Molecule of the Month: Hyaluronidases

Our bodies are built of trillions of cells, all working together to perform the many biological tasks of daily life. These cells are not connected rigidly like bricks and mortar. Instead, a tough but flexible layer of connective tissue ties them together, allowing our bodies the freedom to move and breathe, and repair themselves if damaged. Hyaluronan is a key component of this connective tissue. It is a long carbohydrate chain composed of two simple types of sugars. Like many carbohydrates, it can sop up a thousand times its own weight of water to form gluey, flexible aggregates. In connective tissue these are combined in different proportions with more rigid elements, like collagen, to create everything from resilient sheets that bind cells together to slippery liquids that lubricate joints.

Our cells make several types of enzymes that break down hyaluronan chains when they are no longer needed. Hyaluronidase-2 (shown from a predicted computational model, AF_AFQ12891F1) begins by breaking the long chains into manageable pieces. Hyaluronidase-1 (PDB ID 2pe4) then breaks these down into small fragments with four sugars. Finally, two other enzymes break these fragments into individual sugars.

Amazingly, about a third of our hyaluronan chains are recycled every day as they respond to the changing needs of our bodies. They play many roles in our health. They assist with the developing interactions between dividing cells as embryos grow. They help wounds heal and help motile cells push their way through the body. As shown below, they also assist sperm cells in fertilizing an egg. Unfortunately, they also have a darker side, since they may be used by cancer cells to assist with metastasizing from a tumor to other parts of the body.

Bacteria contain slightly different enzymes that degrade hyaluronan, termed hyaluronate lyases. The immune system is always on the lookout for stray hyaluronan fragments, since they could be a sign of bacterial infection. For example, the enzymes shown here are from the bacterium Cutibacterium acnes, which is important in the formation of acne. They produce fragments of hyaluronan and the immune system mounts an inflammatory response against them. This response is very selective, however. Researchers have found that some strains of these bacteria cause acne, and others don’t. The difference lies in their slightly different hyaluronidases, HylA and HylB, which cleave hyaluronan in different ways. HylA (PDB ID 8fyg) chops hyaluronan into large fragments that promote inflammation and cause acne, but HyaB (PDB ID 8fnx) chops it into tiny two-sugar fragments that aren’t sensed as strongly by the immune system.