Background of Hyaluronidases
Hyaluronidases are a family of enzymes that degrade hyaluronic acid, a major constituent of the extracellular matrix. The first recorded discovery of hyaluronidase took place in 1928 during research on bacteria. However, it was not until the 1940s that the presence of hyaluronidase in human tissues and physiological fluids was confirmed. Among these hyaluronidases, Human hyaluronidases (HYALs) are critical regulatory enzymes present in various tissues and body fluids.
Gene Locus and Protein Structure
Human hyaluronidases comprise 6 isoforms - HYAL1, HYAL2, HYAL3, HYAL4, HYALP1, and PH-20. The gene locus for these enzymes exists on chromosome 3p21.3. The structure of the HYAL1 gene is highly similar to the HYAL2 gene, suggesting a common evolutionary origin. The protein structure comprises numerous glycosaminoglycan side chains that contribute to its enzymatic activity.
Human Hyaluronidase Function and Related Signaling Pathways
Human hyaluronidase functions primarily to degrade hyaluronic acid, thereby controlling its size and makeup in the human body. This function is crucial in cellular proliferation, migration, and differentiation - core processes involved in tissue repair, embryogenesis, and tumor regulation.
The signaling pathways associated with human hyaluronidase are interrelated and function coordinately to mediate hyaluronan metabolism. A major pathway is the CD44 Receptor-Ligand Interaction Pathway. Here, hyaluronic acid binds to the CD44 receptors, triggering a signal transduction process that regulates the function of these cells. The second crucial process involves the Ras-MAPK pathway. Hyaluronidase acts as a downstream effector, stimulating the SOS-Ras-MAPK cascade to affect cell proliferation, differentiation, and apoptosis.
Human Hyaluronidase in Diseases
Human hyaluronidase plays a significant role in various pathological conditions as changes in its expression and activity can result in alterations in the extracellular matrix, affecting organ function. For instance, in cancer metastasis, elevated levels of hyaluronidase could enhance tissue infiltration capability, promoting tumor progression and invasion. In macular degeneration (AMD), where there's loss of central vision, the enzyme's overexpression can cause the vulnerability of the retina to inflammation and oxidative stress.
Medical Application of Human Hyaluronidase
Given its essential role in degrading hyaluronic acid in physiological conditions, Human hyaluronidase has significant potential in medicine. For instance, the enzyme has been applied in enhancing drug absorption. By breaking down hyaluronic acid in the subcutaneous layer, hyaluronidase can facilitate the distribution and absorption of other substances, such as local anesthetics, subcutaneous fluids, and vaccines. It also has a promising role in treating solid tumors by enhancing the penetration of chemotherapeutic drugs.
Drug Candidates Related to Human Hyaluronidase
Several biotherapeutic drug candidates involving human hyaluronidase have been developed and tested in clinical trials. One notable drug is Hylenex (recombinant human hyaluronidase), which is approved by the FDA to increase the absorption and dispersion of other injected drugs. Another drug, ELELYSO (taliglucerase alfa), is an enzyme replacement therapy that breaks down glucocerebroside in cells.
