Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Scientists Discover a New Type of Protein Modification that May Play a Role in Cancer and Diabetes

Published: Tuesday, August 06, 2013
Last Updated: Tuesday, August 06, 2013
Bookmark and Share
Scientists at The Scripps Research Institute (TSRI) have discovered a new type of chemical modification that affects numerous proteins within mammalian cells.

The modification appears to work as a regulator of important cellular processes including the metabolism of glucose. Further study of this modification could provide insights into the causes of diabetes, cancer and other disorders.

“It appears to be an intrinsic feedback mechanism in glucose metabolism, but I suspect that its other functions throughout the cell will prove at least as interesting when they are more fully elucidated,” said Benjamin F. Cravatt, chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Physiology at TSRI.

Cravatt and his postdoctoral fellow Raymond E. Moellering reported the finding in the August 2, 2013 issue of the journal Science.

In Search of New Protein Modifiers

The Cravatt laboratory has long studied the natural chemical modifications that can change the functions of proteins “on the fly,” switching their biological activities on or off or otherwise altering them. The better known of these modifications include phosphorylation, the addition of a small molecule known as a phosphate group, and acetylation, the addition of an acetyl group.

In search of new protein modifiers, Cravatt and Moellering, whose postdoctoral fellowship is sponsored in part by the Howard Hughes Medical Institute and the Damon Runyon Cancer Research Foundation, decided to investigate a small molecule known as 1,3-bisphosphoglycerate (1,3-BPG). The molecule’s chemical makeup suggested that it might readily react with some proteins to form semipermanent, function-altering modifications. 1,3-BPG is one of the main “intermediate” molecules produced during glycolysis, which is a core metabolic pathway that converts glucose to cellular fuel.

 “1,3-BPG’s intrinsic reactivity seemed odd to us, considering that it is such a central metabolite,” remembered Moellering.

Moellering’s initial test-tube experiments showed that 1,3-BPG does indeed react with certain lysine amino acids to modify GAPDH, the enzyme that mediates the production of 1,3-BPG. “That gave us the first indication that this reaction does happen, and that we should therefore start looking for it in cells,” he said.

A Role in Glucose Metabolism

After devising new methods to detect this unique lysine modification in human cell cultures, Moellering soon found it—on other glucose-metabolizing enzymes, as well as on proteins seemingly unrelated to glucose metabolism.

“With every step we took, the project became more interesting, because we were finding signs that this reaction occurs frequently in cells and in animal tissues, and in unexpected cellular locations, too,” Moellering said.

He detected the signature of the new lysine modification not only on proteins in the main volume of the cell (the cytosol), but also in the DNA-containing cell nucleus and even on the cell’s membrane compartments.

“It appears that wherever GAPDH goes within cells, it is capable of catalyzing the localized production of 1,3-BPG, which in turn reacts with nearby proteins to modify their structure and function,” said Cravatt.

Moellering found that when 1,3-BPG’s lysine modification occurs on glucose-metabolizing enzymes, it tends to inhibit their activities, causing a slowdown of central glucose processing and a consequent buildup of certain glucose metabolites in the processing pathway. Moellering and Cravatt suspect that these overabundant metabolites may end up being shunted into other cellular processes besides basic fuel-making—processes that contribute to the synthesis of new molecules and even cell proliferation.

Moellering also discovered that 1,3-BPG and the modification it makes on proteins become more prevalent as glucose levels rise. Within the context of glucose metabolism, 1,3-BPG’s modification thus seems to act as a “very old, maybe ancient feedback mechanism for regulating that central metabolic pathway,” Moellering said.

Looking Ahead

The abnormal processing of glucose within cells features in a number of major diseases including cancer and diabetes. “Cancer cells, for example, bring in as much as 20 times more glucose than non-cancerous cells of the same type,” Moellering noted. He now wants to find out whether 1,3-BPG is part of the problem in such cells. At abnormally high levels, it conceivably could help force glucose metabolism toward the runaway cell proliferation that is a hallmark of cancer.

Cravatt and Moellering also want to learn more about what 1,3-BPG’s lysine modification does in the nuclei and membrane compartments of cells, where they found evidence of it. “We suspect that it works to connect glucose metabolism to other pathways, perhaps as a kind of signaling mechanism,” said Moellering.

Already Moellering has uncovered evidence that there are enzymes that work to reverse 1,3-BPG’s modification of lysines—which underscores the likelihood that this modification represents a fundamental, dynamic mechanism in cells. “We’d like to discover which enzymes catalyze the removal of the modification,” said Cravatt, “because then, in principle, we could use inhibitors of these enzymes to control the levels of the modification and get a better understanding of its biological functions as well as the conditions under which it occurs.”

