Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Genomics researchers discover protein deficit that causes drug toxicity

11.07.2005


Mayo Clinic researchers have discovered an inherited structural mechanism that can make drugs for some diseases toxic for some patients. The mechanism decreases a protein and in turn causes certain individuals to metabolize thiopurine drugs differently. Thiopurine therapies are used to treat patients with childhood leukemia, autoimmune diseases and organ transplants. The Mayo researchers say their finding advances the field of pharmacogenomics, which tailors medicine to a patient’s personal genetic makeup.



In the current issue of the Proceedings of the National Academy of Sciences, (http://www.pnas.org/cgi/content/abstract/102/26/9394) Mayo researchers report that under certain genetic conditions, key proteins are not formed properly -- they are "misfolded." When misfolding happens, the quality-control process in the cell detects the misfolded proteins and tags them for immediate destruction or quarantines them in a "cellular trash can" known as an aggresome (last syllable rhymes with "foam"). Whether destroyed or aggregated into the aggresome, the effect is the same: the patient’s body suffers a protein deficit that disrupts the enzyme that metabolizes thiopurine.

"Our finding is surprising because the aggresome is a new kind of mechanism to study to explain this. It’s quite different from what we were thinking even a few years ago," says Liewei Wang, M.D., Ph.D., lead Mayo researcher in the study. "People are still debating what its function really is, but it appears to play a role here by receiving misfolded proteins."


Significance of the Research

"Nobody has shown before that the aggresome plays a role in thiopurine metabolism, and it’s a significant contribution," says Richard Weinshilboum, M.D., the Mayo Clinic researcher who first described the genetically variable response to thiopurine drugs over 20 years ago. "From a clinical point of view, the genetic test we developed at Mayo to predict response to thiopurine drugs has been invaluable to pharmacogenomic medicine -- and now this finding is taking us in promising new directions because we believe our findings can be generalized to apply to many instances in the field."

The finding helps explain what goes wrong under certain genetic conditions -- and suggests mechanisms which might help predict which genetic changes could alter the effect of drugs. Prior efforts to explain the mystery of thiopurine metabolism had focused on biochemical mechanisms -- not changes in protein levels.

Background

Researchers have known for decades that 1 in 300 patients of Caucasian European genetic background has two copies of the variant gene -- specifically, a switch in 2 out of 245 amino acids -- that results in the absence of the protein needed to properly metabolize thiopurine drugs. In patients with the genetic defect, instead of helping heal, a standard dose of thiopurine drugs can cause fatal bone marrow destruction. Though Mayo Clinic researchers described this genetically variable response and the danger it presents over 20 years ago, no one had been able to explain the cellular mechanism behind it.

Robert Nellis | EurekAlert!
Further information:
http://www.mayoclinic.com)

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>