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Information on EC 2.4.1.212 - hyaluronan synthase and Organism(s) Homo sapiens and UniProt Accession Q92839

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EC Tree
     2 Transferases
         2.4 Glycosyltransferases
             2.4.1 Hexosyltransferases
                2.4.1.212 hyaluronan synthase
IUBMB Comments
The enzyme from Streptococcus Group A and Group C requires Mg2+. The enzyme adds GlcNAc to nascent hyaluronan when the non-reducing end is GlcA, but it adds GlcA when the non-reducing end is GlcNAc . The enzyme is highly specific for UDP-GlcNAc and UDP-GlcA; no copolymerization is observed if either is replaced by UDP-Glc, UDP-Gal, UDP-GalNAc or UDP-GalA. Similar enzymes have been found in a variety of organisms.
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Homo sapiens
UNIPROT: Q92839
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
hyaluronan synthase, ha synthase, hyaluronan synthase 2, has-2, hyaluronic acid synthase, sehas, has-1, pmhas, hyaluronan synthase-2, hyaluronate synthase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hyaluronan synthase
-
hyaluronan synthase 1
-
CHAS2
-
-
-
-
CHAS3
-
-
-
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DG42 protein
-
-
-
-
HA synthase
HsHAS1
-
-
HuHAS1
-
-
-
-
hyaluronan synthase
hyaluronan synthase 1
-
-
hyaluronan synthase 2
hyaluronan synthase 3
hyaluronan synthase-2
-
hyaluronan synthases 2
-
hyaluronan synthethase
-
-
-
-
hyaluronate synthase
-
-
-
-
hyaluronate synthetase
-
-
-
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hyaluronic acid synthase
-
-
-
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hyaluronic acid synthetase
-
-
-
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XHAS1
-
-
-
-
XHAS2
-
-
-
-
XHAS3
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hexosyl group transfer
-
hexosyl group transfer
SYSTEMATIC NAME
IUBMB Comments
Alternating UDP-alpha-N-acetyl-D-glucosamine:beta-D-glucuronosyl-(1->3)-[nascent hyaluronan] 4-N-acetyl-beta-D-glucosaminyltransferase and UDP-alpha-D-glucuronate:N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan] 3-beta-D-glucuronosyltransferase
The enzyme from Streptococcus Group A and Group C requires Mg2+. The enzyme adds GlcNAc to nascent hyaluronan when the non-reducing end is GlcA, but it adds GlcA when the non-reducing end is GlcNAc [3]. The enzyme is highly specific for UDP-GlcNAc and UDP-GlcA; no copolymerization is observed if either is replaced by UDP-Glc, UDP-Gal, UDP-GalNAc or UDP-GalA. Similar enzymes have been found in a variety of organisms.
CAS REGISTRY NUMBER
COMMENTARY hide
39346-43-5
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
show the reaction diagram
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
show the reaction diagram
-
-
-
?
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
show the reaction diagram
UDP-D-glucosamine + UDP-D-glucuronate
[beta-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + n UDP
show the reaction diagram
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
show the reaction diagram
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
show the reaction diagram
-
-
-
?
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
show the reaction diagram
-
-
-
?
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
show the reaction diagram
-
-
-
?
