UDP-N-acetyl-D-glucosamine 2-epimerase and UDP-N-acetyl-D-mannosamine dehydrogenase are responsible for the formation of UDP-N-acetyl-D-mannosaminuronic acid from UDP-N-acetyl-D-glucosamine
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
enzyme of the N-acetylneuraminic acid metabolic pathway
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
enzyme of biosynthesis of N-acetylneuraminic acid
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
initial enzyme responsible for the biosynthesis of CMP-N-acetylneuraminic acid
-
-
-
UDP-N-acetyl-D-glucosamine
?
-
possible role in the biogenesis of N-acetylmannosamine-containing macromolecules
-
-
-
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
first step of sialic acid biosynthesis
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
first step of sialic acid biosynthesis
-
-
?
UDP-N-acetyl-D-glucosamine
UDP + N-acetyl-D-mannosamine
-
key enzyme of sialic acid biosynthesis
-
-
?
UDP-N-acetyl-D-glucosamine + H2O
UDP + N-acetylmannosamine
-
-
-
-
?
additional information
?
-
Q9Y223
key enzyme for biosynthesis of N-acetylneuraminate is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, catalyzing the first two steps of the biosynthesis in the cytosol
-
?
additional information
?
-
-
rate-limiting step in sialic acid biosynthesis pathway. The enzyme is the major determinant of cell surface sialylation in hematopoietic cell lines and is a critical regulator of the function of specific cell surface adhesion molecules
-
?
additional information
?
-
-
downregulation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase in hyposialylated HIV-infected T cells with consequential glycosylation modification (the deficiency can be entirely corrected by nutrient complementation with N-acetylmannosamine). The promoter of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is de novo hypermethylated in HIV-infected CEM cells
-
-
-
additional information
?
-
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is a rate-limiting enzyme of sialic acid biosynthesis
-
-
-
additional information
?
-
-
the homozygous M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities but not in altered overall cellular sialylation in hereditary inclusion body myopathy
-
-
-
additional information
?
-
-
role of splice variant GNE1 in basic supply of cells with sialic acids, whereas GNE2 and GNE3 may have a function in finetuning of the sialic acid pathway
-
-
-
additional information
?
-
-
GNE interacts with proteins involved in the regulation of development, e.g. the transcription factor promyelotic leukemia zinc finger protein, which might play a crucial role in the hereditary inclusion body myopathy. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. Multienzyme complexes of GNE with the other enzymes of the sialic acid biosynthesis pathway, either close to the Golgi CMP sialic acid transporter or in particular with the nuclear localized CMP-sialic acid synthetase, are possible
-
-
-
additional information
?
-
-
role of splice variant GNE1 in basic supply of cells with sialic acids, whereas GNE2 and GNE3 may have a function in finetuning of the sialic acid pathway. No significant differences in activities of splice variants mGNE 1 and mGNE2
-
-
-
additional information
?
-
-
GNE interacts with proteins involved in the regulation of development, e.g. the transcription factor promyelotic leukemia zinc finger protein, which might play a crucial role in the hereditary inclusion body myopathy. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac. Multienzyme complexes of GNE with the other enzymes of the sialic acid biosynthesis pathway, either close to the Golgi CMP sialic acid transporter or in particular with the nuclear localized CMP-sialic acid synthetase, are possible
-
-
-
additional information
?
-
-
key enzyme of N-acetylneuraminic acid biosynthesis
-
?
additional information
?
-
-
the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/ManNAc kinase catalyzes the first two steps in the biosynthesis of the sialic acids
-
?
additional information
?
-
-
the enzyme catalyzes the first step of sialic acid biosynthesis
-
?
additional information
?
-
-
GNE interacts with proteins involved in the regulation of development, e.g. the transcription factor promyelotic leukemia zinc finger protein, which might play a crucial role in the hereditary inclusion body myopathy. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac. Multienzyme complexes of GNE with the other enzymes of the sialic acid biosynthesis pathway, either close to the Golgi CMP sialic acid transporter or in particular with the nuclear localized CMP-sialic acid synthetase, are possible
-
-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanamide
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]butanoic acid
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(3,5-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(3-chloro-4-methoxyphenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(3-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-bromo-3-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-bromo-3-chlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-bromophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-bromophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-chlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-fluorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-iodophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-4-[[5-(4-methoxyphenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-5-oxo-2-thioxo-4-([5-[4-(trifluoromethoxy)phenyl]furan-2-yl]methylidene)imidazolidin-1-yl]-3-phenylpropanoic acid
(2S)-2-[(4E)-5-oxo-4-[(5-phenylfuran-2-yl)methylidene]-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
2',3'-dialdehydro-ADP
-
efficient inhibition is most likely due to the structural similarity to o-UDP and not to an allosteric effect via the ATP binding site
2',3'-dialdehydro-UDP-alpha-D-N-acetylglucosamine
-
0.05 mM, 70% inhibition after 30 min. 0.25 mM, 90% inhibition. Covalently bound to amino acids in the active site causing an irreversible inhibition. Effective inhibitor may serve as a basis for the chemical synthesis of further inhibitors
CMP-sialic acid
GNE/MNK is feedback inhibited by binding of the downstream product, CMP-sialic acid, in its allosteric site. The allosteric regulation by CMP-sialic acid involves residues D255, E260, R263, R266, K268, and N275
ethyl (2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoate
-
ethyl (2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoates
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]-1,1,1-trifluoromethanesulfonamide
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]methanesulfonamide
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]propyl]methanesulfonamide
uridine 5'-(3-acetamido-3-deoxy-2-O-methyl-alpha-D-gluco-hept-2-ulopyranos-1-yl diphosphate)
-
-
uridine 5'-(3-acetamido-3-deoxy-2-O-methyl-alpha-D-manno-hept-2-ulopyranos-1-yl diphosphate)
-
weak
uridine 5'-[(Z)-2,6-anhydro-1-deoxy-D-galactohept-1-enitol-1-yl phosphono] phosphate
-
weak
uridine 5'-[(Z)-2,6-anhydro-1-deoxy-D-glucohept-1-enitol-1-yl phosphono] phosphate
-
-
uridine 5'-[(Z)-2,6-anhydro-1-deoxy-D-mannohept-1-enitol-1-yl phosphono] phosphate
-
-
uridine 5'-[(Z)-3-acetamido-2,6-anhydro-1,3-dideoxy-D-arabino-hept-1-enitol-1-yl phosphono] phosphate
-
-
uridine 5'-[(Z)-3-acetamido-2,6-anhydro-1,3-dideoxy-D-gluco-hept-1-enitol-1-yl phosphono] phosphate
-
-
[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]cyanamide
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanamide
-
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanamide
-
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
; i.e. Epimerox, 2-epimerase inhibition through a target-specific mechanism, in vivo efficacy against Staphylococcus aureus and Bacillus anthracis
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
; i.e. Epimerox, 2-epimerase inhibition through a target-specific mechanism, in vivo efficacy against Staphylococcus aureus and Bacillus anthracis
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]butanoic acid
-
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]butanoic acid
-
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3,4-dichlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3,5-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3,5-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3-chloro-4-methoxyphenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3-chloro-4-methoxyphenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(3-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromo-3-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromo-3-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromo-3-chlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromo-3-chlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-bromophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-chlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-chlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-chlorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-fluorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-fluorophenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-iodophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-iodophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-methoxyphenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-4-[[5-(4-methoxyphenyl)thiophen-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-5-oxo-2-thioxo-4-([5-[4-(trifluoromethoxy)phenyl]furan-2-yl]methylidene)imidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-5-oxo-2-thioxo-4-([5-[4-(trifluoromethoxy)phenyl]furan-2-yl]methylidene)imidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-5-oxo-4-[(5-phenylfuran-2-yl)methylidene]-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
(2S)-2-[(4E)-5-oxo-4-[(5-phenylfuran-2-yl)methylidene]-2-thioxoimidazolidin-1-yl]-3-phenylpropanoic acid
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]-1,1,1-trifluoromethanesulfonamide
