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Information on EC 1.1.1.22 - UDP-glucose 6-dehydrogenase and Organism(s) Homo sapiens and UniProt Accession O60701
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1.1.1.22 UDP-glucose 6-dehydrogenaseIUBMB Comments
Also acts on UDP-alpha-D-2-deoxyglucose.
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Word Map
- 1.1.1.22
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udp-glucuronic
- polysaccharide
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ugdhs
- glycosaminoglycans
- hyaluronan
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pyrophosphorylase
- udp-xylose
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glucuronic
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glucuronidation
- udp-glca
- exopolysaccharide
- udp-sugars
- medicine
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glca
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udpga
- udp-d-glucuronate
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udp-glucuronyltransferase
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hasas
- pharmacology
- agriculture
- molecular biology
- 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
udp-glucose dehydrogenase, udpgdh, udpgd, udp-glucose 6-dehydrogenase, uridine diphosphoglucose dehydrogenase, udpglucose dehydrogenase, udp-gdh, udp-glc dehydrogenase, udpg dehydrogenase, udp-glcdh, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dehydrogenase, uridine diphosphoglucose
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-
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Sugarless protein
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-
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UDP-alpha-D-glucose:NAD oxidoreductase
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-
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UDP-D-glucose dehydrogenase
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-
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UDP-Glc dehydrogenase
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-
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UDP-Glc DH
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-
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UDP-GlcDH
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-
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UDPG dehydrogenase
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-
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UDPG:NAD oxidoreductase
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-
-
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UDPGDH
-
-
-
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UDPGlc dehydrogenase
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-
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UDPglucose dehydrogenase
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-
-
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UDPglucose:NAD+ oxidoreductase
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-
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uridine diphosphate D-glucose dehydrogenase
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uridine diphosphate glucose dehydrogenase
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uridine diphosphoglucose dehydrogenase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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-
-
-
reduction
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PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
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-, -
SYSTEMATIC NAME
IUBMB Comments
UDP-alpha-D-glucose:NAD+ 6-oxidoreductase
Also acts on UDP-alpha-D-2-deoxyglucose.
CAS REGISTRY NUMBER
COMMENTARY
9028-26-6
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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-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
-
r
UDP-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
?
UDP-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
-
?
UDP-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
?
UDP-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
-
?
UDP-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
?
UDP-glucose + 2 NAD+ + H2O
UDP-glucuronate + 2 NADH + 2 H+
-
-
-
?
UDP-glucose + 2 NAD+ + H2O
UDP-glucuronate + 2 NADH + 2 H+
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-
-
-
?
UDP-glucose + 2 NAD+ + H2O
UDP-glucuronate + 2 NADH + 2 H+
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C276 is an active catalytic residue and critically involved in the substrate binding
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-
?
additional information
?
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enzyme displays hysteresis, observed as a lag in progress curves, and is sensitive to product inhibition during the lag. The inhibition results in a systematic decrease in steady-state velocity and makes the lag appear to have a second-order dependence on enzyme concentration.The lag is in fact due to a substrate and cofactor-induced isomerization of the enzyme. The cofactor binds to the enzyme:substrate complex with negative cooperativity, suggesting that the isomerization may be related to the formation of an asymmetric enzyme complex
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-
?
additional information
?
-
-
enzyme displays hysteresis, observed as a lag in progress curves, and is sensitive to product inhibition during the lag. The inhibition results in a systematic decrease in steady-state velocity and makes the lag appear to have a second-order dependence on enzyme concentration.The lag is in fact due to a substrate and cofactor-induced isomerization of the enzyme. The cofactor binds to the enzyme:substrate complex with negative cooperativity, suggesting that the isomerization may be related to the formation of an asymmetric enzyme complex
-
-
?
additional information
?
-
the transient capacity to dissociate and reorganize the hydrogen bond network at the interface between dimeric units is an important element of the normal catalytic cycle
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-
?
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-alpha-D-glucose + 2 NAD+ + H2O
UDP-alpha-D-glucuronate + 2 NADH + 2 H+
-
-
-
?
additional information
?
