title: Metabolic control of hyaluronan synthases.
abstract: Hyaluronan (HA) is a glycosaminoglycan composed by repeating units of D-glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc) that is ubiquitously present in the extracellular matrix (ECM) where it has a critical role in the physiology and pathology of several mammalian tissues. HA represents a perfect environment in which cells can migrate and proliferate. Moreover, several receptors can interact with HA at cellular level triggering multiple signal transduction responses. The control of the HA synthesis is therefore critical in ECM assembly and cell biology; in this review we address the metabolic regulation of HA synthesis. In contrast with other glycosaminoglycans, which are synthesized in the Golgi apparatus, HA is produced at the plasma membrane by HA 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 GAGs, which is an energy consuming process. AMP activated protein kinase (AMPK), which is considered a sensor of the energy status of the cell and is activated by low ATP:AMP ratio, leads to the inhibition of HA secretion by HAS2 phosphorylation at threonine 110. However, 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 β-N-acetylglucosamine (O-GlcNAcylation) to specific aminoacid residues. Such highly dynamic and ubiquitous protein modification affects serine 221 residue of HAS2 that lead to a dramatic stabilization of the enzyme in the membranes.
authors.affiliation: Dipartimento di Scienze Chirurgiche e Morfologiche, Università degli Studi dell'Insubria, via J.H. Dunant 5, 21100 Varese, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Vigetti
authors.affiliation: Dipartimento di Scienze Chirurgiche e Morfologiche, Università degli Studi dell'Insubria, via J.H. Dunant 5, 21100 Varese, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Viola
authors.affiliation: Dipartimento di Scienze Chirurgiche e Morfologiche, Università degli Studi dell'Insubria, via J.H. Dunant 5, 21100 Varese, Italy.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Karousou
authors.affiliation: Dipartimento di Scienze Chirurgiche e Morfologiche, Università degli Studi dell'Insubria, via J.H. Dunant 5, 21100 Varese, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: De Luca
authors.affiliation: Dipartimento di Scienze Chirurgiche e Morfologiche, Università degli Studi dell'Insubria, via J.H. Dunant 5, 21100 Varese, Italy. Electronic address: alberto.passi@uninsubria.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Passi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D053898:Biosynthetic Pathways / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D015398:Signal Transduction / Q000502:physiology*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D014535:Uridine Diphosphate Glucuronic Acid; D014537:Uridine Diphosphate N-Acetylglucosamine; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; D000076002:Hyaluronan Synthases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Glycosaminoglycan; HBP; O-GlcNAcylation; UDP-GlcNAc; UDP-GlcUA