Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New compound class found to trigger changes in cell garbage can

25.07.2003


Researchers have discovered a novel class of compounds that affects the cell’s garbage disposal system which degrades proteins and opens a window for understanding a vital cell function as well as for treating heart disease and cancer.



The distinctive mechanisms of these compounds are reported in the July 29 issue of Biochemistry and online earlier this month by Dr. Michael Simons, professor of medicine and of pharmacology and toxicology at Dartmouth Medical School and head of cardiology at Dartmouth-Hitchcock Medical Center, with colleagues from Dartmouth and the University of Texas.

Just as cells produce proteins, they must also get rid of those they no longer need. Structures called proteasomes chew up proteins made within the cell -- including viruses and other parasites -- that are targeted for destruction.


Proteasomes are a complex of enzymes with a cylinder core and a lid on the top and bottom. "The proteins come in and are digested like a big garbage can." Simons said. Proteasomes are an attractive target for drug development because manipulating them to prevent or provoke degradation of a particular protein affects most cell activities.

In studying compounds that promote the formation of new blood vessels, (angiogenesis), Simons and his colleagues found these compounds constituted a new class of inhibitor that changes the shape of the proteasome. "This is a completely different class of proteasome inhibitors with unusual mechanisms," Simons said.

Generally, proteasome inhibitors interact with an active site of the protein-digesting enzymes on chains inside the proteasome cylinder. The new-found class, proline/arginine-rich peptides, instead bind to the outside of the proteasome cylinder, triggering it to change shape in a way that limits the proteins they can ingest. The effects appear in all proteasomes, from yeast to humans.

Normal proteasomes look like regular circles; when the researchers add the peptide, the proteasome takes a dumbbell shape. Substances cannot easily get into the proteasome and its activity range is restricted. As a result, it will destroy only a small number of proteins.

"So this is a new mechanism of action, a new class of inhibitors and has interesting therapeutic implications," Simons said.

Since the compounds do not act on the active site of an enzyme, but on its shape, the effects are reversible, meaning that treatment options are controllable. Moreover, there is intriguing therapeutic potential for both heart disease and cancer.

These peptides are especially powerful agents for inducing vessel growth and their angiogenic activity correlates with their ability to interact with certain proteasomes and change their shapes. One result is that they turn off degradation of master switch genes that activate several different angiogenic cascades.

These peptides also prevent degradation of a molecule that normally inhibits activity of nuclear factor kappa B that controls a number of cell processes including growth and inflammation. High levels of the molecule, IkB, impede cell growth, which has implications for use against cancers. Simons speculates that by changing peptide structure, the dual effects of stimulating and stopping growth can be separated.

The findings provide insights into proteasome functions. This peptide appears to regulate how proteasomes interact with the proteins destined for obliteration. Proteasomes are known to change shape when they interact with an inhibitor, but "this is a very unusual shape change; it does not fit any known patterns," Simons added.

Now the researchers are detailing the functions of this naturally occurring immune response peptide . It was originally isolated form pig intestines for use in healing wounds because of its multiple roles as an agent that stimulates vessel growth, inhibits inflammatory responses and kills bacteria.

Coauthors include Mark Post, visiting associate professor of medicine at DMS, as well as M. Maria Gaczynska and Pawel A. Osmulski, of the University of Texas Health Science Center at San Antonio and Youhe Gao of Beijing.

DMS Communications | EurekAlert!
Further information:
http://www.dartmouth.edu

More articles from Life Sciences:

nachricht At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History

nachricht New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

Im Focus: Autonomous 3D scanner supports individual manufacturing processes

Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).

Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Fingerprints of quantum entanglement

16.02.2018 | Information Technology

'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers

16.02.2018 | Health and Medicine

Hubble sees Neptune's mysterious shrinking storm

16.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>