-
the transient capacity to dissociate and reorganize the hydrogen bond network at the interface between dimeric units is an important element of the normal catalytic cycle
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
cofactor binding triggers the formation of the 32 symmetry enzyme hexamer, which is the catalytically relevant state
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
phycocyanin
mixed-type inhibitor with respect to both UDP-glucose and NAD+
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phycocyanobilin
competitive with respect to UDP-glucose and non-competitive with respect to NAD+. Phycocyanobilin is also effective in reducing the colony formation capacity of PC-3 prostate cancer cells and FTC-133 thyroid cancer cells
UDP-alpha-D-xylose
competitive. The DELTA132 deletion mutant and the UDP-alpha-D-xylose-inhibited structures have similar hexamer-building interfaces, suggesting that the hinge-bending motion represents a path for the allosteric transition between the different hexameric states
gallic acid
-
is a non-competitive inhibitor with respect to UDP-glucose and NAD+. It decreases specific activities of UGDH, but does not affect UGDH protein expression, thus UGDH activity is inhibited by polyphenols at the post-translational level. Gallic acid exerts strong antiproliferative activity in breast cancer cells. Heat inactivation of UGDH is accelerated to a greater degree by quercetin than by gallic acid. In the presence of gallic acid, the activity remaining after 30 min is 55% that of control
quercetin
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shows a competitive inhibition and a mixed-type inhibition with respect to UDP-glucose and NAD+, decreases specific activities of UGDH, but does not affect UGDH protein expression, thus UGDH activity is inhibited by polyphenols at the post-translational level. Quercetin exerts strong antiproliferative activity in breast cancer cells. Heat inactivation of UGDH is accelerated to a greater degree by quercetin than by gallic acid. In the presence of quercetin, the activity remaining after 30 min is 20% that of control
additional information
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in the presence of 0.12 mM 5-azido-UDP-glucose, 89% of the enzyme activity is lost after 5 min of photolabeling. When the enzyme is photolyzed in presence of 1 mM UDP-glucose, 11% of the enzyme activity is lost. 5-azido-UDP-glucose is photoinserting into a UDP-glucose-binding site on the human enzyme in a specific manner. Uracil, uridine, and glucose have a poor protective effect on the labeling, while UDP and UDP-glucose strongly inhibit photoinsertion
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additional information
-
inhibition of human UDP-glucose dehydrogenase expression using siRNA expression vector in breast cancer cells
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Michaelis-Menten kinetic, cooperative kinetic behavior occurs in the hexameric enzyme
-
0.0076
UDP-alpha-D-glucose
wild-type, K0.5 value, Hill coefficient 1, pH 7.5, 25°C
0.0094
UDP-alpha-D-glucose
mutant A104L, K0.5 value, Hill coefficient 1, pH 7.5, 25°C
0.015
UDP-alpha-D-glucose
pH 7.4, 37°C, recombinant His-tagged mutant T325D
0.034
UDP-alpha-D-glucose
pH 7.4, 37°C, recombinant His-tagged wild-type enzyme
0.048
UDP-alpha-D-glucose
pH 7.4, 37°C, recombinant His-tagged mutant T325A
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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increased UGDH expression in cancerous acini and decreased expression in normal-appearing acini of the same prostate relative to acini of non-cancerous prostates
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siRNA for the human enzyme is put into a pRNA-U6.1/Neo vector and chemically transfected into bresat cancer cells. The UGDH siRNA plasmid then knocks down UGDH expression in ZR-75-1 cells
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
physiological function
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UGDH oxidizes UDP-glucose to UDP-glucuronate, an essential precursor for production of hyaluronan, proteoglycans, and xenobiotic glucuronides. High levels of hyaluronan turnover in prostate cancer are correlated with aggressive progression. UGDH expression is high in the normal prostate even though hyaluronan accumulation is virtually undetectable. The enzyme's common role in the prostate may be to provide precursors for glucuronosyltransferase enzymes, which inactivate and solubilize androgens by glucuronidation. Androgen dependence of UGDH, glucuronosyltransferase, and hyaluronan synthase expression, overview
additional information
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dysregulated expression of UGDH can promote the development of androgen independent tumor cell growth by increasing available levels of intracellular androgen. UGDH activity is the rate limiting factor in solubilization of excess androgen from prostate tumor cells, overview
malfunction
