2.4.1.212: hyaluronan synthase
This is an abbreviated version!
For detailed information about hyaluronan synthase, go to the full flat file.
Word Map on EC 2.4.1.212
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2.4.1.212
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glycosaminoglycans
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collagen
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polysaccharide
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keratinocytes
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cartilage
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4-methylumbelliferone
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proteoglycans
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hyaluronidases
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chondrocytes
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dermal
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mesenchymal
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pericellular
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pasteurella
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udp-glucuronic
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hyals
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versican
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cumulus
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synovial
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vocal
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articular
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aggrecan
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osteoarthritis
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streptococcal
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udp-n-acetylglucosamine
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multocida
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rhamm
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pyogenes
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udp-sugars
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chondroitin
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glucuronic
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procollagen
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synoviocytes
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cumulus-oocyte
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decorin
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udp-glcua
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photoaging
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filaggrin
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equisimilis
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ha-binding
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temporomandibular
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glcua
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perineuronal
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ophthalmopathy
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zooepidemicus
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uvb-irradiated
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ha-mediated
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tnfaip6
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medicine
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hyaluronan-binding
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fibromodulin
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biglycan
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analysis
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synthesis
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drug development
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biotechnology
- 2.4.1.212
- glycosaminoglycans
- collagen
- polysaccharide
- keratinocytes
- cartilage
- 4-methylumbelliferone
- proteoglycans
- hyaluronidases
- chondrocytes
-
dermal
- mesenchymal
-
pericellular
- pasteurella
-
udp-glucuronic
-
hyals
- versican
-
cumulus
- synovial
-
vocal
-
articular
- aggrecan
- osteoarthritis
- streptococcal
- udp-n-acetylglucosamine
- multocida
-
rhamm
- pyogenes
- udp-sugars
- chondroitin
-
glucuronic
- procollagen
- synoviocytes
-
cumulus-oocyte
- decorin
- udp-glcua
-
photoaging
- filaggrin
- equisimilis
-
ha-binding
-
temporomandibular
-
glcua
-
perineuronal
- ophthalmopathy
- zooepidemicus
-
uvb-irradiated
-
ha-mediated
-
tnfaip6
- medicine
-
hyaluronan-binding
- fibromodulin
- biglycan
- analysis
- synthesis
- drug development
- biotechnology
Reaction
Synonyms
CHAS2, CHAS3, class I hyaluronan synthase, CPS1, DG42 protein, HA synthase, HA synthase 3, HA1, HA2, HA3, HAS, HAS-1, HAS-2, HAS-3, HAS1, Has2, Has3, hasA, HASs, HsHAS1, HuHAS1, HyaD, hyaluronan synthase, hyaluronan synthase 1, hyaluronan synthase 2, hyaluronan synthase 3, hyaluronan synthase-1, hyaluronan synthase-2, hyaluronan synthases 2, hyaluronan synthethase, hyaluronate synthase, hyaluronate synthetase, hyaluronic acid synthase, hyaluronic acid synthetase, More, PmHAS, seHAS, XHAS1, XHAS2, XHAS3
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2.4.1.212 hyaluronan synthaseAdvanced search results
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results (General Information
General Information on EC 2.4.1.212 - hyaluronan synthase
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GENERAL INFORMATION 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
evolution
the three HAS isoenzymes, HAS1, HAS2, and HAS3, expressed in mammalian cells differ in their enzymatic properties and regulation by external stimuli
malfunction
metabolism
physiological function
additional information
malfunction
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catalytically inactive mutant K190R HAS2 forms dimers with wild-type HAS2 and quenches the activity of wild-type HAS2
malfunction
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HAS-1 overexpression in dermal wounds decreases elements of scar formation
malfunction
reduction of HA due to decreased HAS activity, caused by phosphorylation at Thr110 through AMP-activated protein kinase, decreases the ability of aortic smooth muscle cells to proliferate, migrate, and recruit immune cells, thereby reducing the pro-atherosclerotic AoSMC phenotype. AMP-activated protein kinase can block the pro-atherosclerotic signals driven by HA by interaction with its receptors
malfunction
downregulation of HAS2 initiates and regulates fibroblast senescence through a p27-CDK2-SKP2 pathway. Deletion of HAS2 in mouse mesenchymal cells increases the cellular senescence of fibroblasts in bleomycin-induced mouse lung fibrosis in vivo. Overexpression of HAS2 in mesenchymal cells promotes an invasive phenotype resulting in severe fibrosis and downregulation of HAS2 promotes resolution. HAS2 deficiency leads to embryonic lethality. Downregulation of HAS2 increases p27 protein stability. p27 inhibits cell proliferation by regulating CDK2 activity. HAS2 deletion enhances cell stress responses. Phenotypes, detailed overview
malfunction
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embryonic lethality of genetic deletion of HAS2, some HAS2-specific functions are not compensated for by isozyme HAS1 or HAS3
malfunction
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in a ligation-induced carotid artery injury model, attenuated neointimal hyperplasia occurs in HAS3-null animals compared with wild-type control C57BL/6J mice. No changes are observed in medial and neointimal cell density, proliferation, or apoptosis. A lack of compensatory upregulation of isozymes HAS1 or HAS2, HAS3 deletion is associated with a reduction in vascular hyaluronan content, most dramatically in the media rather than the neointima. Transcriptome analysis of injured vessels from wild-type and HAS3-null mice reveals differential activation of pathways associated with a migratory VSMC phenotype. Isozyme HAS3 overexpression in VSMCs supports a migratory phenotype in response to platelet-derived growth factor BB (PDGF-BB), whereas knockdown of HAS3 results in reduced PDGF-BB-induced migration. Isozyme HAS3 knockdown also leads to a decrease in PDGF-B mRNA levels
malfunction
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isozyme HAS3 overexpression downregulates MV3 melanoma cell proliferation, migration and adhesion. Overexpression of isozyme HAS3 decreases cell proliferation, directional and random cell migration, and promotes cell cycle arrest at G1/G0 and decreases ERK1/2 phosphorylation suggesting that inhibition of MAP-kinase signaling is responsible for the suppressive effects on the malignant phenotype of MV3 melanoma cells. EGFP-HAS3 overexpression downregulates several signaling pathways in MV3 melanoma cells
malfunction
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the regulation of isozyme HAS2 by O-GlcNAcylation can have important therapeutic consequences considering that the excess of glucose can lead to a dramatic increase of UDP-GlcNAc and hyaluronan (in particular in cells where the uptake of glucose is insulin-independent). Clinical and experimental evidences show that in hyperglycemic patients and in streptozotocin-induced diabetes animals there is evidence of hyaluronan accumulation both in plasma and in vascular wall
malfunction
Has2-/- mice are embryonic lethal. Has2-/- embryos die between embryonic day 9.5 and 10.5 and exhibit severe cardiac and vascular abnormalities, in addition to yolk sac and somite deformities
malfunction
Has3/Apoe double deficient mice develop less atherosclerosis characterized by decreased Th1-cell responses, decreased IL-12 release, and decreased macrophage-driven inflammation
malfunction
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in a ligation-induced carotid artery injury model, attenuated neointimal hyperplasia occurs in HAS3-null animals compared with wild-type control C57BL/6J mice. No changes are observed in medial and neointimal cell density, proliferation, or apoptosis. A lack of compensatory upregulation of isozymes HAS1 or HAS2, HAS3 deletion is associated with a reduction in vascular hyaluronan content, most dramatically in the media rather than the neointima. Transcriptome analysis of injured vessels from wild-type and HAS3-null mice reveals differential activation of pathways associated with a migratory VSMC phenotype. Isozyme HAS3 overexpression in VSMCs supports a migratory phenotype in response to platelet-derived growth factor BB (PDGF-BB), whereas knockdown of HAS3 results in reduced PDGF-BB-induced migration. Isozyme HAS3 knockdown also leads to a decrease in PDGF-B mRNA levels
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malfunction