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]-1,1,1-trifluoromethanesulfonamide
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]methanesulfonamide
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]methanesulfonamide
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]propyl]methanesulfonamide
-
N-[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]propyl]methanesulfonamide
-
[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]cyanamide
-
[1-[(4E)-4-[[5-(3,4-dichlorophenyl)furan-2-yl]methylidene]-5-oxo-2-thioxoimidazolidin-1-yl]-2-phenylethyl]cyanamide
-
additional information
synthesis and evaluation of specific inhibitors, overview
-
additional information
-
UDP-glycal derivatives as transition state analogues of GNE substrates are synthesized, especially UDP-exo-glycal derivatives, C-glycosidic derivatives of 2-acetamidoglucal, and ketosides as bisubstrate analogues and bis-product analogues, respectively. Derivatives of 1-deoxyiminosugars with and without substitution of the iminogroup in the ring are promising GNE inhibitors, designed as transition-state analogues of the known enzymatic mechanism of UDP-GlcNAc 2-epimerase
-
additional information
-
UDP-glycal derivatives as transition state analogues of GNE substrates are synthesized, especially UDP-exo-glycal derivatives, C-glycosidic derivatives of 2-acetamidoglucal, and ketosides as bisubstrate analogues and bis-product analogues, respectively. Derivatives of 1-deoxyiminosugars with and without substitution of the iminogroup in the ring are promising GNE inhibitors, designed as transition-state analogues of the known enzymatic mechanism of UDP-GlcNAc 2-epimerase
-
additional information
-
UDP-glycal derivatives as transition state analogues of GNE substrates are synthesized, especially UDP-exo-glycal derivatives, C-glycosidic derivatives of 2-acetamidoglucal, and ketosides as bissubstrate analogues and bis-product analogues, respectively. Derivatives of 1-deoxyiminosugars with and without substitution of the iminogroup in the ring are promising GNE inhibitors, designed as transition-state analogues of the known enzymatic mechanism of UDP-GlcNAc 2-epimerase
-
additional information
synthesis and evaluation of specific inhibitors, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
UDP-GlcNAc
-
allosteric activitation by substrate via direct interactions between UDP and substrate
UDP-N-acetylglucosamine
-
the reverse reaction with UDP-N-acetylmannosamine requires the presence of UDP-N-acetylglucosamine
UDP-N-acetylglucosamine
-
the reverse reaction with UDP-N-acetylmannosamine requires the presence of UDP-N-acetylglucosamine
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Hill coefficient of 2.7, positive cooperativity
-
0.08
UDP-N-acetyl-D-glucosamine
-
UDP-N-acetyl-D-glucosamine, liver enzyme of tumor-bearing animals
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.5 - 8.6
-
6.5: about 30% of maximal activity, 8.6: about 65% of maximal activity
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
HIV-infected. Downregulation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase in hyposialylated HIV-infected T cells
-
cell proliferation is directly correlated with GNE-expression and the cellular sialic acid concentration. Growth-related genes are differentially expressed in GNE-deficient embryonic stem cells compared to wild-type embryonic stem cells
-
enzyme activity is 18% of the activity found in normal livers
additional information
-
GNE2 and GNE3 display tissue-specific expression patterns
-
enzyme activity is significantly elevated at 8 h after intradermal injection of carageenan or urate crystals, falling to normal levels by day 3
-
enzyme activity is significantly elevated at 8 h after intradermal injection of carageenan or urate crystals, falling to normal levels by day 3
-
-
colonic mucosa: normal mucosa, non-malignant mucosa in azomethane treated animals, low activity in azomethane-induced tumor tissue
-
enzyme is detected only in sialoglycoprotein-secreting tissues
-
activity in colonic tissue is 25-50times lower than in liver
-
activity in colonic tissue is 25-50times lower than in liver; colonic mucosa: normal mucosa, non-malignant mucosa in azomethane treated animals, low activity in azomethane-induced tumor tissue
-
-
enzyme is detected only in sialoglycoprotein-secreting tissues
-
-
enzyme activity is low at birth, increases to a maximum value on day 15, and falls gradually until day 30, thereafter it increases up to the 60th day
-
enzyme activity is significantly elevated at 8 h after intradermal injection of carrageenan or urate crystals, falling to normal levels by day 3
-
enzyme activity is low at birth, increases to a maximum value on day 15, and falls gradually until day 30, thereafter it increases up to the 60th day
-
enzyme activity is significantly elevated at 8 h after intradermal injection of carrageenan or urate crystals, falling to normal levels by day 3
-
-
enzyme is detected only in sialoglycoprotein-secreting tissues
-
enzyme is detected only in sialoglycoprotein-secreting tissues
-
-
developmentally regulated: high levels in immature myoblast but low levels in mature skeletal muscle
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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PDB
SCOP
CATH
ORGANISM
UNIPROT
Burkholderia vietnamiensis (strain G4 / LMG 22486)
Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679 / EGD-e)
Methanocaldococcus jannaschii (strain ATCC 43067 / DSM 2661 / JAL-1 / JCM 10045 / NBRC 100440)
Methanocaldococcus jannaschii (strain ATCC 43067 / DSM 2661 / JAL-1 / JCM 10045 / NBRC 100440)
Vibrio cholerae serotype O1 (strain ATCC 39315 / El Tor Inaba N16961)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40000
42400
2 * 40000, SDS-PAGE, 2 * 42400, calculated, recombinant enzyme
40000
2 * 40000, SDS-PAGE, 2 * 42400, calculated, recombinant enzyme
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
hexamer
tetramer
additional information
?
-
x * 39368, calculation from nucleotide sequence; x * 40000, SDS-PAGE
dimer
-
recombinant splice variant hGNE1, mixture of tetramers and dimers in ratio of 3:1. Recombinant splice variant hGNE2, dimer. Gel filtration expreriments
dimer
2 * 40000, SDS-PAGE, 2 * 42400, calculated, recombinant enzyme
dimer
-
recombinant splice variant mGNE1, mixture of tetramers and dimers in ratio of 4:1. Gel filtration expreriments
tetramer
-
recombinant splice variant hGNE1, mixture of tetramers and dimers in ratio of 3:1, gel filtration
tetramer
-
recombinant splice variant mGNE1, mixture of tetramers and dimers in ratio of 4:1. Splice variant mGNE2, fully tetrameric state, gel filtration expreriments
additional information
-
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase interacts with the non-muscle form of alpha-actinin, alpha-actinin-1, in mature skeletal muscle cells
additional information
-
comparison of the GNE primary structures reveals a high sequence similarity between human and rodent GNE, indicating high evolutionary conservation
additional information
modeling of the active sites of human GNE/MNK using vailable structural data of GNE/MNK homologues, overview
additional information
-
comparison of the GNE primary structures reveals a high sequence similarity between human and rodent GNE, indicating high evolutionary conservation
additional information
-
comparison of the GNE primary structures reveals a high sequence similarity between human and rodent GNE, indicating high evolutionary conservation
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
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Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ternary complex between the UDP-GlcNAc 2-epimerase, its substrate UDP-GlcNAc and the reaction intermediate UDP, at 1.7 A resolution. Direct interactions between the substrate and UDP via two hydrogen bonds to the alpha- and beta-phosphates of the adjacent UDP molecule, and between the complex and highly conserved enzyme residues. The binding of UDP-GlcNAc is associated with conformational changes in the active site of the enzyme
-
hanging drop vapor diffusion method, selenomethionyl enzyme, X-ray structure at 2.5 A of the enzyme with bound UDP
-
sitting-drop vapor-diffusion method, crystal structures in open and closed conformations. A comparison of these crystal structures shows that upon UDP and UDPGlcNAc binding, the enzyme undergoes conformational changes involving a rigid-body movement of the C-terminal domain
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the purified enzyme is 80% pure, no further purification because it is unstable to freezing and has limited stability upon storage at 4°C
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UDP and UDP-N-acetylglucosamine protect the enzyme from inactivation by aging
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-10°C, overnight, in a saturated (NH4)2SO4 solution, approximately 20% loss of activity
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-18°C, stable for several months
4°C, purified enzyme is 80% pure, no further purification because it is unstable to freezing and has limited stability upon storage at 4°C
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
enzyme expressed in Escherichia coli and enzyme expressed in insect cells
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recombinant enzyme expressed in Spodoptera frugiperda cells using a baculovirus expression system
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cloning of the neuC gene into an intein expression vector to facilitate purification
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DNA sequencing of the GNE coding region of 64 symptomatic patients with autosomal recessive hereditary inclusion body myopathy, genotyping-phenotyping of patients from different ethnics, overview
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expression in Escherichia coli
expression in Insect Cells and supercompetent InvalphaF' Escherichia coli cells (Invitrogen)
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expression in Sf9 insect cells, wild-type enzyme and mutant enzymes DELTA1-39, DELTA1-234, DELTA1-356, DELTA383-722, DELTA490-722, DELTA597-722, DELTA697-722, DELTA717-722
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expression of wild-type and mutant enzymes (C13S, H132Q, D176V, D177C, V331A, I472T, G708S, A631V, V572L and A630T) in COS-7 cells
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functional expression in Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris or insect cells. In all cell types, the expressed enzyme displayes both epimerase and kinase activities. In Escherichia coli up to 2 mg protein/l cell culture is expressed in yeast cells only 0.4 mg/ml, in insect cells up to 100 mg/L. In all three cell systems, insoluble protein aggregates are also observed. Expression and purification of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase in Sf-900 cells can yield the miligram amount of protein required for structural characterization of the enzyme. The easier expression in Escherichia coli and yeast provides sufficient quantities for enzymatic and kinetic characterization