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1-4)-beta-D-glucuronosyl-(1-3)-N-acetyl-beta-D-glucosaminyl-(1-4)-[nascent hyaluronan]
show the reaction diagram
UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
show the reaction diagram
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
the enzyme requires Mg2+ or Mn2+ for activity
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4-Methylumbelliferone
inhibits HAS because it depletes UDPGlcUA in cells
AG825
ErbB2 inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation
mannose
inhibits HAS because it depletes UDP-GlcNAc in cells
thiazolidinedione
ERK inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation
2-deoxyglucose
-
4-Methylumbelliferone
5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside
modulates aortic smooth muscle cell motility and adhesive properties through AMP-activated protein kinase, AMPK
AG825
ErbB2 inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation
brefeldin A
-
-
HAS1 siRNA
-
-
-
mannose
inhibits HAS because it depletes UDP-GlcNAc in cells
metformin
modulates aortic smooth muscle cell motility and adhesive properties through AMP-activated protein kinase, AMPK
sodium salicylate
-
sodium salicylate is a potent suppressor of HAS1 activation
thiazolidinedione
ERK inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ERK
heregulin-mediated HAS isozyme phosphorylation/activation
-
black rice hydrolized peptides
BRP from germinated Oryza sativa L. var. japonica
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carbocyclic thromboxane A2
-
-
Epidermal growth factor
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EGF
Epstein-Barr virus
-
-
-
ERK
heregulin-mediated HAS isozyme phosphorylation/activation
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interleukin 1beta
-
activation of enzyme in plasma membrane fraction
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interleukin-1beta
-
-
-
O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate
-
increases O-GlcNAcylation and HA synthesis
phorbol 12-myristate 13-acetate
-
activation of enzyme in plasma membrane fraction
pinane thromboxane A2
-
-
platelet derived growth factor BB
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PDGF-BB
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platelet-derived growth factor BB
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activation of enzyme in plasma membrane fraction
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prostaglandin E2
-
-
prostaglandin I2
-
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synthetic single-stranded poly(A)
-
-
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synthetic single-stranded poly(C)
-
-
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synthetic viral RNA analog poly(I,C)
-
-
-
Transforming growth factor
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TGF-1beta
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transforming growth factor-beta1
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TGF-beta1
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tunicamycin
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significant increase in HAS activity in the cytosolic membrane fraction after tunicamycin treatment
UVB irradiation
-
additional information
-
HAS2 can be O-GlcNAcylated on serine 221, which strongly increases its activity and its stability to half-life of over 5 h versus 17 min without O-GlcNAcylation
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
availability of substrate UDP-GlcNAc does not considerably influence the Km of Has1 toward UDP-GlcUA, whereas levels of UDP-GlcUA have a significant effect of the Km toward UDP-GlcNAc
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0000000062
HAS activity, HAS1siRNA + HAS2siRNA + HAS3siRNA treatment, plus heregulin
0.0000000092
HAS activity, HAS1siRNA + HAS2siRNA + HAS3siRNA treatment
0.000000017
HAS activity, HAS2siRNA treatment
0.0000000175
HAS activity, HAS1siRNA treatment
0.0000000188
HAS activity, HAS3siRNA treatment
0.0000000222
HAS activity, AG825 treatment
0.0000000227
HAS activity, HAS2siRNA treatment, plus heregulin
0.000000023
HAS activity, thiazolidinedione treatment
0.0000000233
HAS activity, no treatment, control
0.0000000237
HAS activity, scrambled sequence treatment, control
0.0000000248
HAS activity, HAS1siRNA treatment, plus heregulin
0.000000025
HAS activity, HAS3siRNA treatment, plus heregulin
0.0000000257
HAS activity, AG825 treatment, plus heregulin
0.0000000263
HAS activity, thiazolidinedione treatment, plus heregulin
0.0000000583
HAS activity, scrambled sequence treatment, control, plus heregulin
0.0000000627
HAS activity, no treatment, control, plus heregulin
0.0000000062
HAS activity, HAS1siRNA + HAS2siRNA + HAS3siRNA treatment, plus heregulin
0.0000000092
HAS activity, HAS1siRNA + HAS2siRNA + HAS3siRNA treatment
0.000000017
HAS activity, HAS2siRNA treatment
