New compound class found to trigger changes in cell garbage can

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.

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