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HAS-1 overexpression in dermal wounds decreases elements of scar formation
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metabolism
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regulation of hexosamine biosynthetic pathway, biosynthesis of hyaluronan and other glycoconjugates, and protein O-GlcNAcylation, overview
metabolism
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role of hyaluronan in vascular disease, a multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases are involved in its metabolism
metabolism
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role of hyaluronan in vascular disease, a multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases are involved in its metabolism
metabolism
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the most general sensor of cellular nutritional status is the hexosamine biosynthetic pathway that brings to the formation of UDP-GlcNAc and intracellular protein glycosylation by O-linked attachment of the monosaccharide beta-N-acetylglucosamine (O-GlcNAcylation) to specific aminoacid residues. Such highly dynamic and ubiquitous protein modification affects residue Ser221 residue of isozyme HAS2 that lead to a dramatic stabilization of the enzyme in the membrane
metabolism
histamine controls hyaluronan metabolism by up-regulating HYBID (hyaluronan-binding protein) and down-regulating hyaluronan synthase 2 (HAS2) via distinct signaling pathways downstream of histamine receptor H1
metabolism
hyaluronan is expressed in a temporal-spatial expression pattern and may play a role in embryonic tooth morphogenesis. The difference in the distribution and expression of the three hyaluronan synthases at different developmental stages also supports their roles in cell proliferation, cell differentiation and cell migration
metabolism
hyaluronan synthase 2 expression is elevated in both human and murine liver fibrosis. The enzyme actively synthesizes hyaluronan in hepatic stellate cells and promotes activation of hepatic stellate cells and liver fibrosis through Notch1
metabolism
hyaluronan synthase 2 expression is elevated in both human and murine liver fibrosis. The enzyme actively synthesizes hyaluronan in hepatic stellate cells and promotes activation of hepatic stellate cells and liver fibrosis through Notch1
metabolism
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role of hyaluronan in vascular disease, a multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases are involved in its metabolism
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physiological function
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hyaluronan concentration in follicular fluids increases during atresia. Isoform HAS1 may be the dominant HAS protein in theca cells to produce hyaluronan in pig ovaries
physiological function
inhibition of HAS2 expression by siRNA decreases matrix metalloprotein MMP-7 expression by about 20%, and dramaticlly decreases MMP-7 protein, and enzymatic activity. HAS isoforms and hyaluronan may mediate cellular invasion via changes in matrix metalloprotein MMP-7 expression
physiological function
inhibition of HAS2 expression by siRNA decreases matrix metalloprotein MMP-7 expression by about 30%, and dramaticlly decreases MMP-7 protein, and enzymatic activity. HAS isoforms and hyaluronan may mediate cellular invasion via changes in matrix metalloprotein MMP-7 expression
physiological function
mainly high molecular weight hyaluronan synthesized by isoform HAS1 regulates HT-1080 cell motility
physiological function
the reduction of hyaluronan caused by enzyme downregulation through 4-methylumbelliferone is associated with a significant inhibition of cell migration, proliferation and invasion
physiological function
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HAS-1 treatment of wounds promotes a more organized extracellular matrix with the regeneration of dermal appendages, including hair follicles, increased regenerative healing, overview
physiological function
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hyaluronan synthase mediates dye translocation across liposomal membranes
physiological function
hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells
physiological function
the expression of the Has1 isoenzyme, most dependent on high UDP-sugar contents, is coordinated with a metabolic state that maintains a high level of these substrates
physiological function
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the hyaluronan synthase catalyzes the synthesis and membrane translocation of hyaluronan, it is both necessary and sufficient to translocate hyaluronan in a reaction that is tightly coupled to hyaluronan elongation. Hyaluronan synthesis and translocation are spatially coupled events, which allow hyaluronan synthesis even in the presence of a large excess of hyaluronan-degrading enzyme
physiological function
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the role of UDP-N-acetylglucosamine and O-GlcNAc-acylation of hyaluronan synthase 2 in the control of chondroitin sulfate and hyaluronan synthesis, overview. O-linked GlcNAc (O-GlcNAcylation) is regulated by the action of two enzymes, O-GlcNAc transferase and O-GlcNAc hydrolase. The HA increase due to O-GlcNAcylation regulates inflammatory cell adhesion, the number of monocytes that adhere on AoSMC monolayer cultures is increased
