Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Enzymes Attack One Another In "Cathepsin Cannibalism"

14.08.2012
Researchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade.

Dubbed “cathepsin cannibalism,” the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.

Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.

Using a combination of modeling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.

“These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,” said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.”

The research was supported by the National Institutes of Health, the National Science Foundation and the Georgia Cancer Coalition. Details of the study were reported August 10, 2012, in the Journal of Biological Chemistry.

Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.

When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.

Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specializes in modeling – to examine what possible conditions could account for the experimental result. Barry’s modeling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.

That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.

“We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,” said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. “We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.”

The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.

Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.

“The effect of the cathepsins on one another complicates the system,” said Platt. “If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-target binding and side effects that were not anticipated.”

Platt’s long-term research has focused on cathepsins, including the development of sensitive tools and assays to quantify their activity in cells and tissue, as well as potential diagnostic applications for breast, lung and cervical cancer. Cathepsins normally operate within cells to carry out housekeeping tasks such as breaking down proteins that are no longer needed.

“These enzymes are very powerful, but they have been overlooked because they are difficult to study,” said Platt. “We are changing the way that people view them.”

For the future, Platt plans to study interactions of additional cathepsins – as many as three or four are released during certain disease processes – and to develop a comprehensive model of how these proteases interact while they degrade collagen and elastin. That model could be useful to the designers of future drugs.

“As we build toward a comprehensive model of how these enzymes work, we can begin to understand how they behave in the extracellular matrix around these cells,” said Platt. “That will help us be smarter about how we go about treating diseases and designing new drugs.”

The project described was supported by Award Number DP2OD007433 from the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Office of the Director, National Institutes of Health, or the National Institutes of Health. This material is also based on work supported by the National Science Foundation under the Science and Technology Center Emergent Behaviors of Integrated Cellular systems (EBICS) Grant No. CBET-0939511.

Research News & Publications Office
Georgia Institute of Technology
75 Fifth Street, N.W, Suite 309
Atlanta, Georgia 30308 USA
Media Relations Assistance: John Toon (404-894-6986)(jtoon@gatech.edu).
Writer: John Toon

John Toon | Newswise Science News
Further information:
http://www.gatech.edu

More articles from Life Sciences:

nachricht Microscope measures muscle weakness
16.11.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

nachricht Good preparation is half the digestion
16.11.2018 | Max-Planck-Institut für Stoffwechselforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: UNH scientists help provide first-ever views of elusive energy explosion

Researchers at the University of New Hampshire have captured a difficult-to-view singular event involving "magnetic reconnection"--the process by which sparse particles and energy around Earth collide producing a quick but mighty explosion--in the Earth's magnetotail, the magnetic environment that trails behind the planet.

Magnetic reconnection has remained a bit of a mystery to scientists. They know it exists and have documented the effects that the energy explosions can...

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Purdue cancer identity technology makes it easier to find a tumor's 'address'

16.11.2018 | Health and Medicine

Good preparation is half the digestion

16.11.2018 | Life Sciences

Microscope measures muscle weakness

16.11.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>