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Literature summary extracted from

  • Vigetti, D.; Viola, M.; Karousou, E.; De Luca, G.; Passi, A.
    Metabolic control of hyaluronan synthases (2014), Matrix Biol., 35, 8-13.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.4.1.212 cardiolipin the bacterial enzyme is strictly associated with cardiolipin and the catalytic activity is dependent on such lipid Streptococcus sp.
2.4.1.212 cardiolipin the bacterial enzyme is strictly associated with cardiolipin and the catalytic activity is dependent on such lipid Pasteurella multocida
2.4.1.212 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 Mammalia

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.4.1.212 microsome
-
 Mammalia
-
-
2.4.1.212 plasma membrane isozymes HAS1-3 Mammalia 5886
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.4.1.212 UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan] Mammalia
-
 UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan] Streptococcus sp.
-
 UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan] Pasteurella multocida
-
 UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan] Mammalia
-
 UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan] Streptococcus sp.
-
 UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan] Pasteurella multocida
-
 UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.4.1.212 Mammalia
-
-
-
2.4.1.212 Pasteurella multocida Q7BLV3 gene hyaD
-
2.4.1.212 Streptococcus sp.
-
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.4.1.212 additional information the treatments of plasma membranes or microsomal membranes with phosphatases or N-glycosidase F reveals that also HAS activity in internal vesicles can be modulated Mammalia
2.4.1.212 phosphoprotein ERK-mediated serine phosphorylation of all the three HAS isozymes increases their specific activity. AMP activated protein kinase (AMPK) is considered a sensor of the energy status of the cell and is activated by low ATP:AMP ratio, AMPK leads to the inhibition of hyaluronan secretion by HAS2 phosphorylation at residue Thr110 Mammalia

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.4.1.212 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 Pasteurella multocida ?
-
 ?
2.4.1.212 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 Mammalia ?
-
 ?
2.4.1.212 UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 Mammalia UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 Streptococcus sp. UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-D-glucuronate + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 Pasteurella multocida UDP + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 Mammalia UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 Streptococcus sp. UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 ?
2.4.1.212 UDP-alpha-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 Pasteurella multocida UDP + N-acetyl-beta-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->3)-N-acetyl-beta-D-glucosaminyl-(1->4)-[nascent hyaluronan]
-
 ?

Subunits

EC Number Subunits Comment Organism
2.4.1.212 More a single protein exerts many functions as binding of two distinct UDP-sugars and binding of two distinct hyaluronan acceptor or donor species. Class 1 mammalian isozymes have two N-terminal transmembrane domains and several of C-terminal transmembrane domains or membrane associated domains, predicted structural organization of mammalian isozymes, Class 1 mammalian HAS with 6 transmembrane domains and 2 membrane associated domains, structure comparisons, overview Mammalia
2.4.1.212 More Streptococcal enzymes have two N-terminal transmembrane domains and several of C-terminal transmembrane domains or membrane associated domains, predicted structural organization of Streptococcal isozymes, structure comparisons, overview Streptococcus sp.
2.4.1.212 More the only member of Class 2 HAS, expressed by Pasteurella multocida, has a short C-terminal domain with only 4 transmembrane regions and 2 membrane associated domains, structure comparisons, overview Pasteurella multocida

Synonyms

EC Number Synonyms Comment Organism
2.4.1.212 HAS
-
 Mammalia
2.4.1.212 HAS
-
 Streptococcus sp.

General Information

EC Number General Information Comment Organism
2.4.1.212 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 Mammalia
2.4.1.212 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 Mammalia
2.4.1.212 additional information the mechanism of HAS2 proteasomal degradation is complex and requires additional processes considering the several transmembrane domains of HAS2 and its localization in the plasma membrane Mammalia
2.4.1.212 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 Mammalia