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Information on EC 2.4.1.212 - hyaluronan synthase
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2.4.1.212 hyaluronan synthaseIUBMB 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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Word Map
- 2.4.1.212
- glycosaminoglycans
- collagen
- polysaccharide
- proteoglycans
- 4-methylumbelliferone
- keratinocytes
- cartilage
- hyaluronidases
-
dermal
- chondrocytes
- mesenchymal
-
pericellular
-
hyals
- synovial
- versican
- pasteurella
-
udp-glucuronic
-
cumulus
- udp-n-acetylglucosamine
- osteoarthritis
- streptococcal
-
vocal
- multocida
-
articular
- aggrecan
-
glucuronic
- chondroitin
-
rhamm
- procollagen
- pyogenes
- udp-sugars
-
photoaging
-
cumulus-oocyte
- equisimilis
- udp-glcua
- filaggrin
- decorin
- synoviocytes
-
ha-binding
- zooepidemicus
-
glcua
-
ha-mediated
-
perineuronal
- biglycan
- ophthalmopathy
- fibromodulin
- medicine
-
temporomandibular
-
tnfaip6
-
uvb-irradiated
-
hyaluronan-binding
- drug development
- synthesis
- analysis
- biotechnology
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
CHAS2, CHAS3, class I hyaluronan synthase, CPS1, DG42 protein, HA synthase, HA synthase 3, HA1, HA2, HA3, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CHAS2
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CHAS3
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-
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DG42 protein
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-
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HA synthase
HA synthase 3
HA2
HA3
HAS
HAS-1
HAS1
Has2
Has3
HASs
HuHAS1
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-
-
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hyaluronan synthase
hyaluronan synthase 1
hyaluronan synthase 2
hyaluronan synthase 3
hyaluronan synthase-1
hyaluronan synthase-2
hyaluronan synthases 2
hyaluronan synthethase
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hyaluronate synthase
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hyaluronate synthetase
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hyaluronic acid synthase
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hyaluronic acid synthetase
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PmHAS
XHAS1
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-
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XHAS2
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-
-
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XHAS3
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-
-
-
additional information
HA synthase
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-
-
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HAS
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Has2
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additional information
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the enzyme of Pasteurella multocida belongs to the group of class II hyaluronan synthases
additional information
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enzyme belongs to class I of hyaluronan synthases
additional information
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the enzyme belongs to the class I hyaluronan synthases
additional information
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the enzyme belongs to the group of class I hyaluronan synthases
additional information
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enzyme belongs to class I of hyaluronan synthases
additional information
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the enzyme of Streptococcus pyogenes belongs to the group of class I hyaluronan synthases
additional information
the enzyme belongs to the group of class I hyaluronan synthases
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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]
UDP-N-acetyl-alpha-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]
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]
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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]
a mechanistic shift from a steady-state ordered bi-bi to rapid equilibrium ordered bi-bi mechanism is observed at the NAc-site between the HA6 and HA8 elongation
UDP-N-acetyl-alpha-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]
catalytic mechanism
-
UDP-N-acetyl-alpha-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]
highly specific
-
-
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UDP-N-acetyl-alpha-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]
The enzyme from Streptococcus Group A and Group C requires Mg2+. It is highly specific for UDP-GlcNAc and UDP-GlcA
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-
-
UDP-N-acetyl-alpha-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]
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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UDP-N-acetyl-alpha-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]
2 active sites, the 2 DXD motifs of the transferase sites in the C-terminus, residues 686-703, are essential for activity
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UDP-N-acetyl-alpha-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]
addition of monosaccharides to the reducing end to form a linear heteropolysaccharide chain
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UDP-N-acetyl-alpha-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]
addition of monosaccharides to the reducing end to form a linear heteropolysaccharide chain
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UDP-N-acetyl-alpha-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]
catalytic mechanism, no covalent intermediates
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UDP-N-acetyl-alpha-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]
catalytically relevant Cys226 and Cys262 are located near the UDP-binding site and might be cross-linked, structural and functional role of cysteine residues, overview
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UDP-N-acetyl-alpha-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]
Cys307 might be a catalytic residue or be involved in maintaining structure, Cys337 is involved in UDP-sugar substrate binding, enzyme amino acid residues involved in interactions with the substrate, overview
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UDP-N-acetyl-alpha-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]
a mechanistic shift from a steady-state ordered bi-bi to rapid equilibrium ordered bi-bi mechanism is observed at the NAc-site between the HA6 and HA8 elongation
UDP-N-acetyl-alpha-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]
2 active sites, the 2 DXD motifs of the transferase sites in the C-terminus, residues 686-703, are essential for activity
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hexosyl group transfer
hexosyl group transfer
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hexosyl group transfer
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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.
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CAS REGISTRY NUMBER
COMMENTARY
39346-43-5
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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
hyaluronic acid tetrasaccharide + UDP-alpha-N-acetyl-D-glucosamine
?
-
-
-
-
?
UDP-alpha-D-glucuronate + hyaluronan oligomer HA5
UDP + beta-D-glucuronosyl-(1->3)-hyaluronan oligomer HA5
-
-
-
?
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]
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]
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]
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]
UDP-alpha-N-acetyl-D-glucosamine + hyaluronan oligomer HA4
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-hyaluronan oligomer HA4
-
-
-
?
UDP-alpha-N-acetyl-D-glucosamine + hyaluronan oligomer HA6
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-hyaluronan oligomer HA6
-
-
-
?
UDP-alpha-N-acetyl-D-glucosamine + hyaluronan oligomer HA8
UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-hyaluronan oligomer HA8
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-
-
?
UDP-D-glucosamine + UDP-D-glucuronate
[beta-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + n UDP
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-
-
-
?
UDP-D-glucosamine + UDP-D-glucuronate
[beta-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
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-
-
-
?
UDP-D-glucuronate + chondroitin 4-sulfate trisaccharide
?
-
3.6% of the activity with hyaluronan
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-
?
UDP-D-glucuronate + chondroitin 6-sulfate pentasaccharide
?
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61% of the activity with hyaluronan
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-
?
UDP-D-glucuronate + chondroitin 6-sulfate trisaccharide
?
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80% of the activity with hyaluronan
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-
?
UDP-D-glucuronate + chondroitin sulfate
?
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12% of the activity with hyaluronan
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-
?
UDP-D-glucuronate + unsulfated chondroitin
?
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54% of the activity with hyaluronan
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-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
[hyaluronan](n) + UDP-alpha-D-glucuronate
H+ + beta-D-glucuronosyl-(1->4)-[hyaluronan](n) + UDP
-
-
-
?
[hyaluronan](n) + UDP-N-acetyl-alpha-D-glucosamine
H+ + N-acetyl-beta-D-glucosaminyl-(1->4)-[hyaluronan](n) + UDP
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-
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?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
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?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the linear heteropolysaccharide chain
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the linear heteropolysaccharide chain, recombinant isozyme HAS2 prefers the production of a mixture of 8mers and 16mers
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
chains growth at the non-reducing end, which is terminated by lack of substrate with a non-reducing end, active with exogenously added acceptors substrates
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
formation of linear hyaluronan polymers composed of alternating beta3-N-acetylglucosamine-beta4-glucuronic acid
the product chain length can grow at the reducing end up to 40000 monosaccharides with a MW of over 8 million Da before it is released by the class I enzyme
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
formation of linear hyaluronan polymers composed of alternating beta3-N-acetylglucosamine-beta4-glucuronic acid
the product chain length can grow at the reducing end up to 40000 monosaccharides with a MW of over 8 million Da before it is released by the class I enzyme
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
product is a linear chain
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the reducing end to form a linear heteropolysaccharide chain
product chain length depends on reaction conditions, overview
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
biosynthesis of hyaluronan
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the linear heteropolysaccharide chain composed of repeating disaccharides
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
highly specific for UDP-N-acetyl-D-glucosamine and UDP-D-glucuronate, addition of monosaccharides to the heteropolysaccharide chain consisting of repeated disaccharides up to 25000
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the reducing end to form a linear heteropolysaccharide chain
product chain length depends on reaction conditions, overview
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
biosynthesis of hyaluronan
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the reducing end of the acceptor substrate, no binding and activity with exogenously added hyaluronan chains
the product chain length can grow at the reducing end up to 40000 monosaccharides with a MW of over 8 million Da before it is released by the class I enzyme
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the linear heteropolysaccharide chain
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
additional information
?
-
-
hyaluronic acid synthase contributes to the pathogenesis of Cryptococcus neoformans infection
-
-
?
additional information
?
-
-
regulation mechanism of hyaluronan biosynthesis, stimulation of cells by cytokines effects the different expression patterns of the isoforms, especially during embryonic development, the isozymes have different roles in hyaluronan biosynthesis
-
-
?
additional information
?
-
-
the isozymes form products of different size, HA synthesis modeling, active site and substrate binding site are located on the big cytoplasmic loop
-
-
?
additional information
?
-
-
HAS2, localized in the plasma membrane, uses cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates
-
-
?
additional information
?
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
two glycosyltransferase activities in HAS that add glucuronic acid and N-acetylglucosamine into their alternating positions in the chain, using UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP-GlcNAc) as substrates. Sufficient supply of both UDP-GlcUA and UDP-GlcNAc is important for hyaluronan synthesis
-
-
?
additional information
?
-
two glycosyltransferase activities in HAS that add glucuronic acid and N-acetylglucosamine into their alternating positions in the chain, using UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP-GlcNAc) as substrates. Sufficient supply of both UDP-GlcUA and UDP-GlcNAc is important for hyaluronan synthesis
-
-
?
additional information
?
-
two glycosyltransferase activities in HAS that add glucuronic acid and N-acetylglucosamine into their alternating positions in the chain, using UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP-GlcNAc) as substrates. Sufficient supply of both UDP-GlcUA and UDP-GlcNAc is important for hyaluronan synthesis
-
-
?
additional information
?
-
-
two glycosyltransferase activities in HAS that add glucuronic acid and N-acetylglucosamine into their alternating positions in the chain, using UDP-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP-GlcNAc) as substrates. Sufficient supply of both UDP-GlcUA and UDP-GlcNAc is important for hyaluronan synthesis
-
-
?
additional information
?
-
-
a single protein exerts many functions as binding of two distinct UDP-sugars and binding of two distinct HA acceptor or donor species. The enzyme transfers two different sugars in two different linkages, catalyzes repetitive sugar polymerization, and transfers hyaluronan across the membrane
-
-
?
additional information
?
-
-
isozyme expression and regulation by interleukin-1beta, progesterone, and low-molecular-weight hyaluronan in pregnant mouse uterine cervix, overview
-
-
?
additional information
?
-
-
regulation mechanism of hyaluronan biosynthesis, stimulation of cells by cytokines effects the different expression patterns of the isoforms, especially during embryonic development, the isozymes have different roles in hyaluronan biosynthesis, isozymes exhibit different functions in tumor growth, progression, and determination of malignancy
-
-
?
additional information
?
-
-
the isozymes form products of different size, HA synthesis modeling, active site and substrate binding site are located on the big cytoplasmic loop
-
-
?
additional information
?
-
-
HA made by the has-1 transduced arterial smooth muscle cells is larger or part of a larger complex that resists proteolytic degradation when compared to the has-3 tansduced ASMCs. There is evidence that the different has enzymes have an inherent ability to regulate hyaluronan size
-
-
?
additional information
?
-
hyaluronan synthase 1 and hyaluronan synthase 2 synthesize high molecular weight hyaluronan, while hyaluronan synthase 3 synthesizes low lecular weight hyaluronan
-
-
-
additional information
?
-
hyaluronan synthase 1 and hyaluronan synthase 2 synthesize high molecular weight hyaluronan, while hyaluronan synthase 3 synthesizes low lecular weight hyaluronan
-
-
-
additional information
?
-
hyaluronan synthase 1 and hyaluronan synthase 2 synthesize high molecular weight hyaluronan, while hyaluronan synthase 3 synthesizes low lecular weight hyaluronan
-
-
-
additional information
?
-
-
hyaluronan synthase 1 and hyaluronan synthase 2 synthesize high molecular weight hyaluronan, while hyaluronan synthase 3 synthesizes low lecular weight hyaluronan
-
-
-
additional information
?
-
-
enzyme is responsible for hyaluronan biosynthesis, the hyaluronan capsule is an important, but not the only, virulence factor, physiological role of the enzyme
-
-
?
additional information
?
-
-
the produced hyaluronan capsule enhances infection
-
-
?
additional information
?
-
-
enzyme is not processive, enzyme requires other proteins for hyaluronan translocation
-
-
?
additional information
?
-
-
substrate specificity, the GlcNAc-transferase, but not the GlcUA-transferase activity depends on the WGGED motif, overview
-
-
?
additional information
?
-
-
PmHAS elongates a range of acceptor molecules in addition to the cognate sugars. Certain glycosaminoglycans are very poor acceptors in comparison to the cognate molecules, but elongated products are detected. The interaction between the acceptor and the enzyme (a) the orientation of the hydroxyl at the C-4 position of the hexosamine is not critical, (b) the conformation of C-5 of the hexuronic acid (glucuronic versus iduronic) is not crucial, and (c) additional negative sulfate groups are well tolerated in certain cases, such as on C-6 of the hexosamine, but others, including C-4 sulfates, are not or are poorly tolerated
-
-
?
additional information
?
-
Pasteurella multocida hyaluronan synthase encompasses two transferase domains that elongate a growing hyaluronan oligosaccharide chain by addition of either GlcNAc or GlcUA residues from a corresponding UDP-sugar
-
-
?
additional information
?
-
a monodispersed hyaluronan chain can be obtained by finely tuning the reaction stoichiometry. The molar ratio of precursors and acceptor molecules has an important role in enzyme kinetics
-
-
?
additional information
?
-
initial velocity studies of single-step elongations are conducted for both domains by independently varying the concentrations of the hyaluronan oligosaccharide and the UDP-sugar. Two-substrate models are discriminated by their goodness-of-fit parameters and by dead-end inhibition studies. Coupled-enzyme assay using LDH, PK; NADH and phosphoenolpyruvate, as well as hyaluronan oligosaccharides, UDP-GlcNAc and UDP-GlcUA, overview
-
-
?
additional information
?
-
-
the produced hyaluronan capsule enhances infection
-
-
?
additional information
?
-
-
substrate specificity, the GlcNAc-transferase, but not the GlcUA-transferase activity depends on the WGGED motif, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview, repression of HAS2 expression leads to reduced hyaluronan synthesis and reduced tumorigenicity in the peritoneum
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview, repression of HAS2 expression leads to reduced hyaluronan synthesis and reduced tumorigenicity in the peritoneum
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview, repression of HAS2 expression leads to reduced hyaluronan synthesis and reduced tumorigenicity in the peritoneum
-
-
?
additional information
?
-
-
conserved cysteine residues are not essential for enzyme function
-
-
?
additional information
?
-
-
determination of polymer synthesis progression direction, overview
-
-
?
additional information
?
-
-
the enzyme is inactive without bound cardiolipins
-
-
?
additional information
?
-
a catalysis-transformation-translocation model is proposed for the hyaluronic acid synthesis and translocation processes. The residue R406 and R413 are primarily involved in catalysis, while the residues between 414 and 417 are involved in hyaluronic acid translocation
-
-
-
additional information
?
-
-
a catalysis-transformation-translocation model is proposed for the hyaluronic acid synthesis and translocation processes. The residue R406 and R413 are primarily involved in catalysis, while the residues between 414 and 417 are involved in hyaluronic acid translocation
-
-
-
additional information
?
-
the enzyme uses chitin-UDPs as primers to initiate hyaluronan synthesis, leaving the non-hyaluronan primer at the nonreducing end. chitin-UDP functions in vitro and in live cells as a primer to initiate synthesis of all HA chains and these primers remain at the nonreducing-ends of hyaluronan chains as residual chitin
-
-
-
additional information
?
-
-
the enzyme uses chitin-UDPs as primers to initiate hyaluronan synthesis, leaving the non-hyaluronan primer at the nonreducing end. chitin-UDP functions in vitro and in live cells as a primer to initiate synthesis of all HA chains and these primers remain at the nonreducing-ends of hyaluronan chains as residual chitin
-
-
-
additional information
?
-
a three-dimensional atomic scale model of class I hyaluronan synthase enzymes is presented to gain insights on functional features. 9 hyaluronan synthase-specific sub-structural elements are identified. Docking studies with UDP-substrates in the enzyme show highly overlapping single binding sites for the two UDP-substrates. In-silico and mutation studies identify functional elements implicated in polymer binding and influencing hyaluronic acid production. The studies indicate a substrate binding role for Lys139, and a critical role for Gln248 and Thr283. Anisotropic Network Modeling (ANM)-based model is analysed to assess collective global dynamics in the enzyme. Based on ligand binding landscape and architecture of functional elements, a plausible three-step molecular mechanism to extend hyaluronic acid polymer from its reducing end is proposed. The release of UDP from polymeric end may be required for glycosyltransferase reaction
-
-
-
additional information
?
-
-
enzyme is responsible for hyaluronan biosynthesis, the hyaluronan capsule is an important, but not the only, virulence factor, physiological role of the enzyme
-
-
?
additional information
?
-
conserved cysteine residues are not essential for enzyme function
-
-
?
additional information
?
-
-
conserved cysteine residues are not essential for enzyme function
-
-
?
additional information
?
-
-
determination of polymer synthesis progression direction, overview
-
-
?
additional information
?
-
-
enzyme acts processive, the enzyme is active as a complex with cardiolipin, a bacterial membrane lipid
-
-
?
additional information
?
-
-
the substrate binding selectivity is more relaxed than the specificity of catalytic transfer, a nucleotide with 2 phosphate groups and complexed with a Mg2+ ion is absolutely required for activity
-
-
?
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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-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]
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]
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]
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]
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
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]
-
-
-
?
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]
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the linear heteropolysaccharide chain
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the reducing end to form a linear heteropolysaccharide chain
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
biosynthesis of hyaluronan
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
addition of monosaccharides to the reducing end to form a linear heteropolysaccharide chain
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
biosynthesis of hyaluronan
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + UDP-D-glucuronate
[beta-N-acetyl-D-glucosaminyl(1-4)beta-D-glucuronosyl(1-3)]n + UDP
-
-
-
-
?
additional information
?
-
-
hyaluronic acid synthase contributes to the pathogenesis of Cryptococcus neoformans infection
-
-
?
additional information
?
-
-
regulation mechanism of hyaluronan biosynthesis, stimulation of cells by cytokines effects the different expression patterns of the isoforms, especially during embryonic development, the isozymes have different roles in hyaluronan biosynthesis
-
-
?
additional information
?
-
-
HAS2, localized in the plasma membrane, uses cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates
-
-
?
additional information
?
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
-
isozyme HAS1 requires higher cellular UDP-GlcNAc concentration than isozymes HAS2 and HAS3. HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. HAS works on the cytosolic pool of the UDPsugars
-
-
?
additional information
?
-
-
isozyme expression and regulation by interleukin-1beta, progesterone, and low-molecular-weight hyaluronan in pregnant mouse uterine cervix, overview
-
-
?
additional information
?
-
-
regulation mechanism of hyaluronan biosynthesis, stimulation of cells by cytokines effects the different expression patterns of the isoforms, especially during embryonic development, the isozymes have different roles in hyaluronan biosynthesis, isozymes exhibit different functions in tumor growth, progression, and determination of malignancy
-
-
?
additional information
?
-
-
HA made by the has-1 transduced arterial smooth muscle cells is larger or part of a larger complex that resists proteolytic degradation when compared to the has-3 tansduced ASMCs. There is evidence that the different has enzymes have an inherent ability to regulate hyaluronan size
-
-
?
additional information
?
-
-
enzyme is responsible for hyaluronan biosynthesis, the hyaluronan capsule is an important, but not the only, virulence factor, physiological role of the enzyme
-
-
?
additional information
?
-
-
the produced hyaluronan capsule enhances infection
-
-
?
additional information
?
-
Pasteurella multocida hyaluronan synthase encompasses two transferase domains that elongate a growing hyaluronan oligosaccharide chain by addition of either GlcNAc or GlcUA residues from a corresponding UDP-sugar
-
-
?
additional information
?
-
-
the produced hyaluronan capsule enhances infection
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview, repression of HAS2 expression leads to reduced hyaluronan synthesis and reduced tumorigenicity in the peritoneum
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview, repression of HAS2 expression leads to reduced hyaluronan synthesis and reduced tumorigenicity in the peritoneum
-
-
?
additional information
?
-
isozyme expression and effects on tumor development and growth in rats, overview, repression of HAS2 expression leads to reduced hyaluronan synthesis and reduced tumorigenicity in the peritoneum
-
-
?
additional information
?
-
-
enzyme is responsible for hyaluronan biosynthesis, the hyaluronan capsule is an important, but not the only, virulence factor, physiological role of the enzyme
-
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Co2+
K+
coactivation occurs if K+ is applied together with Mn2+ or Mg2+. With Mn2+, a high UDP reaction rate and high molecular mass of hyaluronic acid (2.45 MDa after 8 h) are achieved. With Mg2+, a low reaction rate and low molecular mass (1.55 MDa after 8 h) are reached. If 10 mM K+ are added to 15 mM Mg2+, a significant increase of the reaction rate by a factor of 2.7 is observed, and the molecular mass is doubled (3.11 MDa after 8 h). The coactivating effect of K+ together with Mn2+ is less pronounced
KCl
-
activates at 50 mM, slightly more effective than NaCl
Mg2+
Mn2+
NaCl
-
activates at 50 mM, slightly less effective than KCl
additional information
-
metal requirements of mutant enzymes, overview
Co2+
-
2% as effective as Mn2+ at similar concentrations
Co2+
-
18% and 39% of the wild-type GlcUA-transferase and GlcNAc-transferase activity with Mn2+, respectively, 0.2 mM
Mg2+
-
20% as effective as Mn2+ at similar concentrations
Mg2+
-
66% and 77% of the wild-type GlcUA-transferase and GlcNAc-transferase activity with Mn2+, respectively, 0.2 mM
Mg2+
Mg2+ activates with an optimum of 15-20 mM leading to about half of the yield obtained with Mn2+ after 8 h
Mg2+
-
a nucleotide with 2 phosphate groups and complexed with a Mg2+ ion is absolutely required for activity
Mn2+
Mn2+ is the preferred metal ion with an optimum of 10 mM. Presence of Mn2+ induces a concentration-dependent decomposition of UDP-GlcA to its 1,2-cyclic phosphate and UMP, especially promoted at basic pH
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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; ErbB2 inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation; ErbB2 inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation
mannose
inhibits HAS because it depletes UDP-GlcNAc in cells; inhibits HAS because it depletes UDP-GlcNAc in cells; 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
PEG
-
increasing MW increases the inhibitory effect on the enzyme, overview
thiazolidinedione
ERK inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation; ERK inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation; ERK inhibitor, blocks the heregulin-mediated HAS isozyme phosphorylation/activation
UDP-glucuronate
The substrate UDP-GlcA inhibits pmHAS in concentrations above 8 mM
4-Methylumbelliferone
inhibits HAS because it depletes UDPGlcUA in cells; inhibits HAS because it depletes UDPGlcUA in cells; inhibits HAS because it depletes UDPGlcUA in cells
4-Methylumbelliferone
-
changes the localization of the enzyme by preventing its association with the plasma membrane
iodoacetamide
-
15% inhibition at 5 mM, biphasic inhibition
methylmethanethiosulfonate
-
93% reduced activity at 0.05 mM
N-ethylmaleimide
-
reacts with the Cys residues C226, C262, and C281, but not with C367, binding of substrates UDP-N-acetyl-D-glucosamine, UDP-D-glucuronate, or of product UDP protects the enzyme from inhibition by NEM, level of inhibition of wild-type and mutant enzymes, overview
N-ethylmaleimide
-
biphasic inhibition, about 50% reduced reaction velocity, unaltered Km-value, 70% inhibition at 5 mM
N-ethylmaleimide
-
inhibits wild-type and mutant enzymes by about 90% at 0.2 mM, UDP-N-acetyl-D-glucosamine protects the enzyme best against inactivation by NEM compared to diverse other nucleotide compounds, overview
sodium arsenite
-
inhibition of wild-type and mutant enzymes, no inhibition of C262 deletion mutant, overview
sulfhydryl reagents
-
enzyme is inhibited by sulfhydryl-modifying reagents, inhibition mode and mechanism
sulfhydryl reagents
enzyme is inhibited by sulfhydryl-modifying reagents, inhibition mode and mechanism
additional information
-
using inhibitors for MEK1/2, U0126, and for PI3K, LY294002, and the SN50 inhibitor, a complete inhibition of HAS2 transcriptional activity and hyaluronan sythesis is observed
-
additional information
AMP-activated protein kinase, AMPK, phosphorylates HAS2 at Thr110, which inhibits its enzymatic activity, and is itself inhibit by Compound C. Isoenzymes HAS1 and HAS3 are not modified by the kinase
-
additional information
-
interleukin-1beta augmented the expression of all 3 isozymes in the uterine cervix of pregnant mice, progesterone inhibited expression of isozymes HAS1 and HAS2
-
additional information
-
using inhibitors for MEK1/2, U0126, and for PI3K, LY294002, and the SN50 inhibitor, a complete inhibition of HAS2 transcriptional activity and hyaluronan sythesis is observed
-
additional information
-
enzyme is more active in 25 mM phosphate buffer than in 50 mM, enzyme is inhibited by increasing viscosity via addition of PEG, glycerol, sucrose or ethylene glycol
-
additional information
-
heating, oxidization or cysteine modification with N-ethylmaleimide inhibit the enzyme
-
additional information
-
HA product size is decreased by increasing concentrations of glycerol
