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 Ambush in a petri dish
24.11.2017 | Friedrich-Schiller-Universität Jena

nachricht Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New proton record: Researchers measure magnetic moment with greatest possible precision

High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons

The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...

Im Focus: Frictional Heat Powers Hydrothermal Activity on Enceladus

Computer simulation shows how the icy moon heats water in a porous rock core

Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

IceCube experiment finds Earth can block high-energy particles from nuclear reactions

24.11.2017 | Physics and Astronomy

A 'half-hearted' solution to one-sided heart failure

24.11.2017 | Health and Medicine

Heidelberg Researchers Study Unique Underwater Stalactites

24.11.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>