Recent Advances in the Evolutionary Classification and Structural Insights of Hyaluronan Synthase

Hyaluronan synthase (HAS) is a membrane-bound enzyme with specific multifunctional glycosyltransferase activity that catalyzes the alternating addition of UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylglucosamine (UDP-GlcNAc) to synthesize hyaluronic acid (HA). Widely found in microorganisms, vertebrate, and virus, HAS plays a vital role in HA biosynthesis, determining both its yield and molecular weight. Variations in sequence and catalytic properties among HASs from different sources result in HA products with distinct molecular weights and production efficiencies. High-molecular-weight HA is in high demand for biomedical applications due to its superior physiological properties. However, its industrial production faces challenges such as low yields and poor batch consistency, influenced by host strain characteristics, HAS enzyme activity, and fermentation conditions. Modulating HAS function to control HA molecular weight has become a research focus, yet its underlying mechanisms remain poorly understood due to the enzyme's small size, complex membrane-bound nature, and unresolved catalytic mechanism. This study systematically reviews the origins, phylogenetic relationships, and sequence-structural features of HAS. Using structural modeling, it explores the potential mechanisms underlying high-molecular-weight HA synthesis and highlights recent advances in HAS engineering aimed at enhancing product molecular weight. These insights provide a foundation for the rational design of HAS and the efficient biosynthesis of high-molecular-weight HA, while also contributing to a broaden understanding of multifunctional membrane protein catalysis.