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
black rice hydrolized peptides
BRP from germinated Oryza sativa L. var. japonica
-
dioleoyl phosphatidic acid
-
stimulates about 10fold
ERK
heregulin-mediated HAS isozyme phosphorylation/activation
-
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
platelet-derived growth factor BB
-
activation of enzyme in plasma membrane fraction
-
tunicamycin
-
significant increase in HAS activity in the cytosolic membrane fraction after tunicamycin treatment
cardiolipin
the bacterial enzyme is strictly associated with cardiolipin and the catalytic activity is dependent on such lipid
cardiolipin
-
required for full activity, activates up to 10fold, 14-18 molecules of cardiolipin are bound to one molecule of enzyme
cardiolipin
-
the bacterial enzyme is strictly associated with cardiolipin and the catalytic activity is dependent on such lipid
tetraoleoyl cardiolipin
-
strong activation, same pattern of lipid preference between pH 6 and 10.5. Lipid-independent activity at pH 11.5
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
-
additional information
-
the isozymes use cytoplasmic UDP-GlcNAc and UDP-GlcUA as precursors to polymerize the hyaluronan chain and to extrude it out of the cell without the necessity of a primer or an anchor protein or lipid
-
additional information
-
progesterone activates the expression of HAS3, low-molecular-weight hyaluronan activates the expression of isozyme HAS1
-
additional information
-
enzyme is more active in 25 mM phosphate buffer than in 50 mM
-
additional information
-
tetramyristoyl cardiolipin is ineffective in activation
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.7
hyaluronan oligomer HA4
with UDP-alpha-N-acetyl-D-glucosamine, pH 8.0, 35°C, recombinant enzyme
-
0.6
hyaluronan oligomer HA5
with UDP-alpha-D-glucuronate, pH 8.0, 35°C, recombinant enzyme
-
1
hyaluronan oligomer HA6
with UDP-alpha-N-acetyl-D-glucosamine, pH 8.0, 35°C, recombinant enzyme
-
0.7
hyaluronan oligomer HA8
with UDP-alpha-N-acetyl-D-glucosamine, pH 8.0, 35°C, recombinant enzyme
-
23.4
UDP-N-acetyl-alpha-D-glucosamine
pH 7.0, 25 °C, 10 mM MnCl2 and 5 mM UDP-GlcA (in absence of HA oligosaccharide as acceptor substrate)
0.8
UDP-alpha-D-glucuronate
pH 7.0, 25 °C, 10 mM MnCl2 and 15 mM UDP-GlcNAc (in absence of HA oligosaccharide as acceptor substrate)
0.04
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C281A
0.044
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C226S
0.056
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C281S
0.077
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant wild-type enzyme
0.079
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C367S
0.085
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C367A
0.088
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C226A
0.096
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C262S
0.11
UDP-D-glucuronate
-
pH 7.5, 30°C, recombinant wild-type enzyme at low UDP-N-acetyl-D-glucosamine concentration, and mutant C239S
0.146
UDP-D-glucuronate
-
pH 7.0, 30°C, recombinant mutant C262A
0.053
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C226A/C281A
0.065
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C281A/C367A
0.074
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant wild-type enzyme
0.079
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C226A/C367A
0.09
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C367A
0.091
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C367S
0.098
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C281S
0.113
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C262A/C281A
0.121
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C262A/C367A
0.13
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C281A
0.134
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C226A/C262A
0.153
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C262S
0.154
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C226A
0.186
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C262A
0.232
UDP-N-acetyl-D-glucosamine
-
pH 7.0, 30°C, recombinant mutant C226S
0.26
UDP-N-acetyl-D-glucosamine
-
pH 7.5, 30°C, recombinant wild-type enzyme at low UDP-glucuronate concentration
0.4
UDP-N-acetyl-D-glucosamine
-
pH 7.5, 30°C, recombinant wild-type enzyme and mutants C210S, C337S at low UDP-glucuronate concentration
0.88
UDP-N-acetyl-D-glucosamine
-
pH 7.5, 30°C, recombinant mutant C337S at higher UDP-glucuronate concentration
1.1
UDP-N-acetyl-D-glucosamine
-
pH 7.5, 30°C, recombinant mutant C304S/C337S
additional information
additional information
-
values for other substrate concentrations
-
additional information
additional information
-
kinetics, wild-type and mutant enzymes
-
additional information
additional information
-
kinetics, kinetic analysis of Cys-deletion mutants, overview
-
additional information
additional information
-
Km values of the enzyme in standard reaction in presence of diverse protecting nucleotide compounds, overview
-
additional information
additional information
-
recombinant enzyme, kinetics at different pH, thermodynamics
-
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
-
additional information
additional information
structural and kinetic analysis and modeling, both NAc- and UA-transferase domains follow a sequential kinetic mechanism, most likely an ordered one in which the UDP-sugar donor binds first, followed by the HA oligosaccharide. After transfer of the sugar moiety, both products are released, first the elongated HA oligosaccharide and then the UDP sugar. A mechanistic shift from a steady-state ordered bi-bi to rapid equilibrium ordered bi-bi mechanism is observed at the NAc-site between the HA6 and HA8 elongation, detailed overview
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
7.9
hyaluronan oligomer HA4
with UDP-alpha-N-acetyl-D-glucosamine, pH 8.0, 35°C, recombinant enzyme
-
7.9
hyaluronan oligomer HA5
with UDP-alpha-D-glucuronate, pH 8.0, 35°C, recombinant enzyme
-
13.5
hyaluronan oligomer HA6
with UDP-alpha-N-acetyl-D-glucosamine, pH 8.0, 35°C, recombinant enzyme
-
8.8
hyaluronan oligomer HA8
with UDP-alpha-N-acetyl-D-glucosamine, pH 8.0, 35°C, recombinant enzyme
-
120
UDP-D-glucuronate
-
recombinant enzyme, pH 7.0, 30°C
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4.5
ethylene glycol
-
recombinant enzyme, pH 7.0, 30°C
3.3
glycerol
-
recombinant enzyme, pH 7.0, 30°C
3.5
PEG 20000
-
recombinant enzyme, pH 7.0, 30°C
1.2
sucrose
-
recombinant enzyme, pH 7.0, 30°C
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0000000062
HAS activity, HAS1siRNA + HAS2siRNA + HAS3siRNA treatment, plus heregulin
0.0000000092
HAS activity, HAS1siRNA + HAS2siRNA + HAS3siRNA treatment
0.0000000227
HAS activity, HAS2siRNA treatment, plus heregulin
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
14
-
deletion mutant DELTA3-C281, pH 7.0, 30°C
27
-
deletion mutant DELTA3-C367, pH 7.0, 30°C
31.6
-
deletion mutant DELTA3-C262, pH 7.0, 30°C
38.6
-
deletion mutant DELTA3-C226, pH 7.0, 30°C
additional information
additional information
activity in wild-type cells and their oncogenic transformants
additional information
activity in wild-type cells and their oncogenic transformants
additional information
activity in wild-type cells and their oncogenic transformants
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.1
7.4
7.5
additional information
highest activity in MES, MOPS and HEPES buffers and lower activity in TRIS-buffer
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
30
37
60
22
-
HAS capture assay, overnight at room temperature
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
3 isozymes HAS1, HAS2, and HAS3 encoded by genes HAS1, HAS2, and HAS3
-
-
brenda
isoform HAS1; patients with multiple myeloma and Waldenstrom macroglobulinemia
SwissProt
brenda
3 isozymes HAS1, HAS2, and HAS3 encoded by genes HAS1, HAS2, and HAS3
-
-
brenda
-
-
-
brenda
human pathogen, single gene hasA in the has operon, class I enzyme
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
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
brenda
tumorigenic cell line, 3-5fold higher hyaluronan accumulation than in the parental cell line 3Y1
brenda
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
brenda
-
HAS1 expression is shown in 55.7% of SIRPA-positive macrophages in stage III follicles
brenda
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
brenda
embryonic mouse molar. Difference in the distribution and expression of the three hyaluronan synthases at different developmental stages. Hyaluronan synthase 1 and hyaluronan synthase 2, but not hyaluronan synthase 3, are highly expressed in the bud stage
brenda
-
expression of isoform HAS1 in theca cells of healthy and early atretic follicles of stage I and stage II and in progressing atretic stage III follicles
brenda
serous epithelial ovarian tumor
brenda
platelet-derived growth factor BB exerts dominant influence on HAS2 isoform expression by osteoblasts
brenda
metastatic cell line, 3-5fold higher hyaluronan accumulation than in the parental cell line 3Y1
brenda
-
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
brenda
additional information
fibroblast, expression of isozymes HAS1 and HAS2 is increased after oncogenic malignant transformation with v-sre and/or v-fos, while only the expression of isozyme HAS2 is increased by transformation with v-HA-ras
brenda
fibroblast, oncogenic malignant transformation with v-sre and/or v-fos, and v-HA-ras
brenda
-
HAS2 is the main synthase in aortic smooth muscle cells
brenda
at embryonic day 7.5, Has1 is expressed throughout the gastrulating embryo. After ambryonic day 8.5, Has1 expression disappears
brenda
at embryonic day 7.5, Has2 is expressed throughout the gastrulating embryo. After ambryonic day 8.5, Has2 continues to be strongly, albeit transiently, expressed in numerous tissues, including the branchial arches and craniofacial structures such as the palatal shelves and lens pit. Has2 is also expressed during cardiac, skeletal, and tail development
brenda
Has3 transcripts are first detected at embryonic day 10.5 in the maxillary and mandibular components of the first branchial arch. Has3 expression in the developing teeth, vibrissae hair follicles, nasal cavity, and inner ear complements the expression pattern of Has2
brenda
expression of different HAS isoenzymes during embryonic development, overview. Intense hyaluronan staining is observed throughout the development in the tissues of mesodermal origin, like heart and cartilages, but also for example during the maturation of kidneys and stratified epithelia. In general, staining for one or several HAS isozymes correlates with hyaluronan staining. While epithelial cells are mostly negaÂtive for HASs, stratified epithelia become HAS positive during differentiation
brenda
expression of different HAS isoenzymes during embryonic development, overview. Intense hyaluronan staining is observed throughout the development in the tissues of mesodermal origin, like heart and cartilages, but also for example during the maturation of kidneys and stratified epithelia. In general, staining for one or several HAS isozymes correlates with hyaluÂronan staining. While epithelial cells are mostly negaÂtive for HASs, stratified epithelia become HAS positive during differentiation
brenda
HAS2 is suppressed in senescent fibroblasts, real time PCR enzyme expresion in fibrotic and senescent fibroblasts