mutant dimeric species of UGDH have reduced activity in vitro and in supporting hyaluronan production by cultured cells. The purified enzymes reveal a significant decrease in the enzymatic activity of the obligate dimer and hexamer mutants. Both T325A and T325D mutants were significantly less efficient in promoting downstream hyaluronan production by HEK293 cells
malfunction
UGDH specific siRNAs markedly inhibits UGDH mRNA and protein expression, and leads to an obvious suppression of proteoglycans synthesis in human articular chondrocytes. UGDH protein level in human osteoarthritis cartilage are much lower than the corresponding controls and negatively correlated to the degree of osteoarthritis. Interleukin-1beta inhibits UGDH gene expression through modulating UGDH transregulators and the downstream signaling cascades, including the SAP/JNK and p38 MAPK pathways which might be involved in the proteoglycans loss of osteoarthritis cartilage and contribute to the osteoarthritis pathogenesis
physiological function
enzyme displays hysteresis, observed as a lag in progress curves, and is sensitive to product inhibition during the lag. The inhibition results in a systematic decrease in steady-state velocity and makes the lag appear to have a second-order dependence on enzyme concentration.The lag is in fact due to a substrate and cofactor-induced isomerization of the enzyme. The cofactor binds to the enzyme:substrate complex with negative cooperativity, suggesting that the isomerization may be related to the formation of an asymmetric enzyme complex. The hysteresis may be the consequence of a functional adaptation, by slowing the response of the enzyme to sudden increases in the flux of substrate, the other biochemical pathways that use this important metabolite will have a competitive edge
physiological function
UDP-glucose dehydrogenase activity and optimal downstream cellular function require dynamic reorganization at the dimer-dimer subunit interfaces
physiological function
UGDH is essential in the proteoglycan synthesis in articular chondrocytes, overview. UDP-glucuronic acid is a key precursor for the synthesis of the glycosaminoglycan chain in proteoglycans
physiological function
epirubicin accumulation increases and apoptosis decreases during UGDH knockdown. Hyaluronan-coated matrix increases and a positive modulation of autophagy is detected. Higher levels of UGDH are correlated with worse prognosis in triple-negative breast cancer patients that receive chemotherapy. High expression of UGDH is found in tumoral tissue from HER2--patients. UGDH knockdown contributes to epirubicin resistance
physiological function
in breast cancer cells, depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. Depletion of UDP-glucuronic acid alters the expression of PPAR-gamma target genes and increases PPAR-gamma DNA binding activity
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). UGDH_HUMAN
494
0
55024
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
120000
gel filtration, mutant containing 4-benzoyl-L-phenylalanine at position 96
360000
gel filtration, mutant containing 4-benzoyl-L-phenylalanine at position 458
57000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hexamer
additional information
additional information
identification of amino acids I7 through T19 as NAD+ binding-site by photoaffinity labeling with nicotinamide 2-azidoadenosine dinucleotide
additional information
-
identification of amino acids I7 through T19 as NAD+ binding-site by photoaffinity labeling with nicotinamide 2-azidoadenosine dinucleotide
additional information
significant amount of dimeric and monomeric species can be detected
additional information
-
significant amount of dimeric and monomeric species can be detected
additional information
examination of the dimer-dimer subunit interface reveals an extensive network of charge interactions and hydrogen bonding that coordinately stabilize the hexamer in the presence and absence of its cofactor or substrate, involving residue T325. The wild-type UGDH enzyme purifies in a hexamer-dimer equilibrium and transiently undergoes dynamic motion that exposes the dimer-dimer interface during catalysis. Only dynamic UGDH hexamers support robust cellular function, mutant dimeric species of UGDH have reduced activity in vitro and in supporting hyaluronan production by cultured cells. Molecular interactions at the subunit interface, overview. In the apo form Thr325 directly forms a hydrogen bond with Asp105 of the opposite subunit
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
2.3 A resolution crystal structure of the deletion construct DELTA132 reveals an open conformation that relaxes steric constraints and facilitates repacking of the protein core. The open conformation stabilizes the deletion construct as a hexamer with point group symmetry 32, similar to that of the active complex. In contrast, the UDP-alpha-D-xylose-inhibited enzyme forms a lower-symmetry, horseshoe-shaped hexameric complex. The DELTA132 and the UDP-alpha-D-xylose-inhibited structures have similar hexamer-building interfaces
