Researchers Shed Light on Cathepsin Interactions and Develop Tool to Model System Activity

Researchers Shed Light on Cathepsin Interactions and Develop Tool to Model System Activity

A family of enzymes called cathepsins are responsible for getting rid of unneeded protein in cells by breaking them down into amino acids. Excessive amounts of protein can be toxic, so these enzymes play a very important role.

Cathepsins are best known for their role in lysosomes, organelles in the cytoplasm that contain digestive enzymes that digest worn out organelles, engulfed bacteria and viruses, and food particles. If cells are damaged beyond repair, lysosomes also play an important role in cell death.

Cathepsins have been implicated in several diseases such as atherosclerosis, sickle cell disease, and cancer. Cathepsins are powerful enzymes and if they are overexpressed can cause considerable harm. In the wrong place, they can break down structural proteins such as collagen, tendons, and the endometrium. The enzymes also promote cancer. For example, Cathepsin K breaks down bone to recycle calcium. In breast cancer, the cancerous cells make cathepsin K, which then breaks down collagen surrounding the tumor, which allows the cancerous cells to escape and metastasize to bone.

Some experimental drugs have been developed that target specific cathepsins, and while the drugs are effective, they produce many side effects. As a result, they are not safe to use. What is not known is what causes those side effects, but a team of researchers at the Georgia Institute of Technology has shed light on how cathepsins work, and why targeting a specific cathepsin produces undesirable side effects.

Rather than focusing on a single cathepsin, the researchers looked at the system as a whole – cathepsins K, L, and S. They found that not only to these cathepsins break down unneeded proteins, they also attack and deactivate each other. Cathepsins are proteins that break down proteins. When they are in close proximity to each other, they attack.

The researchers have now developed a computational model that shows how small changes can ripple through the cathepsin system. This model of the cathepsin system could help improve understanding of how cathepsins interact, which could be of great use in drug development. If it is not known how cathepsins work as a system, it will not be possible to develop effective drugs that target cathepsins without resulting in damaging side effects. For example, it may be possible in situations where one of the cathepsins is not implicated in disease, to boost numbers to break down one or both of the other cathepsins that are.

The online tool has now been made available to researchers. “[Researchers] can set up their own experiments and make predictions, including what inhibitors will do, so they can test inhibitors at varying strengths in this system,” said Manu Platt, principal investigator and associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “They can ask questions that they can’t answer yet experimentally then test the model’s predictions in the lab.”

You can read more about the study in the paper – Reassessing enzyme kinetics: Considering protease-as-substrate interactions in proteolytic networks– which was recently published in the journal Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.1912207117

Image: Ribbon diagram of human cathepsin K, via Wikimedia Commons

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