Navigation Links
A new mechanism for reversible proteasome inhibition
Date:12/13/2010

What makes cancer cells so dangerous is that they grow in an unregulated way and proliferate much faster than other cells. The proteasome, a large protein complex, plays a key role in this process: By breaking down used proteins for recycling, it clears the way for the next cycle. New hope was spawned several years ago with the discovery that inhibiting proteasomes can be used as a means to put the brakes on cell growth. In the mean time, the first drug using this approach, Bortezomib, generates revenues in excess of one billion U.S. dollars per year. However, it also inhibits other important proteins and thus sets off a host of severe side effects. Hence, there is a worldwide search for alternatives.

A variant of the proteasome, the immuno-proteasome, is a leading actor in another vital process: the immune reaction. The production of human insulin in genetically modified bacteria is a boon for diabetes patients. But calculating required doses and injecting insulin on a daily basis is a considerable burden. The transplantation of intact insulin-producing islet cells from pigs could be a solution, but the immune reaction stands in the way. If physicians were able to curb the immuno-proteasome temporarily, they could possibly get the rejection reaction under control.

In both cases, targeting the intervention as specifically as possible is essential to minimizing the damage caused by side effects. Besides Bortezomib two other proteasome inhibitors Carfilzomib and Salinosporamide A, derived from a poison produced by a marine bacterium are already in the human clinical trial stage. In earlier research, Professor Groll's team succeeded in explaining the mechanism of action of both substances. They follow the same principle, which is considerably more specific than Bortezomib in binding at the desired location in the proteasome and thus produce significantly fewer side effects. Yet, when they take effect, they destroy the proteasomes irreversibly. While healthy cells survive by building up a new proteasome, the fast-growing cancer cells suffocate in their own waste and end up in apoptosis.

The trick of both of these proteasome blockers is a two-step reaction. The tiny molecule fits a specific site on the proteasome like a key going into a lock. However, the reversible docking at the binding site is followed by an irreversible ring formation that prevents the key from being pulled back out. By choosing another head group, Professor Michael Groll und Dr. Melissa Graewert were able to achieve a reversible ring formation. The new head group contains an aldehyde and a keto group in immediate proximity. They also react with the binding sites on the proteasome by forming a ring. However, the reaction of these two groups is reversible: The key can be removed from the lock and the proteasome can resume its work.

Within the framework of their work supported by the Cluster of Excellence Center for Integrated Protein Science Munich (CIPSM), the TUM scientists succeeded in confirming the assumed mechanism using X-ray structure analysis of inhibited proteasome crystals. It also became clear how this binding mechanism could be developed into a drug with fewer side effects. In addition to the head group, the binding mechanism contains a short chain of amino acids that can be designed to fit into the binding pockets of the proteasome. By varying the amino acids, the binding can be optimized to specifically attack immuno-proteasomes.

"The reversible two-step binding mechanism shown here is unique to proteasomes," says Michael Groll, who holds the Chair of Biochemistry at the Department of Chemistry of the Technische Universitaet Mnchen. "This explains the high selectivity and leads us to expect relatively minor side effects. The reversible reaction opens up a much wider field of application. We can now develop these binding mechanisms further in the direction of immunosuppressive agents." It is precisely this challenge the researchers are now taking on, in close collaboration with physicians, through a new SFB-transregional initiative: "Biology of xenogenic cell and organ transplantation from bench to bedside."


'/>"/>

Contact: Andreas Battenberg
battenberg@zv.tum.de
49-892-891-0510
Technische Universitaet Muenchen
Source:Eurekalert  

Related medicine news :

1. IU research team discovers TB disease mechanism and molecule to block it
2. UCR researcher identifies mechanism malaria parasite uses to spread in red blood cells
3. Tumor mechanism identified
4. Multiple sclerosis, Italian researchers discover a possible onset mechanism for the disease
5. Pancreatic Cancer Study Reveals Mechanism Initiating Disease, In Mice
6. Pancreatic cancer study reveals mechanism initiating disease, in mice
7. Study identifies 1 of the mechanisms behind breast cancer metastasis
8. Mechanism that may trigger degenerative disease identified
9. A key mechanism links virgin olive oil to protection against breast cancer
10. Scripps Research scientists uncover previously unknown natural mechanism that controls cocaine use
11. Study makes exciting progress in elucidating the mechanisms of bortezomib in lymphoma
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
A new mechanism for reversible proteasome inhibition
(Date:3/1/2017)... York, NY & Greenwich, CT (PRWEB) , ... March 01, 2017 ... ... many runners, especially in the winter months when people don’t want to stop training ... the knees – and setting the treadmill to a small incline can help protect ...
(Date:3/1/2017)... ... , ... “McFarnia”: a suspenseful tale of a father who vanishes without a ... disappearance. “McFarnia” is the creation of published author Tony Pierzchala, a former Army man, ... a Chaplain with Transport for Christ at a truck stop in the Greensboro area. ...
(Date:3/1/2017)... ... ... of Love”: a tale of young love and war. ““Letter of Love”” is the ... Salvador, wife, mother, and co-founder of a Christian College. , “I turned to ... poor communities, and I study psychology. I lived the civil war. ” --Maria Teresa ...
(Date:3/1/2017)... ... , ... “The Affair is Over Now Go Live Your Life Abundantly”: a ... affair. “The Affair is Over Now Go Live Your Life Abundantly” is the creation ... dedicated her professional life to teaching and writing about marriage and family life in ...
(Date:2/28/2017)... ... , ... Answering strong demand for its medical device software design and development ... in the Soma neighborhood in San Francisco on March 1, 2017. The opening also ... systems architecture subject matter experts. , Orthogonal serves a sizeable clientele in the Bay ...
Breaking Medicine News(10 mins):
(Date:3/1/2017)... DIEGO , March 1, 2017  Aethlon ... European Patent Office has granted European Patent Number ... In recent years, exosomes have emerged ... a wide range of disease conditions, including cancer, ... (CTE).  This granted European Patent is an important ...
(Date:3/1/2017)... 1, 2017  Numotion, the nation,s leading provider of ... Tek RMD ("robotic mobilization device") by Matia Robotics in ... is a motorized standing movement device that offers the ... to complete everyday activities from a standing position. Unlike ... RMD unassisted. Numotion is the exclusive distributor of the ...
(Date:3/1/2017)... ... and Markets has announced the addition of the "Global Infertility ... The Global Infertility Therapy Partnering Terms and Agreements since 2010 ... into by the world,s leading healthcare companies. The report ... discovery or development stage whereby the licensee obtains a right or ...
Breaking Medicine Technology: