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Information on EC 5.1.3.2 - UDP-glucose 4-epimerase and Organism(s) Homo sapiens and UniProt Accession Q14376
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5.1.3.2 UDP-glucose 4-epimeraseIUBMB Comments
Requires NAD+. Also acts on UDP-2-deoxyglucose.
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Word Map
- 5.1.3.2
- polysaccharide
- galactokinase
-
leloir
- galactosemia
- galactose-1-phosphate
- udp-galnac
- udp-n-acetylglucosamine
-
galactose-inducible
-
kluyveromyces
-
pyrophosphorylase
- fragilis
-
uridylyltransferase
- udp-n-acetylgalactosamine
- udpglucose
- udp-sugars
- galnac
- mutarotase
-
galactose-containing
-
o-antigens
-
udp-glucuronic
- medicine
- synthesis
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
gal10, udp-galactose 4-epimerase, 4-epimerase, udp-glucose 4-epimerase, udp-galactose-4-epimerase, udp-galactose 4'-epimerase, udp-glucose 4'-epimerase, udp-glucose-4-epimerase, udp-glucose epimerase, gal10p, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
4-Epimerase
-
-
-
-
Epimerase, uridine diphosphoglucose
-
-
-
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Galactowaldenase
-
-
-
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UDP-D-galactose 4-epimerase
-
-
-
-
UDP-galactose 4-epimerase
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-
-
-
UDP-glucose epimerase
-
-
-
-
UDPG-4-epimerase
-
-
-
-
UDPgalactose 4-epimerase
-
-
-
-
Uridine diphosphate galactose 4-epimerase
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-
-
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Uridine diphosphate glucose 4-epimerase
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-
-
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Uridine diphospho-galactose-4-epimerase
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-
-
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Uridine diphosphoglucose 4-epimerase
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-
-
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Uridine diphosphoglucose epimerase
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
UDP-glucose 4-epimerase
Requires NAD+. Also acts on UDP-2-deoxyglucose.
CAS REGISTRY NUMBER
COMMENTARY
9032-89-7
-
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-alpha-D-glucose
UDP-alpha-D-galactose
-
The enzyme UDP-glucose 4'-epimerase (GalE) interconverts UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal).
-
-
r
UDP-galactose
UDP-glucose
-
enzyme contributes to the Lelpoir pathway and also functions as a gatekeeper overseeing the ratios of important substrate pools required for the synthesis of glycosylated macromolecules
-
-
r
UDP-galactose
UDP-glucose
-
point mutations in UDP-galactose 4-epimerase are associated with the genetic disease, type III galactosemia
-
-
r
UDP-GalNAc
UDP-GlcNAc
-
enzyme contributes to the Lelpoir pathway and also functions as a gatekeeper overseeing the ratios of important substrate pools required for the synthesis of glycosylated macromolecules
-
-
r
additional information
?
-
-
catalyzes the interconversion of UDP-glucose and UDP-galactose during normal galactose metabolism
-
?
additional information
?
-
-
impairement of the enzyme results in galacosemia III that can lead to symptoms ranging from benign to severe
-
?
NATURAL SUBSTRATE
NATURAL 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-GalNAc
UDP-GlcNAc
-
enzyme contributes to the Lelpoir pathway and also functions as a gatekeeper overseeing the ratios of important substrate pools required for the synthesis of glycosylated macromolecules
-
-
r
UDP-alpha-D-glucose
UDP-alpha-D-galactose
-
The enzyme UDP-glucose 4'-epimerase (GalE) interconverts UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal).
-
-
r
UDP-galactose
UDP-glucose
-
enzyme contributes to the Lelpoir pathway and also functions as a gatekeeper overseeing the ratios of important substrate pools required for the synthesis of glycosylated macromolecules
-
-
r
UDP-galactose
UDP-glucose
-
point mutations in UDP-galactose 4-epimerase are associated with the genetic disease, type III galactosemia
-
-
r
additional information
?
-
-
impairement of the enzyme results in galacosemia III that can lead to symptoms ranging from benign to severe
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
the NAD+ cofactor can be removed from human GalE without denaturation. Fewer protein-NAD+ contacts are observed in the crystal structure, which explains the reversible character of cofactor binding
NAD+
-
the amino acid side chains responsible for anchoring the NAD+ to the protein include Asp33, Asn37, Asp66, Tyr157 and Lys161
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
diamino(dimethylamino)methyl (E)-{(8alpha,13E,14alpha)-14-[2-(furan-3-yl)ethyl]-8-methylpodocarpan-13-ylidene}methyl sulfate
-
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.048
UDP-galactose
-
wild type enzyme, in 20 mM HEPES-KOH, pH 7.5, 1 mM dithiohreitol, and 0.3 mg/ml bovine serum albumin, at 37°C
0.2
UDP-galactose
-
mutant enzyme M284K, in 20 mM HEPES-KOH, pH 7.5, 1 mM dithiohreitol, and 0.3 mg/ml bovine serum albumin, at 24°C
0.25
UDP-galactose
-
mutant enzyme M284K, in 20 mM HEPES-KOH, pH 7.5, 1 mM dithiohreitol, and 0.3 mg/ml bovine serum albumin, at 37°C
0.38
UDP-galactose
-
wild type enzyme, in 20 mM HEPES-KOH, pH 7.5, 1 mM dithiohreitol, and 0.3 mg/ml bovine serum albumin, at 24°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
12
diamino(dimethylamino)methyl (E)-{(8alpha,13E,14alpha)-14-[2-(furan-3-yl)ethyl]-8-methylpodocarpan-13-ylidene}methyl sulfate
Homo sapiens
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
UDP-Gal 4-epimerases and the other GalE-like UDP-sugar 4-epimerases belong to the short-chain dehydrogenase/reductase (SDR) superfamily of proteins. Classification of UDP-hexose 4-epimerases into three groups with distinct substrate promiscuity. Group 1 contains the 4-epimerases that exhibit a strong preference for non-acetylated substrates (such as Escherichia coli enzyme eGalE), group 2 members can epimerize both non-acetylated and N-acetylated substrates equally well (such as the human enzyme hGalE), and group 3 epimerases are very specific for N-acetylated substrates (like the WbpP from Pseudomonas aeruginosa)
malfunction
metabolism
physiological function
malfunction
-
GALE deficiency leads to mild or severe disease with clinical symptoms similar to classical galactosemia
metabolism
-
GALE catalyzes the third step of the Leloir pathway of galactose metabolism
additional information
malfunction
UDP-galactose-4-epimerase deficiency causes galactosemia. Altered protein stability is due to misfolding and loss or reduction of enzyme activity is responsible for the molecular defects underlying GALE-deficiency galactosemia
malfunction
silencing GALE gene with specific siRNAs results in a markedly inhibition of proteoglycans (PGs)synthesis in human articular chondrocytes. GALE protein levels are also decreased in both human osteoarthritis cartilage, thus leading to losses of PGs contents. GALE inhibition might contribute to osteoarthritis progress. Mutations of gene GALE in humans results in an inherited metabolic disease, the type III galactosemia
metabolism
UDP-sugar 4-epimerase (GalE) is one of enzymes in the Leloir pathway
physiological function
UDP-galactose 4-epimerase is important for the biosynthesis of other polysaccharide structures, such as proteoglycans (PGs) of articular chondrocytes. Secondary role of the human enzyme is epimerization of UDP-N-acetylgalactosamine (UDP-Gal-NAc)
physiological function
UDP-galactose-4-epimerase (GALE) is a key enzyme catalyzing the interconversion of UDP-glucose and UDP-galactose, as well as UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine, which are all precursors for the proteoglycans (PGs) synthesis. Role of GALE in PGs synthesis of human articular chondrocytes, the GALE expression in osteoarthritis, and the regulation of GALE expression by interleukin-1beta, overview. GALE mRNA expression is stimulated by interleukin-1beta in early phase, but suppressed in late phase, while the suppression of GALE expression induced by interleukin-1beta is mainly mediated by stress-activated protein kinase/c-Jun N-terminal kinase pathway. Both SAP/JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 attenuate the suppression of interleukin-1beta on GAG synthesis and GALE mRNA expression of chondrocyte. Critical role of GALE in maintaining cartilage homeostasis
additional information
comparison of the hexagonal box model of sugar-binding pockets of several GalE enzymes. The human enzyme has a smaller active site, explaining the secondary role of the human enzyme, which is epimerization of UDP-N-acetylgalactosamine (UDP-Gal-NAc). Activity on the larger acetylated substrates requires a larger active site
additional information
-
comparison of the hexagonal box model of sugar-binding pockets of several GalE enzymes. The human enzyme has a smaller active site, explaining the secondary role of the human enzyme, which is epimerization of UDP-N-acetylgalactosamine (UDP-Gal-NAc). Activity on the larger acetylated substrates requires a larger active site
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). GALE_HUMAN
348
0
38282
Swiss-Prot
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
-
wild-type protein and all the mutants (N34S, G90E, V94M, D103G, L183P, K257R, L313M, G319E and R335H) are able to form dimers. In all cases, especially with the mutant proteins, some higher molecular mass species are also observed
additional information
additional information
determination of the structure of human UDP-Gal 4-epimerase. The C-terminal domain is built from five beta-strands and four alpha-helices
additional information
-
determination of the structure of human UDP-Gal 4-epimerase. The C-terminal domain is built from five beta-strands and four alpha-helices
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
suitable crystallization conditions are both at room temperature and at 4°C using sparse matrix screen and the hanging drop method of vapor diffusion. The best crystals are observed growing from polyethylene glycol 8000 and potassium chloride and in the presence of 2 mM NAD+. Typical large crystals are ontained from 18-20% polyethylene glycol 8000, 100 mM Hepes, pH 7.5, and 250 mM KCl at room temperature, crystallization of a epimerase/NADH/UDP-glucose ternary complex
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G302D
the mutant enzyme is not able to rescue galactose-sensitive cell proliferation when stably expressed in ldlD cells
R239W
the mutant enzyme is not able to rescue galactose-sensitive cell proliferation when stably expressed in ldlD cells
C307Y
-
normal activity with respect to UDP-galactose, complete loss of activity with respect to UDP-N-acetylgalactosamine
D103G
G319E
-
very littel change in steady-state kinetic parameters compared with the wild-type protein
G90E
K257R
-
the ratio of turnover number to Km-value is 6.7fold lower than the wild-type ratio
L183P
L313M
-
the ratio of turnover number to Km-value is 3.0fold lower than the wild-type ratio
M284K
-
the mutant is active in vivo, but not in vitro and shows reduced enzymatic activity (1.1% residual activity) and reduced stability towards denaturants in vitro
N34S
R335H
-
the ratio of turnover number to KM-value is 3.5fold lower than the wild-type ratio
S132A
-
complete loss of activity with respect to interconversion of UDP-glucose and UDP-galactose and of UDP-GalNAc and UDP-GlcNAc
S132A/Y157F
-
complete loss of activity with respect to interconversion of UDP-glucose and UDP-galactose and of UDP-GalNAc and UDP-GlcNAc
V94M
Y157F
-
complete loss of activity with respect to interconversion of UDP-glucose and UDP-galactose and of UDP-GalNAc and UDP-GlcNAc
additional information
D103G
-
the ratio of turnover number to Km-value is 14.4fold lower than the wild-type ratio
G90E
-
the ratio of turnover number to Km-value is 1040fold lower than the wild-type ratio. Mutant enzyme is more susceptible to proteolysis than the wild-type protein, presence of substrate at saturating level (1 mM) partially protect the enzyme from proteolysis
L183P
-
the ratio of turnover number to Km-value is 4.7fold lower than the wild-type ratio. Mutant enzyme is highly susceptible to proteolysis during expression and purification
N34S
-
very little change in steady-state kinetic parameters compared with the wild-type protein. Mutant enzyme is more susceptible to proteolysis than the wild-type protein, presence of substrate at saturating level (1 mM) partially protect the enzyme from proteolysis
V94M
-
the ratio of turnover number to Km-value is 75fold lower than the wild-type ratio
additional information
silencing gene GALE with specific siRNAs in human chondrocytes
additional information
-
silencing gene GALE with specific siRNAs in human chondrocytes
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of GFP-tagged wild-type enzyme in HEK-293T cells, and transient expression of myc-tagged GALER239W and GALEG302D, and of myc- or FLAG-tagged GALE165K and GALEW336X in HEK-293T cells and in GALE-null ldlD cells
gene GALE, real-time quantitative PCR expression analysis in chondrocytes
expressed in Escherichia coli Rosetta cells and in a gal10-null strain of Saccharomyces cerevisiae strain JFy3835
-
expression in GALE-null line of Chineses hamster ovary cells. GALE-null cells accumulats abnormally high levels of Hal-1-P and UDP-Gal and abnormally low levels of UDP-Glc and UDP-GLcNAc in the presence of galactose. Human GALE expression corrects each of theses defects
-
mutant enzymes S132A, Y157F, S132A/Y157F and C307Y are expressed in a null-background strain of Saccharomyces cerevisiae. S132a/Y157F and C307Y are also overexpressed in Pichia pastoris
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
GALE mRNA expression is stimulated by interleukin-1beta in early phase, but suppressed in late phase, while the suppression of GALE expression induced by interleukin-1beta is mainly mediated by stress-activated protein kinase/c-Jun N-terminal kinase pathway
GALE mRNA expression is stimulated by interleukin-1beta in early phase, but suppressed in late phase, while the suppression of GALE expression induced by interleukin-1beta is mainly mediated by stress-activated protein kinase/c-Jun N-terminal kinase pathway. Both SAP/JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 attenuate the suppression of interleukin-1beta on GAG synthesis and GALE mRNA expression of chondrocyte
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bergren, W.R.; Ng, W.G.; Donnell, G.N.
Uridine diphosphate galactose 4-epimerase in human and other mammalian hemolysates
Biochim. Biophys. Acta
315
464-472
1973
Felis catus, Homo sapiens, Mus musculus
-
Daude, N.; Gallaher, T.K.; Zeschnigk, M.; Starzinski-Powitz, A.; Petry, K.G.; Haworth, I.S.; Reichhardt, J.K.V.
Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4'-epimerase
Biochem. Mol. Med.
56
1-7
1995
Homo sapiens
Thoden, J.B.; Wohlers, T.M.; Fridovich-Keil, J.L.; Holden, H.M.
Crystallographic evidence for Tyr 157 functioning as the active site base in human UDP-galactose 4-epimerase
Biochemistry
39
5691-5701
2000
Homo sapiens
Thoden, J.B.; Wohlers, T.M.; Fridovich-Keil, J.L.; Holden, H.M.
Human UDP-galactose 4-epimerase. Accommodation of UDP-N-acetylglucosamine within the active site
J. Biol. Chem.
276
15131-15136
2001
Homo sapiens (Q14376), Homo sapiens
Holden, H.M.; Rayment, I.; Thoden, J.B.
Structure and function of enzymes of the Leloir pathway for galactose metabolism
J. Biol. Chem.
278
43885-43888
2003
Escherichia coli, Homo sapiens
Timson, D.J.
Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase
FEBS J.
272
6170-6177
2005
Homo sapiens
Schulz, J.M.; Watson, A.L.; Sanders, R.; Ross, K.L.; Thoden, J.B.; Holden, H.M.; Fridovich-Keil, J.L.
Determinants of function and substrate specificity in human UDP-galactose 4'-epimerase
J. Biol. Chem.
279
32796-32803
2004
Homo sapiens
Schulz, J.M.; Ross, K.L.; Malmstrom, K.; Krieger, M.; Fridovich-Keil, J.L.
Mediators of galactose sensitivity in UDP-galactose 4'-epimerase-impaired mammalian cells
J. Biol. Chem.
280
13493-13502
2005
Escherichia coli, Homo sapiens
Urbaniak, M.D.; Tabudravu, J.N.; Msaki, A.; Matera, K.M.; Brenk, R.; Jaspars, M.; Ferguson, M.A.
Identification of novel inhibitors of UDP-Glc 4-epimerase, a validated drug target for african sleeping sickness
Bioorg. Med. Chem. Lett.
16
5744-5747
2006
Homo sapiens, Trypanosoma brucei, Homo sapiens CHO-K1
Prodan-Zitnik, I.; Karas-Kuzelicki, N.; Lukac-Bajalo, J.
Positive correlation between galactose-1-phosphate uridyltransferase (GALT) and UDP-galactose-4-epimerase (GALE) activities
Clin. Biochem.
42
1561-1564
2009
Homo sapiens
Bang, Y.L.; Nguyen, T.T.; Trinh, T.T.; Kim, Y.J.; Song, J.; Song, Y.H.
Functional analysis of mutations in UDP-galactose-4-epimerase (GALE) associated with galactosemia in Korean patients using mammalian GALE-null cells
FEBS J.
276
1952-1961
2009
Homo sapiens (Q14376), Homo sapiens
McCorvie, T.J.; Wasilenko, J.; Liu, Y.; Fridovich-Keil, J.L.; Timson, D.J.
In vivo and in vitro function of human UDP-galactose 4-epimerase variants
Biochimie
93
1747-1754
2011
Homo sapiens
Wen, Y.; Qin, J.; Deng, Y.; Wang, H.; Magdalou, J.; Chen, L.
The critical role of UDP-galactose-4-epimerase in osteoarthritis modulating proteoglycans synthesis of the articular chondrocytes
Biochem. Biophys. Res. Commun.
452
906-911
2014
Homo sapiens (Q14376), Homo sapiens
Beerens, K.; Soetaert, W.; Desmet, T.
UDP-hexose 4-epimerases a view on structure, mechanism and substrate specificity
Carbohydr. Res.
414
8-14
2015
Marinithermus hydrothermalis (F2NQX6), Thermus thermophilus (F6DEY6), Saccharomyces cerevisiae (P04397), Escherichia coli (P09147), Streptococcus thermophilus (P21977), Homo sapiens (Q14376), Homo sapiens, Drosophila melanogaster (Q9W0P5), Saccharomyces cerevisiae ATCC 204508 / S288c (P04397), Thermus thermophilus SG0.5JP17-16 (F6DEY6), Marinithermus hydrothermalis DSM 14884 / JCM 11576 / T1 (F2NQX6)
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