brenda
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
brenda
13fold decrease in hyaluronan synthase 3 expression in mineralising MG63 cells
brenda
hyaluronan synthesized by HAS-2 in MG-63 plays a crucial role in osteosarcoma cell proliferation, motility, and invasion
brenda
no significant change in hyaluronan synthase 2 expression in mineralising cells
brenda
TGF-beta2 is the major stimulator of HAS2 isoform expression in osteosarcoma cells
brenda
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
brenda
the SK-OV-3.ipl 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
brenda
-
expression of isoform HAS1 in theca cells of healthy and early atretic follicles of stage I and stage II and in progressing atretic stage III follicles
brenda
additional information
-
while immunoreactivity for HASs increases in the cancer cells, tumor mRNA levels for HASs are not changed, suggesting that reduced turnover of HAS protein may also have contributed to the accumulation of hyaluronan, quantitative expression analysis, overview
brenda
additional information
both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma
brenda
additional information
-
subcellular localization study, intracellular localization of EGFP-HAS1 and Dendra-HAS1 in MCF-7 cells, overview
brenda
additional information
-
isozyme expression profile in uterine cervix of pregnant mice
brenda
additional information
-
immunohistochemic localization, highest content in the granulosa layer
brenda
additional information
immunohistochemic localization, highest content in the granulosa layer
brenda
additional information
immunohistochemic localization, highest content in the granulosa layer
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
bound, enzyme possesses a cysteine cluster localized at the inner surface of the cell membrane near the substrate/product-binding sites
-
brenda
-
most parts of the enzyme, except the transmembrane region, are cytoplasmic including the active site
-
brenda
isozyme HAS2 has the brightest signal in the endoplasmic reticulum
brenda
isozyme HAS1 has the brightest signal in the Golgi network
brenda
isozyme HAS3 has the brightest signal in the Golgi and microvilÂlous protrusions
brenda
-
fraction containing membrane proteins from the endoplasmic reticulum and Golgi apparatus
brenda
are integral membrane proteins with transmembrane domains in addition to membrane-associated domains
brenda
-
enzyme is predicted to be an integral membrane protein
brenda
-
integral, plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity
brenda
in natural membrane extensions
brenda
-
the hyaluronan polymer is synthesized on the cytosolic side of the cell membrane by the membrane-embedded hyaluronan synthase
brenda
additional information
-
the HAS1 enzymatic activity depends on the endoplasmic reticulum-Golgi-plasma membrane traffic, like reported for isozymes HAS2 and HAS3
-
brenda
additional information
the intracellular distribution pattern of HAS1 is distinct from other isoenzymes. In all cell types studied so far, a high proportion of HAS1 is accumulated intracellularly, with a faint signal detected on the plasma membrane and its protrusions. The recombinant GFP-HAS1 signal is mainly cytoplasmic, rather than on the plasma membrane, being distributed either diffusely or in cytoplasmic patches, and partially co-localizing with the Golgi apparatus. Transfected HAS1V-GFP constructs localize with cytoskeletal structures like microtubules
-
brenda
additional information
-
recombinant isozymes GFP-HAS2 and GFP-HAS3 travel through endoplasmic reticulum, Golgi, plasma membrane, and endocytic vesicles in keratinocytes
-
brenda
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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
-
catalytically inactive mutant K190R HAS2 forms dimers with wild-type HAS2 and quenches the activity of wild-type HAS2
malfunction
-
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
-
embryonic lethality of genetic deletion of HAS2, some HAS2-specific functions are not compensated for by isozyme HAS1 or HAS3
malfunction
-
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
-
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
-
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
-
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
-
HAS-1 overexpression in dermal wounds decreases elements of scar formation
-
metabolism
-
regulation of hexosamine biosynthetic pathway, biosynthesis of hyaluronan and other glycoconjugates, and protein O-GlcNAcylation, overview
metabolism
-
role of hyaluronan in vascular disease, a multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases are involved in its metabolism
metabolism
-
role of hyaluronan in vascular disease, a multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases are involved in its metabolism
metabolism
-
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
-
role of hyaluronan in vascular disease, a multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases are involved in its metabolism
-
physiological function
-
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
-
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
-
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
-
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
-
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
-
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
-
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 synÂthases 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 developÂment, 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 CD44âHA 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
-
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