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