Navigation Links
Genomics researchers discover protein deficit that causes drug toxicity

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.


'"/>

Source:Mayo Clinic


Related biology news :

1. Advancements In Genomics Foster Deep Sea Discoveries
2. Ariadne Genomics Announces the Release of PathwayStudio?Central, Client-Server Software for Biological Pathway Analysis
3. Genomics-based vaccine could prevent deadly cattle disease
4. Genomics throws species definition in question for microbes
5. NYU researchers simulate molecular biological clock
6. Vital step in cellular migration described by UCSD medical researchers
7. ASU researchers finds novel chemistry at work to provide parrots vibrant red colors
8. UCSD researchers maintain stem cells without contaminated animal feeder layers
9. Why do insects stop breathing? To avoid damage from too much oxygen, say researchers
10. New protein discovered by Hebrew University researchers
11. First real-time view of developing neurons reveals surprises, say Stanford researchers
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:4/24/2017)... -- Janice Kephart , former 9/11 Commission ... LLP (IdSP) , today issues the following statement: ... 6, 2017 Executive Order: Protecting the Nation ... instilled with greater confidence, enabling the reactivation of ... are suspended by until at least July 2017). ...
(Date:4/18/2017)... , April 18, 2017  Socionext Inc., a global expert ... a media edge server, the M820, which features the company,s hybrid ... software provided by Tera Probe, Inc., will be showcased during the ... the NAB show at the Las Vegas ... ...
(Date:4/13/2017)... , April 13, 2017 UBM,s Advanced ... will feature emerging and evolving technology through ... Innovation Summits will run alongside the expo portion of ... sessions, panels and demonstrations focused on trending topics within ... advanced design and manufacturing event will take place June ...
Breaking Biology News(10 mins):
(Date:10/12/2017)... ... 12, 2017 , ... AMRI, a global contract research, development ... patient outcomes and quality of life, will now be offering its impurity solutions ... new regulatory requirements for all new drug products, including the finalization of ICH ...
(Date:10/11/2017)... YORBA LINDA, CA (PRWEB) , ... October 11, ... ... adapted to upregulate any gene in its endogenous context, enabling overexpression experiments and ... activation (CRISPRa) system with small RNA guides is transformative for performing systematic gain-of-function ...
(Date:10/11/2017)... ... 2017 , ... Proscia Inc ., a data solutions ... “Pathology is going digital. Is your lab ready?” with Dr. Nicolas Cacciabeve, Managing ... how Proscia improves lab economics and realizes an increase in diagnostic confidence.* ...
(Date:10/11/2017)... ... October 11, 2017 , ... Disappearing forests and increased emissions ... over 5.5 million people each year. Especially those living in larger cities are affected ... based in one of the most pollution-affected countries globally - decided to take action. ...
Breaking Biology Technology: