Immune System Enzyme
The serine proteases are enzymes that cut up proteins and by doing this they activate signal molecules. These enzymes are released by neutrophil granulocytes – specialized white blood cells that represent the first line of defense in case of a bacterial infection. The signal molecules obtained from the action of these enzymes are called chemokins, and they play an important role in the inflammation process because they determine other immune cells to migrate in the infected tissue and destroy the pathogens.
If the mechanism is not properly controlled by the body, there are too many activated immune cells and they can harm the healthy tissue. This happens in chronic inflammatory diseases, thus a method to alleviate the symptoms of these diseases is to inhibit the serine proteases. “Proteases sometimes act as accelerants and can even trigger a chronic inflammation quite independently of bacterial intruders. If we dampened down the defences, we could counteract this effect”, explains Dieter Jenne, the research group leader.
A new serine protease was discovered by scientists at Max Plank Institute of Neurobiology in Martinsried: the neutrophil serine protease 4 (NSP4). This protein could be a potential target for new drugs designed to cure diseases that involve an overactive immune system. Dieter Jenne sais: “The special thing about this enzyme is that it cuts proteins that have the amino acid arginine at a particular point. This is where NSP4 differs from the other three known neutrophil serine proteases, which are similar in molecular structure, but have a different recognition motif.”
This different motif of recognition could be used to develop new drugs that inhibit NSP4, thus reducing the inflammation. To date, none of the substances that were thought to have a blocking effect on the neutrophil proteases have been developed into effective drugs: “So far, we don’t know the identity of the NSP4 substrate, but we assume they must be signal molecules”, says Dieter Jenne.
Using gene sequences, it was shown that NSP4 has remained almost unchanged during hundreds of million of years of evolution. “That would indicate that NSP4 regulates a fundamental process”, says Dieter Jenne. The enzyme was not known of until now because its concentration at the inflammation site is much lower than other proteases. Scientists at Max Planck discovered it while searching serine proteases encoding genes in the human genome, and found a gene sequence that was previously unknown.
One of the researchers, Natascha C. Perera, lead author of the study, examined the enzyme in its active, folded state. Now the scientists have to study the enzyme in vivo to understand its whole function besides the pro-inflammatory function, and thus discover the possible side effects that can occur by blocking it. This means another step towards new active substances that may help patients with inflammatory diseses.