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high level overexpression of the active enzyme is established by using the baculovirus/Sf9 system
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overexpression in Escherichia coli BL21(DE3), wild-type enzyme and mutant enzymes D100N, E122Q and D131N
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proteome expression analysis in wild-type and GNE-deficient embryonic stem cells, overview. GNE overexpression in HEK cells
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splice variant hGNE2, expression in insect and mammalian cells. Splice variant hGNE3, expression in Escherichia coli
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D95N
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about 18000 fold decrease in turnover number for UDP-N-acetyl-D-glucosamine, not possible to obtain accurate kinetic constants
E117Q
-
about 18000 fold decrease in turnover number for UDP-N-acetyl-D-glucosamine, not possible to obtain accurate kinetic constants
E131Q
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about 18000 fold decrease in turnover number for UDP-N-acetyl-D-glucosamine, not possible to obtain accurate kinetic constants
H213N
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30fold increase in Km-value and 50fold decrease in turnover-number for UDP-N-acetyl-D-glucosamine. Unlike the wild-type enzyme no inhibition is detected at UDP-concentrations up to 10 mM
K15A
-
more than 100fold increase in KM-value for UDP-N-acetyl-D-glucosamine
A630T
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to 70-80% of wild-type activity
A631V
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a naturally occuring missense mutation in exon 11 of the GNE gene of a patient with hereditary inclusion body myopathy
C13S
C303V
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
C303X
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
D176V
D177C
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to less than 20% of wild-type
D225N
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
D378Y
E2G
-
a naturally occuring missense mutation in exon 2 of the GNE gene of a patient with hereditary inclusion body myopathy
G135V
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
G135V/R246W
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mutation in patients with hereditary inclusion body myopathy: G135V/R246W (GNE/GNE domain mutation), UDP-N-acetylglucosamine 2-epimerase activity is 38% of wild-type, N-acetylmannosamine kinase activity is 72% of wild-type
G206S
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
G708S
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to 50% of wild-type activity
G89R
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
H132Q
I142T
-
a naturally occuring missense mutation in exon 3 of the GNE gene of a patient with hereditary inclusion body myopathy
I200F
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
I241S
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
I298T
-
a naturally occuring missense mutation in exon 5 of the GNE gene of a patient with hereditary inclusion body myopathy
I472T
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to 50% of wild-type activity
L379H
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
L556S
-
a naturally occuring missense mutation in exon 10 of the GNE gene of a patient with hereditary inclusion body myopathy
M171V
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
M29T
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
M712T
M712T/M712T
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M712T/M712T (MNK/MNK domain mutation), UDP-N-acetylglucosamine 2-epimerase activity is 83% of wild-type, N-acetylmannosamine kinase activity is 55% of wild-type
P27S
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
P283S
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
P36L
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
Q436X
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a naturally occuring nonsense mutation in exon 8 of the GNE gene of a patient with hereditary inclusion body myopathy
R11W
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R129Q
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R162C
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R177C
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R202L
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R246Q
R246W
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R263L
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R266Q
R266W
R277C
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R306Q
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R335W
R71W
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a naturally occuring missense mutation in exon 3 of the GNE gene of a patient with hereditary inclusion body myopathy
R8X
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a naturally occuring nonsense mutation in exon 2 of the GNE gene of a patient with hereditary inclusion body myopathy
S615X
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a naturally occuring nonsense mutation in exon 11 of the GNE gene of a patient with hereditary inclusion body myopathy
V216A