physiological function
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hyaluronan is a glycosaminoglycan composed by repeating units of D-glucuronic acid and N-acetylglucosamine that is ubiquitously present in the extracellular matrix where it has a critical role in the physiology and pathology of several mammalian tissues. Hyaluronan represents a perfect environment in which cells can migrate and proliferate. Several receptors can interact with hyaluronan at cellular level triggering multiple signal transduction responses. The control of the hyaluronan synthesis is therefore critical in extracellular matrix assembly and cell biology, analysis of metabolic regulation of hyaluronan synthesis, overview. In contrast with other glycosaminoglycans, which are synthesized in the Golgi apparatus, hyaluronan is produced at the plasma membrane by hyaluronan synthases (HAS1-3), which use cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates. UDP-GlcUA and UDP-hexosamine availability is critical for the synthesis of glycosaminoglycans, an energy consuming process
physiological function
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hyaluronan is a ubiquitous glycosaminoglycan involved in embryonic development, inflammation and cancer. In mammals, three hyaluronan synthase isoenzymes (HAS1-3) inserted in the plasma membrane produce hyaluronan directly on the cell surface. Isozyme hyaluronan synthase 1 (HAS1) produces a cytokine-and glucose-inducible, CD44-dependent cell surface coat
physiological function
hyaluronan is the largest and one of the most abundant glycosaminoglycans of the extracellular space. Hyaluronan synthases are glycosyltransferases acting on the inner face of plasma membrane, adding alternately glucuronic acid and N-acetylglucosamine to the reducing end of the growing chain. Hyaluronan synthase forms a reserve that is transported to the plasma membrane for rapid activation of hyaluronan synthesis. The levels and localizations of HAS isoforms are likely to be highly important in processes like embryonic development, wound healing, inflammation, and malignant growth
physiological function
hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. The role of HAS1 in hyaluronan production seems to be insignificant compared to the two other isoenzymes, HAS2 and HAS3, which have higher enzymatic activity. Isozyme Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. Both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma. The pericellular hyaluronan coat produced by HAS1 is usually thin without induction by inflammatory agents or glycemic stress and depends on CD44HA interactions. These specific interactions regulate the organization of hyaluronan into a leukocyte recruiting matrix during inflammatory responses. Despite the apparently minor enzymatic activity of HAS1 under normal conditions, it may be an important factor under conditions associated with glycemic stress like metabolic syndrome, inflammation, and cancer. HAS1 expression is transcriptionally regulated by transforming growth factor-beta in synoviocytes and by the pro-inflammatory cytokine interleukin-1beta in fibroblasts, while these factors may have similar or opposite effects on other HASs, depending on the cell type. Has1 is associated with breast tumor and with estrogen receptor negativity, HER2 positivity, high relapse rate, and short overall survival
physiological function
hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Senescence is implicated in development, cancer, and tissue fibrosis. The chronic inflammation caused by cellular senescence may be related to the pathogenesis of various chronic diseases. Isozyme HAS2 may be a critical regulator of the fate of pulmonary fibrosis. Isozyme HAS2 is the major isoform responsible for hyaluronan production in mesenchymal cells
physiological function
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hyaluronan synthase isozymes are involved in hyaluronan biosynthesis. Each HAS isoform produces structurally identical hyaluronan, thus, hyaluronan function is independent of the HAS by which it is synthesized. Hyaluronan is an essential component of the pericellular matrix, or alternatively, it can be released in a soluble form and be released and incorporated as part of the extracellular matrix. The composition and architecture of the matrix affect hyaluronan-dependent biochemical signaling, as well as the biophysical and biomechanical properties of tissues. The temporal and spatial relationship of hyaluronan with cells that express hyaluronidases that modify the molecular weight of hyaluronan is another determinant of hyaluronan function. Hyaluronan synthases may affect vascular disease independent of hyaluronan. HAS isoform-specific functions in tissue homeostasis and disease
physiological function
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hyaluronan synthase isozymes are involved in hyaluronan biosynthesis. Each HAS isoform produces structurally identical hyaluronan, thus, hyaluronan function is independent of the HAS by which it is synthesized. Hyaluronan is an essential component of the pericellular matrix, or alternatively, it can be released in a soluble form and be released and incorporated as part of the extracellular matrix. The composition and architecture of the matrix affect hyaluronan-dependent biochemical signaling, as well as the biophysical and biomechanical properties of tissues. The temporal and spatial relationship of hyaluronan with cells that express hyaluronidases that modify the molecular weight of hyaluronan is another determinant of hyaluronan function. Hyaluronan synthases may affect vascular disease independent of hyaluronan. HAS isoform-specific functions in tissue homeostasis and disease. Apotential autocrine loop involving isoyzme HAS3, PDGF-B expression, and PDGF-BB-induced migration. Isoform-specific role for HAS3 in promoting neointimal hyperplasia after carotid artery ligation
physiological function
recombinant hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts against cell death induced by nutrient deprivation, but not against apoptosis evoked by human oxidized LDL. Resistance of fro/fro cells to starvation-induced apoptosis is associated with an increased expression of hyaluronan synthase 2 (HAS2) mRNAs and protein, which is inhibited by ceramide. The protective mechanism of HAS2 involves an increased expression of the heat-shock protein Hsp72, a chaperone with antiapoptotic activity. Antiapoptotic properties of HAS2 , overview
physiological function
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the enzyme is involved in synthesis of hyaluronan that may have anti-cancer like effects in melanoma progression
physiological function
enzyme expression has a pivotal role in cell motility and invasion. The enzyme regulates tumor progression and cell aggressiveness. Mammary tumor biopsies in which the enzyme (HAS2) is overexpressed display enhanced angiogenesis and inflammatory cells recruitment. HAS2 is a critical factor that induces epithelial-mesenchymal transition
physiological function
hyaluronan synthase 3 promotes plaque inflammation and atheroprogression. Hyaluronan synthase 3 expression in vascular smooth muscle cells is found to be regulated by interleukin 1 beta (IL-1beta) in an NFkappaB dependent manner
physiological function
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recombinant hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts against cell death induced by nutrient deprivation, but not against apoptosis evoked by human oxidized LDL. Resistance of fro/fro cells to starvation-induced apoptosis is associated with an increased expression of hyaluronan synthase 2 (HAS2) mRNAs and protein, which is inhibited by ceramide. The protective mechanism of HAS2 involves an increased expression of the heat-shock protein Hsp72, a chaperone with antiapoptotic activity. Antiapoptotic properties of HAS2 , overview
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physiological function
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hyaluronan synthase isozymes are involved in hyaluronan biosynthesis. Each HAS isoform produces structurally identical hyaluronan, thus, hyaluronan function is independent of the HAS by which it is synthesized. Hyaluronan is an essential component of the pericellular matrix, or alternatively, it can be released in a soluble form and be released and incorporated as part of the extracellular matrix. The composition and architecture of the matrix affect hyaluronan-dependent biochemical signaling, as well as the biophysical and biomechanical properties of tissues. The temporal and spatial relationship of hyaluronan with cells that express hyaluronidases that modify the molecular weight of hyaluronan is another determinant of hyaluronan function. Hyaluronan synthases may affect vascular disease independent of hyaluronan. HAS isoform-specific functions in tissue homeostasis and disease. Apotential autocrine loop involving isoyzme HAS3, PDGF-B expression, and PDGF-BB-induced migration. Isoform-specific role for HAS3 in promoting neointimal hyperplasia after carotid artery ligation
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physiological function
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HAS-1 treatment of wounds promotes a more organized extracellular matrix with the regeneration of dermal appendages, including hair follicles, increased regenerative healing, overview
-
additional information
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HA product size is decreased by increasing concentrations of glycerol. The four Cys residues in SeHAS are clustered close together and are located at the membrane-HAS interface within the enzyme active site. Involvement of these Cys residues in HAS activity, overview
additional information
product hyaluronan is secreted to the cell surface or the into the growth medium by HAS-containing cell culture, respectively
additional information
product hyaluronan is secreted to the cell surface or the into the growth medium by HAS-containing cell culture, respectively
additional information
product hyaluronan is secreted to the cell surface or the into the growth medium by HAS-containing cell culture, respectively
additional information
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product hyaluronan is secreted to the cell surface or the into the growth medium by HAS-containing cell culture, respectively
additional information
An important factor affecting activity of all HAS enzymes is the cytoplasmic availability of substrates, namely, UDP-GlcUA and UDP-GlcNAc. This role of substrates is particularly interesting in regulation of HAS1 as its activity of hyaluronan production in many cell models is low or absent unless stimulated