alternate crystal structure of human enzyme in complex with UDP-glucose at 2.8 A resolution. The substrate-bound protein complex consists of the open homohexamer. In all subunits of the open structure, residue Thr131 has translocated into the active site occupying the volume vacated by the absent active water and partially disordered NAD+ molecule. This conformation suggests a mechanism by which the enzyme may exchange NADH for NAD+ and repolarize the catalytic water molecule bound to Asp280 while protecting the reaction intermediates
in mutant E161Q, the hydrolysis step becomes completely rate-limiting so that a thioester enzyme intermediate accumulates at steady state. Crystallization of mutant E161Q in the presence of 5 mM UDP-glucose and 2 mM NAD results in trapping a thiohemiacetal enzyme intermediate. Residue Cys276 is covalently modified in the structure, establishing its role as catalytic nucleophile of the reaction
mutant A104L, structure reveals a reduced cavity C-1 volume. The allosteric switch still adopts the E and E* states, albeit with a more rigid protein core
mutant A136M at 2.05 A resolution, the A136M substitution has stabilized the active conformation of the T131-loop/alpha6 allosteric switch
mutant K94E, to 2.08 A resolution. Cofactor binding triggers the formation of the 32 symmetry hexamer, but substrate UDP-alpha-D-glucose is needed for the stability of the complex. Loop88-110 is the cofactor-responsive allosteric switch that drives hexamer formation, loop88-110 directly links cofactor binding to the stability of the hexamer-building interface. In the interface, loop88-110 packs against the Thr131-loop/alpha6 helix, the allosteric switch that responds to the feedback inhibitor UDP-alpha-D-xylose
the structure of UGDH in the crystal form reveals a hexameric arrangement, composed a trimer of dimers of six subunits
crystallized from a solution of 0.2 M ammonium sulfate, 0.1 M Na cacodylate, pH 6.5, and 21% PEG 8000. Diffraction data are collected to a resolution of 2.8 A. The crystals belong to the orthorhombic space group P2(1)2(1)2(1) with unit-cell parameters a = 173.25, b = 191.16, c = 225.94 A and alpha = beta = gamma = 90.0°
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A104L
ubstitution introduced to fill a cavity in the E state and sterically prevent repacking of the core into the inactive Eomega state. Mutant A104L does not show hysteresis or negative cooperativity, binds UDP-xylose with lower affinity and the inhibition is no longer cooperative
A136M
mutant does not exhibit substrate cooperativity. The inhibitor affinity of A136M is reduced 14fold and does not exhibit hysteresis. Substitution disrupts NAD+-induced negative cooperativity
A44V
mutation is the genetic cause of a developmental epileptic encephalopathy in a consanguineous Palestinian family with three affected siblings. The A44V variant is also found in two additional families from Puerto Rico and from Spain
C276S
DELTA132
deletion of residue Val132 from the Thr131 loop to approximate an intermediate state in the allosteric transition. The crystal structure of the deletion construct reveals an open conformation that relaxes steric constraints and facilitates repacking of the protein core. The open conformation stabilizes the construct as a hexamer with point group symmetry 32, similar to that of the active complex. The DELTA132 and UDP-alpha-D-xylose-inhibited structures have similar hexamer-building interfaces
E110A
site-directed mutagenesis, the mutant, although dimeric in the apo form, exhibits only about 50% reduction in Vmax, but is highly unstable in solution and in cultured cells so it cannot be evaluated unambiguously
E161Q
hydrolysis step becomes completely rate-limiting so that a thioester enzyme intermediate accumulates at steady state. Crystallization of E161Q in the presence of 5 mM UDP-glucose and 2 mM NAD results in trapping a thiohemiacetal enzyme intermediate
G13E
normal expression and stability of mutant, no enzymic activity, no photoaffinity labeling with nicotinamide 2-azidoadenosine dinucleotide
K220A
K279A
K94E
N224A
steady-state kinetic parameters are within an order of magnitude of the native enzyme
T131S
steady-state kinetic parameters are within an order of magnitude of the native enzyme
T325A
site-directed mutagenesis, the mutant occurs as dimeric species that can be induced to form hexamers in the ternary complex with substrate and cofactor. The inducible hexamer shows that upon increasing enzyme concentration, which favors the hexameric species, activity is modestly decreased and exhibits cooperativity. The T325A mutant is significantly less efficient in promoting downstream hyaluronan production by HEK293 cells than the wild-type. The activity of the T325A mutant is the most labile, with a half-life of only 24 h that is not extended significantly by substrate and cofactor addition
T325D
site-directed mutagenesis, the mutant yields exclusively dimeric species. The T325D mutant is significantly less efficient in promoting downstream hyaluronan production by HEK293 cells than the wild-type. UGDH T325D retains its activity similarly to the wild-type enzyme but does not exhibit increased stability in the abortive ternary complex
A222Q/S233G
-
mutation does not affect expression, stability, and secondary structure. Mutant protein is a dimer and catalytic active, with increased Km values for substrates
D280E
-
site-directed mutagenesis, 3-fold increase in Km for UDP-glucose and a 2-fold reduced Vmax relative to that of the wild type
D280N
K220A
-
site-directed mutagenesis, putative active site residue, mutation severly impairs enzyme function
K220H
-
site-directed mutagenesis, putative active site residue, mutation severly impairs enzyme function
K220R
-
site-directed mutagenesis, putative active site residue, mutation severly impairs enzyme function
K339A
-
site-directed mutagenesis, 165fold decrease in affinity for UDP-glucose. Mutant forms a dimer, in contrast to hexameric wild-type
additional information
C276S
no enzymic activity, affinity for NAD+ similar to wild-type, retains predominantly hexameric structure
K279A
no enzymic activity, affinity for NAD+ similar to wild-type, almost exclusively found as dimer
K94E
mutation in the hexamer-building interface, generates a stable enzyme dimer. 160fold decrease in kcat value
K94E
substitution prevents hexamer formation. Mutant does not display hysteresis
D280N
-
site-directed mutagenesis, putative active site residue, mutation severly impairs enzyme function
additional information
perturbation caused by the mutation of a residue at a considerably distant location from the oligomeric interfaces is preferentially distributed throughout specific sites, especially the large flexible regions in the hUGDH structure, thereby changing the motional fluctuation pattern at the oligomeric interfaces. A large-magnitude cooperative motion at the oligomeric interfaces is a critical factor in interfering with the hexamer formation of the enzyme. Structural stability at the dimeric interface is necessary to retain the hexameric structure of UGDH
additional information
-
perturbation caused by the mutation of a residue at a considerably distant location from the oligomeric interfaces is preferentially distributed throughout specific sites, especially the large flexible regions in the hUGDH structure, thereby changing the motional fluctuation pattern at the oligomeric interfaces. A large-magnitude cooperative motion at the oligomeric interfaces is a critical factor in interfering with the hexamer formation of the enzyme. Structural stability at the dimeric interface is necessary to retain the hexameric structure of UGDH
additional information
UDP-glucose dehydrogenase mutants are engineered to perturb hexamer:dimer quaternary structure equilibrium. Dimeric species of UGDH have reduced activity in vitro and in supporting hyaluronan production by cultured cells. The purified enzymes reveal a significant decrease in the enzymatic activity of the obligate dimer and hexamer mutants. The activity of the truncated DELTA132 mutant is negligible. The half-life of UGDH catalytic activity in vitro is reduced by mutations at the dimer interface
additional information
UGDH specific siRNAs markedly inhibits UGDH mRNA and protein expression, and leads to an obvious suppression of PGs synthesis in human articular chondrocytes
additional information
introduction of site-specific unnatural amino acids to facilitate crosslinking of monomeric subunits into predominantly obligate oligomeric species. Optimal crosslinking is achieved by encoding 4-benzoyl-L-phenylalanine at position 458, and exposing to long wavelength UV in the presence of substrate and cofactor. Purified hexameric complexes contain significant fractions of dimer and trimer (approximately 50%) along with another 10% tetramer and higher molecular mass species. Activity of the crosslinked enzyme is reduced by almost 60% relative to the uncrosslinked UGDH mutant
additional information
-
introduction of site-specific unnatural amino acids to facilitate crosslinking of monomeric subunits into predominantly obligate oligomeric species. Optimal crosslinking is achieved by encoding 4-benzoyl-L-phenylalanine at position 458, and exposing to long wavelength UV in the presence of substrate and cofactor. Purified hexameric complexes contain significant fractions of dimer and trimer (approximately 50%) along with another 10% tetramer and higher molecular mass species. Activity of the crosslinked enzyme is reduced by almost 60% relative to the uncrosslinked UGDH mutant
additional information
-
UGDH overexpression stimulates hyaluronan production in HEK293 cells
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
thermal stabilities of wild-type and mutant enzymes, overview
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
the half-life of UGDH catalytic activity in vitro is reduced by mutations at the dimer interface