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
V216A/A631V
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V216A/A631V (GNE/MNK domain mutation), UDP-N-acetylglucosamine 2-epimerase activity is 48% of wild-type, N-acetylmannosamine kinase activity is 63% of wild-type
V331A
V367I
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
V572L
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to 70-80% of wild-type activity
V696M
W204X
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a naturally occuring nonsense mutation in exon 3 of the GNE gene of a patient with hereditary inclusion body myopathy
Y675H
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a naturally occuring missense mutation in exon 12 of the GNE gene of a patient with hereditary inclusion body myopathy
D100N
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no conversion of UDP-N-acetyl-D-glucosamine to UDP + N-acetyl-D-mannosamine
D131N
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no conversion of UDP-N-acetyl-D-glucosamine to UDP + N-acetyl-D-mannosamine, acetamidoglucal is released from the active site during catalysis
E122Q
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no conversion of UDP-N-acetyl-D-glucosamine to UDP + N-acetyl-D-mannosamine, acetamidoglucal is released from the active site during catalysis
D100N
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no conversion of UDP-N-acetyl-D-glucosamine to UDP + N-acetyl-D-mannosamine
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D131N
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no conversion of UDP-N-acetyl-D-glucosamine to UDP + N-acetyl-D-mannosamine, acetamidoglucal is released from the active site during catalysis
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E122Q
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no conversion of UDP-N-acetyl-D-glucosamine to UDP + N-acetyl-D-mannosamine, acetamidoglucal is released from the active site during catalysis
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D413K
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enzyme with mutation in the putative kinase active site shows drastic loss in their kinase activity but retains their epimerase activity
D413N
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enzyme with mutation in the putative kinase active site shows drastic loss in their kinase activity but retains their epimerase activity
H110A
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mutant enzyme shows a drastic loss of epimerase activity, oligomerization is significantly different from that of the wild-type enzyme,loss of epimerase activity can largely by attributed to incorrect protein folding
H132A
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mutant enzyme shows a drastic loss of epimerase activity, oligomerization is significantly different from that of the wild-type enzyme, loss of epimerase activity can largely by attributed to incorrect protein folding
H155A
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mutant enzyme forms mainly trimeric enzyme with small amounts of hexamer; mutant enzyme shows a drastic loss of epimerase activity, loss of epimerase activity can largely by attributed to incorrect protein folding
H157A
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mutant enzyme forms mainly trimeric enzyme with small amounts of hexamer; mutant enzyme shows a drastic loss of epimerase activity, loss of epimerase activity can largely by attributed to incorrect protein folding
R420M
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enzyme with mutation in the putative kinase active site shows drastic loss in their kinase activity but retains their epimerase activity
additional information
C13S
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to less than 20% of wild-type
C13S
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
D176V
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to less than 20% of wild-type
D176V
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
D378Y
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to less than 20% of wild-type
D378Y
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
H132Q
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to less than 20% of wild-type
H132Q
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
M712T
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the homozygous M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities but not in altered overall cellular sialylation in hereditary inclusion body myopathy
M712T
the Persian-Jewish HIBM founder mutation is located at the interface alpha4alpha10 of GNE and likely affects GlcNAc, Mg2+, and ATP binding
R246Q
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a naturally occuring missense mutation in exon 4 of the GNE gene of a patient with hereditary inclusion body myopathy
R246Q
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R266Q
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GNE mutants are created by site-directed mutagenesis with the mutagenic oligonucleotides 5'-GGTTCGAGTGATGCAGAAGAAGGGCATTGAGCA-3' for the R266Q sialuria mutations (where the site of mutation is underlined) through PCR-like amplification with Pfu polymerase.