0.0000000175
HAS activity, HAS1siRNA treatment
0.0000000188
HAS activity, HAS3siRNA treatment
0.0000000222
HAS activity, AG825 treatment
0.0000000227
HAS activity, HAS2siRNA treatment, plus heregulin
0.000000023
HAS activity, thiazolidinedione treatment
0.0000000233
HAS activity, no treatment, control
0.0000000237
HAS activity, scrambled sequence treatment, control
0.0000000248
HAS activity, HAS1siRNA treatment, plus heregulin
0.000000025
HAS activity, HAS3siRNA treatment, plus heregulin
0.0000000257
HAS activity, AG825 treatment, plus heregulin
0.0000000263
HAS activity, thiazolidinedione treatment, plus heregulin
0.0000000583
HAS activity, scrambled sequence treatment, control, plus heregulin
0.0000000627
HAS activity, no treatment, control, plus heregulin
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5
-
HAS capture assay
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
HAS capture assay, overnight at room temperature
60
-
HAS capture assay, 3 h
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
expression of HAS1 splice variants is absent from B cells of healthy donors and in multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS) is restricted to the B-cell compartment
Manually annotated by BRENDA team
SKOV-3.ipl cell, the cell line is established from ascites that developed in a nu/nu mouse given an intraperitoneal injection of SK-OV-3 human ovarian carcinoma cell line
Manually annotated by BRENDA team
-
cell line
Manually annotated by BRENDA team
MDA-MB-231 and Hs-578T breast cancer cell line express higher levels of HAS2 mRNA and synthesize higher amounts of HA than breast cancer cell lines with a less aggressive phenotype, like MCF-7
Manually annotated by BRENDA team
MDA-MB-231 and Hs-578T breast cancer cell line express higher levels of HAS2 mRNA and synthesize higher amounts of HA than breast cancer cell lines with a less aggressive phenotype, like MCF-7. HAS2 is dramatically increased in bone metastases compared to the parental MDA-MB-231 cells
Manually annotated by BRENDA team
serous epithelial ovarian tumor
Manually annotated by BRENDA team
serous epithelial ovarian tumor
Manually annotated by BRENDA team
serous epithelial ovarian tumor
Manually annotated by BRENDA team
platelet-derived growth factor BB exerts dominant influence on HAS2 isoform expression by osteoblasts
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
35 endometrial tissue biopsies from 35 patients, including proliferative and secretory endometrium, post-menopausal proliferative endometrium, complex atypical hyperplasia, grade 1 and grade 2 + 3 endometrioid adenocarcinomas. Immunoreactivity of all HAS proteins is increased in the cancer epithelium
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
malfunction
metabolism
physiological function
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
HYAS1_HUMAN
578
7
64832
Swiss-Prot
Secretory Pathway (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
62000
determined by SDS-PAGE and Western Blot analysis
60000
determined by SDS-PAGE and Western Blot analysis
66000
-
gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
ERK-mediated phosphorylation
glycoprotein
-
HAS activity can be modulated by post-translational modification, such as phosphorylation and N-glycosylation
phosphoprotein
ubiquitination
the enzyme is regulated by post-translational modifications, including ubiquitination. The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function
additional information
-
HAS2 can be O-GlcNAcylated on serine 221, which strongly increases its activity and its stability to half-life of over 5 h versus 17 min without O-GlcNAcylation
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
S221A
-
site-directed mutation of the O-GlcNAcylable Ser-221 to alanine generated an enzyme with a calculated t1/2 of about 70 min
T110A
site-directed mutagenesis of the phosphorylation site residue, the mutant is not inhibited by AMP-activated protein kinase
additional information
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
HAS2 can be O-GlcNAcylated on serine 221, which strongly increases its activity and its stability to half-life of over 5 h versus 17 min without O-GlcNAcylation
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C, Na-phosphate buffer, 10% glycerol, 96 h, 18%
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
partial
-
recombinant isozymes by immunoaffinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene HAS1, expression analysis and recombinant expression in COS-1 cells
gene HAS1, in addition to the full-length form, HAS1 has multiple transcript variants resulting from alternative splicing
a plasmid encoding FLAG epitope-tagged HAS3 for transfection of human prostate tumor cells is constructed, Tet-inducible 22Rv1 cells are generated
-
DNA and amino acid sequence determination and analysis, chromosome mapping of isozymes HAS1-3, genetic organization
-