wild-type UGDH is relatively stable to proteolysis in the apoenzyme form but is further stabilized by addition of NADH cofactor, UDP-glucose substrate, or a combination of the two to form a ternary enzyme complex
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His6-tagged wild-type and mutant enzymes from Escherichia coli strain Rosetta2(DE3)pLysS by nickel affinity chromatography and dialysis
recombinant His6-tagged UGDH from Escherichia coli by nickel affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
recombinant expression of N-terminally His6-tagged wild-type and mutant enzymes in Escherichia coli strain Rosetta2(DE3)pLysS, recombinant expression in HEK293 cells
hUGDH gene is cloned from a LNCaP cDNA library, from LNCaP C33 and C81 cells, expression of His6-tagged UGDH in Escherichia coli, expression of UGDH mutant D280N in HEK.293 cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression of UDP-glucose dehydrogenase is up-regulated in highly metastatic ovarian cancer TOV-21G cells
interleukin-1beta, IL-1beta, suppresses UGDH gene expression in human articular chondrocytes in the late phase, which also modulates gene expression of Sp1, Sp3 and c-Krox and increased both Sp3/Sp1 and c-Krox/Sp1 ratio. The inhibition of SAP/JNK and p38 MAPK pathways both result in an obvious attenuation of the IL-1beta-induced suppression on UGDH gene expression
dihydrotestosterone increases UGDH expression 2.5fold in androgen-dependent cells. However, upregulation of UGDH does not affect hyaluronan synthase expression or enhance hyaluronan production
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
synthesis
use of recombinant Triton-permeabilized cells of Schizosaccharomyces pombe to synthesize UDP-glucuronic acid with 100 % yield and selectivity. 5 mM UDP-glucose are converted into 5 mM UDP-glucuronic acid within 3 h
medicine
medicine
manipulation of UGDH activity by hexamer stabilization may offer therapeutic options in cancer and other pathologies
medicine
biallelic mutations in UGDH cause developmental epileptic encephalopathy. In 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia, mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors
medicine
epirubicin accumulation increases and apoptosis decreases during UGDH knockdown. Hyaluronan-coated matrix increases and a positive modulation of autophagy is detected. Higher levels of UGDH are correlated with worse prognosis in triple-negative breast cancer patients that receive chemotherapy. High expression of UGDH is found in tumoral tissue from HER2--patients. UGDH knockdown contributes to epirubicin resistance
medicine
expression of UDP-glucose dehydrogenase is up-regulated in highly metastatic ovarian cancer TOV-21G cells, but not in normal adjacent tissue. RNAi-mediated silencing results in a significant decrease in metastatic ability in transwell migration, transwell invasion and wound healing assays. The knockdown of UGDH causes cell cycle arrest in the G0/G1 phase and induces a massive decrease of tumour formation rate in vivo. UGDH-depletion leads to the down-regulation of epithelial-mesenchymal transition-related markers as well as MMP2, and inactivation of the ERK/MAPK pathway
medicine
high UGDH expression is associated with decreased patient survival in poor-prognosis breast cancer subsets
medicine
shRNA-mediated knockdown of UGDH inhibits breast cancer invasion, colony formation, and tumor growth
medicine
-
possibility that gallic acid and quercetin may modulate human breast cancer cell proliferation by inhibiting UGDH
medicine
-
UGDH content in prostatic acini is a novel candidate biomarker that may complement the development of a multi-biomarker panel for detecting prostate cancer within the tumor adjacent field on a histologically normal biopsy specimen
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Grubb, M.F.; Kasofsky, J.; Strong, J.; Anderson, L.W.; Cysyk, R.L.
Serum stimulation of UDP-glucose dehydrogenase activity in swiss 3T3 fibroblasts
Biochem. Mol. Biol. Int.
30
819-827
1993
Homo sapiens
Sommer, B.J.; Barycki, J.J.; Simpson, M.A.
Characterization of human UDP-glucose dehydrogenase. CYS-276 is required for the second of two successive oxidations
J. Biol. Chem.
279
23590-23596
2004
Homo sapiens (O60701), Homo sapiens
Huh, J.W.; Yoon, H.Y.; Lee, H.J.; Choi, W.B.; Yang, S.J.; Cho, S.W.
Importance of Gly-13 for the coenzyme binding of human UDP-glucose dehydrogenase
J. Biol. Chem.
279
37491-37498
2004
Homo sapiens (O60701), Homo sapiens
Huh, J.W.; Lee, H.J.; Choi, M.M.; Yang, S.J.; Yoon, S.Y.; Kim, D.W.; Kim, S.Y.; Choi, S.Y.; Cho, S.W.
Identification of a UDP-glucose-binding site of human UDP-glucose dehydrogenase by photoaffinity labeling and cassette mutagenesis
Bioconjug. Chem.
16
710-716
2005
Homo sapiens
Huh, J.W.; Choi, M.M.; Yang, S.J.; Yoon, S.Y.; Choi, S.Y.; Cho, S.W.
Inhibition of human UDP-glucose dehydrogenase expression using siRNA expression vector in breast cancer cells
Biotechnol. Lett.
27
1229-1232
2005
Homo sapiens
Huh, J.W.; Robinson, R.C.; Lee, H.S.; Lee, J.I.; Heo, Y.S.; Kim, H.T.; Lee, H.J.; Cho, S.W.; Choe, H.
Expression, purification, crystallization, and preliminary X-ray analysis of the human UDP-glucose dehydrogenase
Protein Pept. Lett.
13
859-862
2006
Homo sapiens
Easley, K.E.; Sommer, B.J.; Boanca, G.; Barycki, J.J.; Simpson, M.A.
Characterization of human UDP-glucose dehydrogenase reveals critical catalytic roles for lysine 220 and aspartate 280
Biochemistry
46
369-378
2007
Homo sapiens
Huh, J.W.; Yang, S.J.; Hwang, E.Y.; Choi, M.M.; Lee, H.J.; Kim, E.A.; Choi, S.Y.; Choi, J.; Hong, H.N.; Cho, S.W.
Alteration of the quaternary structure of human UDP-glucose dehydrogenase by a double mutation
J. Biochem. Mol. Biol.
40
690-696
2007
Homo sapiens
Lee, H.S.; Son, Y.J.; Chong, S.H.; Bae, J.Y.; Leem, C.H.; Jang, Y.J.; Choe, H.
Computational analysis of the quaternary structural changes induced by point mutations in human UDP-glucose dehydrogenase
Arch. Biochem. Biophys.
486
35-43
2009
Homo sapiens (O60701), Homo sapiens
Hwang, E.Y.; Huh, J.W.; Choi, M.M.; Choi, S.Y.; Hong, H.N.; Cho, S.W.
Inhibitory effects of gallic acid and quercetin on UDP-glucose dehydrogenase activity
FEBS Lett.
582
3793-3797
2008
Homo sapiens
Huang, D.; Casale, G.P.; Tian, J.; Lele, S.M.; Pisarev, V.M.; Simpson, M.A.; Hemstreet, G.P.
UDP-glucose dehydrogenase as a novel field-specific candidate biomarker of prostate cancer
Int. J. Cancer
126
315-327
2009
Homo sapiens
Wei, Q.; Galbenus, R.; Raza, A.; Cerny, R.L.; Simpson, M.A.
Androgen-stimulated UDP-glucose dehydrogenase expression limits prostate androgen availability without impacting hyaluronan levels
Cancer Res.
69
2332-2339
2009
Homo sapiens
Sennett, N.C.; Kadirvelraj, R.; Wood, Z.A.
Conformational flexibility in the allosteric regulation of human UDP-alpha-D-glucose 6-dehydrogenase
Biochemistry
50
9651-9663
2011
Homo sapiens (O60701)
Sennett, N.C.; Kadirvelraj, R.; Wood, Z.A.
Cofactor binding triggers a molecular switch to allosterically activate human UDP-alpha-D-glucose 6-dehydrogenase
Biochemistry
51
9364-9374
2012
Homo sapiens (O60701)
Kadirvelraj, R.; Sennett, N.C.; Custer, G.S.; Phillips, R.S.; Wood, Z.A.
Hysteresis and negative cooperativity in human UDP-glucose dehydrogenase
Biochemistry
52
1456-1465
2013
Homo sapiens (O60701), Homo sapiens
Egger, S.; Chaikuad, A.; Klimacek, M.; Kavanagh, K.L.; Oppermann, U.; Nidetzky, B.
Structural and kinetic evidence that catalytic reaction of human UDP-glucose 6-dehydrogenase involves covalent thiohemiacetal and thioester enzyme intermediates
J. Biol. Chem.
287
2119-2129
2012
Homo sapiens (O60701), Homo sapiens
Rajakannan, V.; Lee, H.S.; Chong, S.H.; Ryu, H.B.; Bae, J.Y.; Whang, E.Y.; Huh, J.W.; Cho, S.W.; Kang, L.W.; Choe, H.; Robinson, R.C.
Structural basis of cooperativity in human UDP-glucose dehydrogenase
PLoS ONE
6
e25226
2011
Homo sapiens (O60701), Homo sapiens
Wen, Y.; Li, J.; Wang, L.; Tie, K.; Magdalou, J.; Chen, L.; Wang, H.
UDP-glucose dehydrogenase modulates proteoglycan synthesis in articular chondrocytes: its possible involvement and regulation in osteoarthritis
Arthritis Res. Ther.
16
484-494
2014
Homo sapiens (O60701), Rattus norvegicus (O70199), Rattus norvegicus Wistar (O70199)
Hyde, A.S.; Thelen, A.M.; Barycki, J.J.; Simpson, M.A.
