Hyaluronan synthase

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Hyaluronic acid synthase (HAS) is a type of enzyme that exists on the plasma membrane and can specifically act in the process of hyaluronic acid (HA) synthesis. In 1993, DeAngelis successfully cloned the first HAS from group A streptococci by using transposon mutation method, named spHAS (S.pyogenesHAS), which opened the prelude to human research expressing HAS from different sources and different functions. In 1996, 4 laboratories in the United States almost simultaneously confirmed the HAS-cDNAs of eukaryotes, confirming that the human HAS gene is a multi-gene family, which encodes 3 isoenzymes: HAS1, HAS2 and HAS3. The phased research of eukaryotic HAS has greatly promoted the biosynthesis of HA. Now, in some mammalian cells and some eukaryotic cells, the synthesis of HA through a single HAS protein has become a reality. Currently, HA is a product of HAS catalyzed synthesis, and its preparations have been widely used in clinical practice. However, the enzyme HAS, which plays a key role in the synthesis of human HA, has just entered a new stage of research and application in both its biological function and clinical application.

Figure 1. Protein structure of hyaluronic acid synthase.

Biological activity

The expression of HAS at different developmental stages. Scientists have studied the expression of HAS in different developmental stages of human body by using naturally occurring mutation method, transgenic technology and gene knockout technology, and found that different HAS play different roles in the process of HA synthesis. HAS1 is expressed throughout the life process. Although the level of high molecular weight HA catalyzed by it is very low in various cells, it is essential to maintain the normal function of the body. HAS2 is significantly expressed in the embryonic development stage. The high molecular weight HA catalyzed by it has an important role in maintaining tissue structure and body fluid balance, which is of great significance in the expansion and growth of body tissue. HAS3 is expressed in many tissues in the late embryo and adult. It can be used in the surrounding matrix of the cell spontaneously, and it can bind to the HA receptor on the cell surface to stimulate a signal cascade and produce a variety of intracellular physiological effects.

Clinical application

The application of HA in the field of pharmacy is in the ascendant. As the key enzyme for the synthesis of HA, HAS has attracted widespread attention.

• HA synthesized by HAS is an extremely important source of HA in human life activities. It has the function of maintaining tissue structure and body fluid balance, and plays an important role in the process of tissue expansion and growth. HA can also assist in enhancing the activity of drugs, thereby exerting its drug carrier effect, and has broad application prospects.
• Participate in the wound repair process.
• HA synthesized by HAS can promote the repair of soft tissue, cartilage tissue, and bone tissue damage, so it has a broad medical prospect for the treatment of burns and the repair of bone damage.
• Treatment of dry eye disease, joint dysfunction and other bone diseases and immune-related dysfunction after birth.
• HAS can regulate the dynamic synthesis of HA, control cell migration, and repair phosphorous epithelial cells. Clinical attempts have been made to use HAS genes for disease treatment. Under pathological conditions, the synthesis of HA is inhibited by adjusting the mRNA level of HAS, thereby maintaining the balance of the extracellular matrix, and regulating the changes in intracellular and extracellular osmotic pressure caused by insufficient HA synthesis.

Role in cancer metastasis

• HAS can play a role in all stages of cancer metastasis. By producing anti-adhesion HA, HAS can release tumor cells from the primary tumor mass. In the process of blood vessel infiltration or exudation, the interaction of HA produced by HAS with receptors such as CD44 or RHAMM promotes cell changes, allowing cancer cells to infiltrate the blood vessel or lymphatic system. When traveling in these systems, HA produced by HAS protects cancer cells from physical damage. Finally, in the formation of metastatic disease, HAS produces HA, so that cancer cells interact with natural cells in secondary sites and generate tumors by themselves.