expression in COS-7 cells
expression of isozyme HAS2-MBP-fusion protein in Escherichia coli strain JM109
-
expression of wild-type FLAG-tagged human HAS1, HAS2, or HAS3, and of HAS T110A mutant enzyme in COS-7 cells
gene HAS1, recombinant expression of GFP-tagged isozyme HAS1 in MCF-7 cells, MCF-7 cells transfected with Dendra-Has1 show intense fluorescence in perinuclear vesicular structures resembling the Golgi apparatus. The MCF-7 cells transfected with EGFP-Has1 produce a pericellular hyaluronan coat, which is attached the synthase itself
-
gene HAS2, expression analysis and recombinant expression in COS-1 cells
gene HAS3, expression analysis and recombinant expression in COS-1 cells
genes HAS1, HAS2 and HAS3, quantitative expression analysis in benign and malign endometrial tissue
-
Homo sapiens hyaluronan synthase 1 is cloned into the plasmid pFLAG-CMV2, for in vitro translation the pF3A WG(BYDV) Flexi vector is used
-
isozyme HAS3 inducible overexpression in MV3/C8161 cells. EGFP-HAS3 overexpression rapidly induced pericellular hyaluronan coat formation and plasma membrane protrusions, induction by doxycycline
-
stable expression of N-terminally Myc-tagged human HAS2 in NIH3T3 cells membranes, the molecular mechanism that underlies the rapid c-Myc-HAS2 turnover involves the 26 S proteasome, overview
-
the coding sequence of HAS1 is cloned into the vector pCR3.1 for transfection of fibroblasts
-
the human HAS2 expression plasmid is prepared by inserting its coding sequence into the vector pcDNA 3.1/CT-GFP-TOPO
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
basic fibroblast growth factor bFGF increases HA-synthase-1 and -2 expression and enhances high molecular weight hyaluronan deposition in the pericellular matrix
both tumor necrosis factor TNFalpha and transforming growth factor 1beta significantly increase HAS1 expression and protein synthesis. Exposure to reactive oxygen species results in increased gene expression and protein formation of HAS1
chondroitin sulfate increases hyaluronan production by osteoarthritic fibroblast-like synoviocytes through up-regulation of the expression of HAS1 and HAS2 associated with activation of ERK-1/2, p38, and Akt, although to a lesser extent. Both p38 and Akt are involved in chondroitin sulfate-induced hyaluronan accumulation. IL-1 increases hyaluronan production and levels of mRNA for HAS1, HAS2, and HAS3. Chondroitin sulfate enhances the IL-1induced level of HAS2 mRNA and reduces the level of HAS3 mRNA. IL-1induced activation of p38 and JNK is slightly decreased by chondroitin sulfate, whereas that of ERK-1/2 and Akt is enhanced. More high molecular weight hyaluronan is found in chondroitin sulfate plus IL-1treated fibroblast-like synoviocytes than in fibroblast-like synoviocytes treated with IL-1 alone
comparison of full-length HAS1 isoform and its splice variants Va, Vb, and Vc. When co-expressed, the properties of HAS1 variants are dominant over those of full length HAS1. Full length HAS1 appears to be diffusely expressed in the cell, but HAS1 variants are concentrated in the cytoplasm and/or Golgi apparatus. HAS1 variants synthesize detectable de novo hyaluronan intracellularly. Each of the HAS1 variants is able to relocalize full length HAS1 protein from diffuse cytoskeleton-anchored locations to deeper cytoplasmic spaces. The HAS1-variants-mediated relocalization occurs through strong molecular interactions, which also serve to protect full length HAS1 from its otherwise high turnover kinetics
Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. The enzyme expression is increased in transcriptional regulation by factors EGF, FGF2, FGF, forskolin, IGF, IL-1beta, PDGF, progesterone, prostaglandin D2, prostaglandin E2, and TGF-beta
the enzyme expression is decreased in transcriptional regulation by estradiol, 4-methylumbelliferone, and TGF-beta1
a cytokine-and glucose-inducible enzyme
-
both tumor necrosis factor TNFalpha and interferon INFgamma significantly induce HAS3 expression
both tumor necrosis factor TNFalpha and transforming growth factor 1beta significantly increase HAS2 expression and protein synthesis. Exposure to reactive oxygen species results in increased gene expression and protein formation of HAS2
chondroitin sulfate increases hyaluronan production by osteoarthritic fibroblast-like synoviocytes through up-regulation of the expression of HAS1 and HAS2 associated with activation of ERK-1/2, p38, and Akt, although to a lesser extent. Both p38 and Akt are involved in chondroitin sulfate-induced hyaluronan accumulation. IL-1 increases hyaluronan production and levels of mRNA for HAS1, HAS2, and HAS3. Chondroitin sulfate enhances the IL-1induced level of HAS2 mRNA and reduces the level of HAS3 mRNA. IL-1induced activation of p38 and JNK is slightly decreased by chondroitin sulfate, whereas that of ERK-1/2 and Akt is enhanced. More high molecular weight hyaluronan is found in chondroitin sulfate plus IL-1treated fibroblast-like synoviocytes than in fibroblast-like synoviocytes treated with IL-1 alone
