Biochemistry of Hyaluronan Synthesis

Hyaluronan (HA) is a ubiquitous component of the extracellular matrix and cell microenvironment made of β D-Glucuronic acid and D-N-Acetylglucosaminedisaccharides bound by alternating glycosidic β(1,3) and β(1,4) linkage, respectively. Although it belongs to the family of glycosaminoglycans, it has several peculiarities. HA chains can greatly vary in length, it is not chemically modified as it does not contain sulfation and epimerization. Further, HA is synthesized by a family of three HA synthases (HAS1, 2, and 3) located on the plasma membrane. These proteins are undefined enzymes as they are never crystallized and contain all the functions required to recognize two different substrates, catalyze two different glycosidic bonds, and extrude the nascent polysaccharide through the membrane. Moreover, HASes are the key point of regulation of HA synthesis and, in Mammals, HAS2 is the most important isoenzyme. HAS2 undergoes a multistep regulation that comprises transcriptional, translational, and epigenetic modifications and integrates the metabolic status of the cell as well as the external stimuli finely adjusting the production of HA. The elucidation of the molecular mechanisms that regulate HA synthesis is of great interest as alterations of HA in the extracellular matrix are found in common pathologies and seems to have a pivotal role in the control of several aspects of cell biology as motility, survival, and proliferation. This chapter will focus on the biochemistry of HA synthesis, HASes and their regulation.