UDP-glucose dehydrogenase activity and optimal downstream cellular function require dynamic reorganization at the dimer-dimer subunit interfaces
J. Biol. Chem.
288
35049-35057
2013
Homo sapiens (O60701)
Grady, G.; Thelen, A.; Albers, J.; Ju, T.; Guo, J.; Barycki, J.J.; Simpson, M.A.
Inhibiting hexamer disassembly of human UDP-glucose dehydrogenase by photoactivated amino acid cross-linking
Biochemistry
55
3157-3164
2016
Homo sapiens (O60701), Homo sapiens
Beattie, N.; Keul, N.; Sidlo, A.; Wood, Z.
Allostery and hysteresis are coupled in human UDP-glucose dehydrogenase
Biochemistry
56
202-211
2017
Homo sapiens (O60701), Homo sapiens
Beattie, N.R.; Pioso, B.J.; Sidlo, A.M.; Keul, N.D.; Wood, Z.A.
Hysteresis and allostery in human UDP-glucose dehydrogenase require a flexible protein core
Biochemistry
57
6848-6859
2018
Homo sapiens (O60701), Homo sapiens
Vitale, D.L.; Caon, I.; Parnigoni, A.; Sevic, I.; Spinelli, F.M.; Icardi, A.; Passi, A.; Vigetti, D.; Alaniz, L.
Initial identification of UDP-glucose dehydrogenase as a prognostic marker in breast cancer patients, which facilitates epirubicin resistance and regulates hyaluronan synthesis in MDA-MB-231 cells
Biomolecules
11
246
2021
Homo sapiens (O60701), Homo sapiens
Weyler, C.; Bureik, M.; Heinzle, E.
Selective oxidation of UDP-glucose to UDP-glucuronic acid using permeabilized Schizosaccharomyces pombe expressing human UDP-glucose 6-dehydrogenase
Biotechnol. Lett.
38
477-481
2016
Homo sapiens (O60701), Homo sapiens
Teoh, S.T.; Ogrodzinski, M.P.; Lunt, S.Y.
UDP-glucose 6-dehydrogenase knockout impairs migration and decreases in vivo metastatic ability of breast cancer cells
Cancer Lett.
492
21-30
2020
Homo sapiens (O60701), Mus musculus (O70475), Mus musculus
Lin, L.H.; Chou, H.C.; Chang, S.J.; Liao, E.C.; Tsai, Y.T.; Wei, Y.S.; Chen, H.Y.; Lin, M.W.; Wang, Y.S.; Chien, Y.A.; Yu, X.R.; Chan, H.L.
Targeting UDP-glucose dehydrogenase inhibits ovarian cancer growth and metastasis
J. Cell. Mol. Med.
24
11883-11902
2020
Homo sapiens (O60701), Homo sapiens
Scoglio, S.; Lo Curcio, V.; Catalani, S.; Palma, F.; Battistelli, S.; Benedetti, S.
Inhibitory effects of Aphanizomenon flos-aquae constituents on human UDP-glucose dehydrogenase activity
J. Enzyme Inhib. Med. Chem.
31
1492-1497
2016
Homo sapiens (O60701), Homo sapiens
Hengel, H.; Bosso-Lefevre, C.; Grady, G.; Szenker-Ravi, E.; Li, H.; Pierce, S.; Lebigot, E.; Tan, T.T.; Eio, M.Y.; Narayanan, G.; Utami, K.H.; Yau, M.; Handal, N.; Deigendesch, W.; Keimer, R.; Marzouqa, H.M.; Gunay-Aygun, M.; Muriello, M.J.; Verhelst, H.; Weckhuysen, S.; Mahida, S.; Naidu, S.; Thomas, T.G.
Loss-of-function mutations in UDP-glucose 6-dehydrogenase cause recessive developmental epileptic encephalopathy
Nat. Commun.
11
595
2020
Danio rerio (A8WGP7), Danio rerio, Homo sapiens (O60701), Homo sapiens
Arnold, J.M.; Gu, F.; Ambati, C.R.; Rasaily, U.; Ramirez-Pena, E.; Joseph, R.; Manikkam, M.; San Martin, R.; Charles, C.; Pan, Y.; Chatterjee, S.S.; Den Hollander, P.; Zhang, W.; Nagi, C.; Sikora, A.G.; Rowley, D.; Putluri, N.; Zhang, X.H.; Karanam, B.; Mani, S.A.; Sreekumar, A.
UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression
Oncogene
39
3089-3101
2020
Homo sapiens (O60701), Homo sapiens
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