doxycycline treatment causes a strong upregulation of HAS3 expression. A distinct EGFP-HAS3 signal is observed already 2 h after starting the doxycycline induction, localized mainly at the plasma membrane and in the Golgi area. After 24 h induction EGFP-HAS3 signal has become more intense, localizing strongly at the Golgi area and at the plasma membrane
-
HAS2 is the major isoenzyme in MCF-7 cells. The mRNA expression is lowered by 4-methylumbelliferone by 81% in MCF-7 cells, and by 88% in A2058 cells. Both HAS substrate and HAS2 and/or HAS3 mRNA are targeted by 4-methylumbelliferone. The reduction of hyaluronan caused by 4-methylumbelliferone is associated with a significant inhibition of cell migration, proliferation and invasion
histamine increases hyaluronan degradation by up-regulating HYBID (hyaluronan-binding protein) and down-regulating hyaluronan synthase 2 in human skin fibroblasts in a dose- and time-dependent manner and thereby decreases the total amounts and sizes of newly produced hyaluronan
hyaluronan synthase 2 expression is elevated in both human and murine liver fibrosis. The enzyme is transcriptionally up-regulated by transforming growth factor-beta through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4, and newly identified downstream effector Notch1
in MDA-MB-361, A2058 and SKOV-3 cells, treatment with 4-methylumbelliferone decreases HAS3 mRNA by 84-60%. The reduction of hyaluronan caused by 4-methylumbelliferone is associated with a significant inhibition of cell migration, proliferation and invasion
isoform HAS2 is a primary target of the cAMP activator forskolin and the nuclear hormone alltrans-retinoic acid. Forskolin and all-trans-retinoic acid modulate the formation of complexes between transcription factor CREB1 and retinoic acid receptor with various co-regulators at the predicted sites.Mediator MED1 and co-repressor nuclear receptor co-repressor NCoR1 are central for the all-trans-retinoic acid induction of the HAS2 gene and CREB-binding protein CBP dominates its forskolin response
MDAMB-231 and HS578T breast cancer cell line express higher levels of hyaluronan synthase 2 mRNA and synthesize higher amounts of hyaluronan than breast cancer cell lines with a less aggressive phenotype, like MCF-7
transforming grwoth factor 1beta significantly inhibits HAS3 expression and protein formation
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
analysis
-
quantification of newly synthesized hyaluronan by polyacrylamide gel electrophoresis of fluorophore-labeled saccharides and high performance liquid chromatography. The method measures HAS activity in the plasma membrane fraction and also in the cytosolic membranes. The technique is used to evaluate the effects of 4-methylumbeliferone, phorbol 12-myristate 13-acetate, interleukin 1, platelet-derived growth factor BB, and tunicamycin on HAS activities
biotechnology
-
optimization of the recombinant enzyme expression in Escherichia coli for large scale production of hyaluronan polymers for usage in basic studies, and for biotechnological creation of functional carbohydrates in medical purposes, engineering of produced product chain length
drug development
the enzyme actively synthesizes hyaluronan in hepatic stellate cells and promotes hepatic stellate cells activation and liver fibrosis through Notch1. Targeted hyaluronan inhibition may have potential to be an effective therapy for liver fibrosis
medicine
synthesis
-
optimization of the recombinant enzyme expression in Escherichia coli for large scale production of hyaluronan polymers for usage in basic studies, and for biotechnological creation of functional carbohydrates in medical purposes, engineering of produced product chain length
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Asplund, T.; Brinck, J.; Suzuki, M.; Briskin, M.J.; Heldin, P.
Characterization of hyaluronan synthase from a human glioma cell line
Biochim. Biophys. Acta
1380
377-388
1998
Homo sapiens
Manually annotated by BRENDA team
Sayo, T.; Sugiyama, Y.; Takahashi, Y.; Ozawa, N.; Sakai, S.; Ishikawa, O.; Tamura, M.; Inoue, S.
Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes
J. Invest. Dermatol.
118
43-48
2002
Homo sapiens
Manually annotated by BRENDA team
Itano, N.; Kimata, K.
Mammalian hyaluronan synthases
IUBMB Life
54
195-199
2002
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Hoshi, H.; Nakagawa, H.; Nishiguchi, S.; Iwata, K.; Niikura, K.; Monde, K.; Nishimura, S.
An engineered hyaluronan synthase: characterization for recombinant human hyaluronan synthase 2 Escherichia coli
J. Biol. Chem.
279
2341-2349
2004
Homo sapiens
Manually annotated by BRENDA team
Goentzel, B.J.; Weigel, P.H.; Steinberg, R.A.
Recombinant human hyaluronan synthase 3 is phosphorylated in mammalian cells
Biochem. J.