R266Q
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R266W
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GNE mutants are created by site-directed mutagenesis with the mutagenic oligonucleotides 5'-GGTTCGAGTGATGTGGAAGAAGGGCATTGAGCA-3' for the R266W sialuria mutations (where the site of mutation is underlined) through PCR-like amplification with Pfu polymerase.
R266W
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
R335W
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a naturally occuring missense mutation in exon 6 of the GNE gene of a patient with hereditary inclusion body myopathy
R335W
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
V331A
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mutation in patients with distal myopathy with rimmed vacuoles, UDP-N-acetylglucosamine 2-epimerase activity of mutant enzyme is reduced to less than 20% of wild-type
V331A
a naturally occuirng missense mutation the epimerase part of the bifunctional enzyme
V696M
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naturally occuring missense mutation G2086A involved in hereditary inclusion body myopathy, phenotype, overview
V696M
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a naturally occuring missense mutation in exon 12 of the GNE gene of a patient with hereditary inclusion body myopathy
additional information
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splice variant hGNE2, recombinantly expressed in insect and mamalian cells, displays selective reduction of UDPGlcNAc 2-epimerase activity by the loss of its tetrameric state, which is essential for full enzyme activity. Splice variant hGNE3 only possesses kinase activity
additional information
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sialuria is caused by the loss of feedback control of UDP-GlcNAc 2-epimerase activity due to the mutation of only one of the two arginine residues 263 and 266
additional information
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the frame shif mutation 1295delA, leading to a premature stop codon at K432, is involved in hereditary inclusion body myopathy, phenotype, overview
additional information
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a synonymous variation, p.Y591Y, codon tac>tat, is seen in a patient bearing compound heterozygous nonsynonymous mutation, p.S615X and p.Y675H
additional information
mutant genotyping, overview. Modeling of effects of GNE/MNK missense mutations associated with HIBM or sialuria on helix arrangement, substrate binding, and enzyme action, overview. All reported mutations are associated with the active sites or secondary structure interfaces of GNE/MNK
additional information
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transgenic Arabidopsis thaliana plants expressing three key enzymes of the mammalian Neu5Ac biosynthesis pathway: UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, N-acetylneuraminic acid phosphate synthase, and CMP-Nacetylneuraminic acid synthetase. Simultaneous expression of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase and N-acetylneuraminic acid phosphate synthase results in the generation of significant Neu5Ac amounts of 1275 nmol per g fresh weight in leaves, which can be further converted to cytidine monophospho-N-acetylneuraminic acid by coexpression of CMP-N-acetylneuraminic acid synthetase
additional information
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generation of GNE knockout mice by gene targeting, enzyme knockout leads to embryonic lethality, phenotype, overview. Impaired sialylation of glycoconjugates induces cell death, either by the loss of the sialic acid specific masking of cells to prevent proteolytic attack or by the prevention of cell migration and differentiation
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
biotechnology
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production of erythropoietin (EPO) in Chinese Hamster Ovary (CHO) cells
drug development
medicine
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UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase interacts with the non-muscle form of alpha-actinin, alpha-actinin-1, in mature skeletal muscle cells. No significant difference in the binding of alpha-actinin-1 with either wild-type or mutant enzyme, and therefore no conclusions wether and how the interaction is relevant to the muscle-restricted pathology of hereditary inclusion body myopathy
synthesis
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transgenic Arabidopsis thaliana plants expressing three key enzymes of the mammalian Neu5Ac biosynthesis pathway: UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, N-acetylneuraminic acid phosphate synthase, and CMP-Nacetylneuraminic acid synthetase. Simultaneous expression of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase and N-acetylneuraminic acid phosphate synthase results in the generation of significant Neu5Ac amounts of 1275 nmol per g fresh weight in leaves, which can be further converted to cytidine monophospho-N-acetylneuraminic acid by coexpression of CMP-N-acetylneuraminic acid synthetase
drug development
the enzyme is a target for development of antibiotic agent for treatment of infections caused by Gram-positive bacteria, such as Staphylococcus aureus and Bacillus anthracis
drug development
the enzyme is a target for development of antibiotic agent for treatment of infections caused by Gram-positive bacteria, such as Staphylococcus aureus and Bacillus anthracis
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LINKS TO OTHER DATABASES (specific for EC-Number 5.1.3.14)
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