396
347-354
2006
Homo sapiens (O00219), Homo sapiens
Manually annotated by BRENDA team
Adamia, S.; Reiman, T.; Crainie, M.; Mant, M.J.; Belch, A.R.; Pilarski, L.M.
Intronic splicing of hyaluronan synthase 1 (HAS1): a biologically relevant indicator of poor outcome in multiple myeloma
Blood
105
4836-4844
2005
Homo sapiens (Q92839), Homo sapiens
Manually annotated by BRENDA team
Nishida, Y.; Knudson, W.; Knudson, C.B.; Ishiguro, N.
Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity
Exp. Cell Res.
307
194-203
2005
Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team
Nikitovic, D.; Zafiropoulos, A.; Katonis, P.; Tsatsakis, A.; Theocharis, A.D.; Karamanos, N.K.; Tzanakakis, G.N.
Transforming growth factor-beta as a key molecule triggering the expression of versican isoforms v0 and v1, hyaluronan synthase-2 and synthesis of hyaluronan in malignant osteosarcoma cells
IUBMB Life
58
47-53
2006
Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team
Adams, J.R.; Sander, G.; Byers, S.
Expression of hyaluronan synthases and hyaluronidases in the MG63 osteoblast cell line
Matrix Biol.
25
40-46
2006
Homo sapiens (O00219), Homo sapiens (Q92819)
Manually annotated by BRENDA team
Kyossev, Z.; Weigel, P.H.
An enzyme capture assay for analysis of active hyaluronan synthases
Anal. Biochem.
371
62-70
2007
Homo sapiens, Streptococcus dysgalactiae subsp. equisimilis
Manually annotated by BRENDA team
Kakizaki, I.; Itano, N.; Kimata, K.; Hanada, K.; Kon, A.; Yamaguchi, M.; Takahashi, T.; Takagaki, K.
Up-regulation of hyaluronan synthase genes in cultured human epidermal keratinocytes by UVB irradiation
Arch. Biochem. Biophys.
471
85-93
2008
Homo sapiens
Manually annotated by BRENDA team
Li, L.; Asteriou, T.; Bernert, B.; Heldin, C.H.; Heldin, P.
Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB
Biochem. J.
404
327-336
2007
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Campo, G.M.; Avenoso, A.; Campo, S.; DAscola, A.; Ferlazzo, A.M.; Calatroni, A.
Differential effect of growth factors on hyaluronan synthase gene expression in fibroblasts exposed to oxidative stress
Biochemistry
72
974-982
2007
Homo sapiens
Manually annotated by BRENDA team
Stuhlmeier, K.M.
Prostaglandin E2: A potent activator of hyaluronan synthase 1 in type-B-synoviocytes
Biochim. Biophys. Acta
1770
121-129
2007
Homo sapiens
Manually annotated by BRENDA team
Bourguignon, L.Y.; Gilad, E.; Peyrollier, K.
Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration
J. Biol. Chem.
282
19426-19441
2007
Homo sapiens (Q92819), Homo sapiens (Q92839), Homo sapiens (Q96RV2), Homo sapiens
Manually annotated by BRENDA team
Bharadwaj, A.G.; Rector, K.; Simpson, M.A.
Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis
J. Biol. Chem.
282
20561-20572
2007
Homo sapiens
Manually annotated by BRENDA team
Meran, S.; Thomas, D.; Stephens, P.; Martin, J.; Bowen, T.; Phillips, A.; Steadman, R.
Involvement of hyaluronan in regulation of fibroblast phenotype
J. Biol. Chem.
282
25687-25697
2007
Homo sapiens
Manually annotated by BRENDA team
Stuhlmeier, K.M.
Hyaluronan production in synoviocytes as a consequence of viral infections: HAS1 activation by Epstein-Barr virus and synthetic double- and single-stranded viral RNA analogs
J. Biol. Chem.
283
16781-16789
2008
Homo sapiens
Manually annotated by BRENDA team
Sim, G.S.; Lee, D.H.; Kim, J.H.; An, S.K.; Choe, T.B.; Kwon, T.J.; Pyo, H.B.; Lee, B.C.
Black rice (Oryza sativa L. var. japonica) hydrolyzed peptides induce expression of hyaluronan synthase 2 gene in HaCaT keratinocytes
J. Microbiol. Biotechnol.
17
271-279
2007
Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team
David-Raoudi, M.; Deschrevel, B.; Leclercq, S.; Galera, P.; Boumediene, K.; Pujol, J.P.
Chondroitin sulfate increases hyaluronan production by human synoviocytes through differential regulation of hyaluronan synthases: Role of p38 and Akt
Arthritis Rheum.
60
760-770
2009
Homo sapiens (O00219), Homo sapiens (Q92819), Homo sapiens (Q92839), Homo sapiens
Manually annotated by BRENDA team
Berdiaki, A.; Nikitovic, D.; Tsatsakis, A.; Katonis, P.; Karamanos, N.K.; Tzanakakis, G.N.
bFGF induces changes in hyaluronan synthase and hyaluronidase isoform expression and modulates the migration capacity of fibrosarcoma cells
Biochim. Biophys. Acta
1790
1258-1265
2009
Homo sapiens (Q92839)
Manually annotated by BRENDA team
Adamia, S.; Reichert, A.A.; Kuppusamy, H.; Kriangkum, J.; Ghosh, A.; Hodges, J.J.; Pilarski, P.M.; Treon, S.P.; Mant, M.J.; Reiman, T.; Belch, A.R.; Pilarski, L.M.
Inherited and acquired variations in the hyaluronan synthase 1 (HAS1) gene may contribute to disease progression in multiple myeloma and Waldenstrom macroglobulinemia
Blood
112
5111-5121
2008
Homo sapiens (Q92839), Homo sapiens
Manually annotated by BRENDA team
Nykopp, T.; Rilla, K.; Sironen, R.; Tammi, M.; Tammi, R.; Hmlinen, K.; Heikkinen, A.; Komulainen, M.; Kosma, V.; Anttila, M.
Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: Inverse correlation between HYAL1 and hyaluronan content
BMC Cancer
9
143
2009
Homo sapiens (O00219), Homo sapiens (Q92819)
Manually annotated by BRENDA team
Campo, G.M.; Avenoso, A.; Campo, S.; DAscola, A.; Traina, P.; Calatroni, A.
Effect of cytokines on hyaluronan synthase activity and response to oxidative stress by fibroblasts
Br. J. Biomed. Sci.
66
28-36
2009
Homo sapiens (O00219), Homo sapiens (Q92819), Homo sapiens (Q92839)
Manually annotated by BRENDA team
Kultti, A.; Pasonen-Seppaenen, S.; Jauhiainen, M.; Rilla, K.J.; Kaernae, R.; Pyoeriae, E.; Tammi, R.H.; Tammi, M.I.
4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3
Exp. Cell Res.
315
1914-1923
2009
Homo sapiens (O00219), Homo sapiens (Q92819)
Manually annotated by BRENDA team
Makkonen, K.M.; Pasonen-Seppaenen, S.; Toerroenen, K.; Tammi, M.I.; Carlberg, C.
Regulation of the hyaluronan synthase 2 gene by convergence in cyclic AMP response element-binding protein and retinoid acid receptor signaling
J. Biol. Chem.
284
18270-18281
2009
Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team
Ghosh, A.; Kuppusamy, H.; Pilarski, L.M.
Aberrant splice variants of HAS1 (hyaluronan synthase 1) multimerize with and modulate normally spliced HAS1 protein: a potential mechanism promoting human cancer
J. Biol. Chem.
284
18840-18850
2009
Homo sapiens (Q92839), Homo sapiens
Manually annotated by BRENDA team
Vigetti, D.; Genasetti, A.; Karousou, E.; Viola, M.; Clerici, M.; Bartolini, B.; Moretto, P.; De Luca, G.; Hascall, V.C.; Passi, A.
Modulation of hyaluronan synthase activity in cellular membrane fractions
J. Biol. Chem.
284
30684-30694
2009
Homo sapiens
Manually annotated by BRENDA team
Dunn, K.M.; Lee, P.K.; Wilson, C.M.; Iida, J.; Wasiluk, K.R.; Hugger, M.; McCarthy, J.B.
Inhibition of hyaluronan synthases decreases matrix metalloproteinase-7 (MMP-7) expression and activity
Surgery
145
322-329
2009
Homo sapiens (O00219), Homo sapiens (Q92819)
Manually annotated by BRENDA team
Nykopp, T.K.; Rilla, K.; Tammi, M.I.; Tammi, R.H.; Sironen, R.; Haemaelaeinen, K.; Kosma, V.M.; Heinonen, S.; Anttila, M.
Hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in the accumulation of hyaluronan in endometrioid endometrial carcinoma
BMC Cancer
10
512
2010
Homo sapiens
Manually annotated by BRENDA team
Vigetti, D.; Clerici, M.; Deleonibus, S.; Karousou, E.; Viola, M.; Moretto, P.; Heldin, P.; Hascall, V.C.; De Luca, G.; Passi, A.
Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells
J. Biol. Chem.
286
7917-7924
2011
Homo sapiens (Q92819)
Manually annotated by BRENDA team
Vigetti, D.; Deleonibus, S.; Moretto, P.; Karousou, E.; Viola, M.; Bartolini, B.; Hascall, V.C.; Tammi, M.; De Luca, G.; Passi, A.
Role of UDP-N-acetylglucosamine (GlcNAc) and O-GlcNAcylation of hyaluronan synthase 2 in the control of chondroitin sulfate and hyaluronan synthesis
J. Biol. Chem.
287
35544-35555
2012
Homo sapiens
Manually annotated by BRENDA team
Rilla, K.; Oikari, S.; Jokela, T.A.; Hyttinen, J.M.; Kaernae, R.; Tammi, R.H.; Tammi, M.I.
Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3
J. Biol. Chem.
288
5973-5983
2013
Homo sapiens (O00219), Homo sapiens (Q92819), Homo sapiens (Q92839), Homo sapiens
Manually annotated by BRENDA team
Pure, E.; Krolikoski, M.; Monslow, J.
Role for hyaluronan synthase 3 in the response to vascular injury
Arterioscler. Thromb. Vasc. Biol.
36
224-225
2016
Homo sapiens, Mus musculus, Mus musculus C57/BL6J
Manually annotated by BRENDA team
Siiskonen, H.; Kaernae, R.; Hyttinen, J.M.; Tammi, R.H.; Tammi, M.I.; Rilla, K.
Hyaluronan synthase 1 (HAS1) produces a cytokine-and glucose-inducible, CD44-dependent cell surface coat
Exp. Cell Res.
320
153-163
2014
Homo sapiens
Manually annotated by BRENDA team
Takabe, P.; Bart, G.; Ropponen, A.; Rilla, K.; Tammi, M.; Tammi, R.; Pasonen-Seppaenen, S.
Hyaluronan synthase 3 (HAS3) overexpression downregulates MV3 melanoma cell proliferation, migration and adhesion
Exp. Cell Res.
337
1-15
2015
Homo sapiens
Manually annotated by BRENDA team
Siiskonen, H.; Oikari, S.; Pasonen-Seppaenen, S.; Rilla, K.
Hyaluronan synthase 1: a mysterious enzyme with unexpected functions
Front. Immunol.
6
43
2015
Homo sapiens (Q92839)
Manually annotated by BRENDA team
Passi, A.; Vigetti, D.; Buraschi, S.; Iozzo, R.V.
Dissecting the role of hyaluronan synthases in the tumor microenvironment
FEBS J.
286
2937-2949
2019
Mus musculus (P70312), Homo sapiens (Q92819)
Manually annotated by BRENDA team
Yoshida, H.; Aoki, M.; Komiya, A.; Endo, Y.; Kawabata, K.; Nakamura, T.; Sakai, S.; Sayo, T.; Okada, Y.; Takahashi, Y.
HYBID (alias KIAA1199/CEMIP) and hyaluronan synthase coordinately regulate hyaluronan metabolism in histamine-stimulated skin fibroblasts
J. Biol. Chem.
295
2483-2494
2020
Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team
Mehic, M.; de Sa, V.K.; Hebestreit, S.; Heldin, C.H.; Heldin, P.
The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function
Oncogenesis
6
e348
2017
Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team
Yang, Y.M.; Noureddin, M.; Liu, C.; Ohashi, K.; Kim, S.Y.; Ramnath, D.; Powell, E.E.; Sweet, M.J.; Roh, Y.S.; Hsin, I.F.; Deng, N.; Liu, Z.; Liang, J.; Mena, E.; Shouhed, D.; Schwabe, R.F.; Jiang, D.; Lu, S.C.; Noble, P.W.; Seki, E.
Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis
Sci. Transl. Med.
11
eaat9284
2019
Mus musculus (P70312), Mus musculus, Homo sapiens (Q92819), Homo sapiens
Manually annotated by BRENDA team