Funding for the study, “Functional Lysine Modification by an Intrinsically Reactive Primary Glycolytic Metabolite,” was provided by the National Institutes of Health (CA087660), the Skaggs Institute for Chemical Biology at TSRI and the Damon Runyon Cancer Research Foundation.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,200+ scientific posters on ePosters
  • More Than 4,600+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Memory Suppressor Gene Identified
Scientists have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, a widely recognized substitute for human memory studies.
Tuesday, April 19, 2016
Promising Results for AIDS Vaccine
Engineered vaccine protein binds key immune cells that exist in nearly everyone.
Wednesday, March 30, 2016
New Targets for Diabetes, Inflammation Discovered
The Scripps Research Institute and Salk Scientists discover 'outlier' enzymes that could offer new targets to treat diabetes and inflammation.
Tuesday, March 29, 2016
Versatile New Molecule-Building Technique
Chemists at The Scripps Research Institute (TSRI) have devised a new and widely applicable technique for building potential drug molecules and other organic compounds.
Tuesday, January 19, 2016
Flipping Molecular 'Switch' May Reduce Nicotine's Effects in the Brain
Scientists at The Scripps Research Institute (TSRI) have discovered that a lipid (fat molecule) in brain cells may act as a “switch” to increase or decrease the motivation to consume nicotine.
Friday, January 15, 2016
TSRI Team Comes Together with Rare Disease Community
Don’t worry, science fiction fans, the machines aren’t taking over quite yet. It turns out humans still beat computers at reading and comprehending text.
Monday, January 11, 2016
Single ‘Transformer’ Proteins
A new study led by scientists at The Scripps Research Institute (TSRI) and St. Jude Children’s Research Hospital shows how a protein involved in cancer twists and morphs into different structures.
Monday, January 11, 2016
Pushing Drug Discovery Forward
A new study, led by scientists at The Scripps Research Institute (TSRI), shows how different pharmaceutical drugs hit either the “on” or “off” switch of a signaling protein linked to asthma, obesity and type 2 diabetes.
Monday, December 14, 2015
TSRI Team Finds Unique Anti-Diabetes Compound
Scientists from The Scripps Research Institute (TSRI) have deployed a powerful new drug discovery technique to identify an anti-diabetes compound with a novel mechanism of action.
Thursday, December 10, 2015
Protein 'Talks' to Wrong Partners in Cystic Fibrosis
Scientists at The Scripps Research Institute (TSRI) have found evidence that a mutant protein responsible for most cases of cystic fibrosis is so busy “talking” to the wrong cellular neighbors that it cannot function normally and is prematurely degraded.
Monday, December 07, 2015
'Fingerprints' for Major Drug Development Targets
For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have created detailed “fingerprints” of a class of surface receptors that have proven highly useful for drug development.
Friday, December 04, 2015
Potential Treatment for Life-Threatening Viral Infections Revealed
The findings point to new therapies for Dengue, West Nile and Ebola.
Thursday, November 26, 2015
Surprising Trait Found in Anti-HIV Antibodies
Scientists at The Scripps Research Institute (TSRI) have new weapons in the fight against HIV.
Monday, November 23, 2015
Potential Persistent Tuberculosis Treatment
Researchers have discovered several first-in-class compounds that target hidden TB infections by attacking a critical process the bacteria use to survive in the hostile environment of the lungs.
Monday, November 23, 2015
Long-Sought Protein Sensor for the ‘Sixth Sense’ Discovered
In a study led by scientists from The Scripps Research Institute (TSRI)the sensor protein for propioception has been identified.
Monday, November 16, 2015
Scientific News
Platelets are the Pathfinders for Leukocyte Extravasation During Inflammation
Findings from the study could help in the prevention and treatment of inflammatory pathologies.
ASMS 2016: Targeting Mass Spectrometry Tools for the Masses
The expanding application range of MS in life sciences, food, energy, and health sciences research was highlighted at this year's ASMS meeting in San Antonio, Texas.
Benchtop Automation Trends
Gain a better understanding of current interest in and future deployment of benchtop automated systems.
Manufactured Stem Cells to Advance Clinical Research
Clinical-grade cell line will enable development of new therapies and accelerate early-stage clinical research.
Dengue Virus Exposure May Amplify Zika Infection
Researchers at Imperial College London have found that the previous exposure to the dengue virus may increase the potency of Zika infection.
Gender Determination in Forensic Investigations
This study investigated the effectiveness of lip print analysis as a tool in gender determination.
Identifying Novel Types of Forensic Markers in Degraded DNA
Scientists have tried to verify the nucleosome protection hypothesis by discovering STRs within nucleosome core regions, using whole genome sequencing.
Proteins in Blood of Heart Disease Patients May Predict Adverse Events
Nine-protein test shown superior to conventional assessments of risk.
Higher Frequency of Huntington's Disease Mutations Discovered
University of Aberdeen study shows that the gene change that causes Huntington's disease is much more common than previously thought.
Starving Stem Cells May Enable Scientists To Build Better Blood Vessels
Researchers from the University of Illinois at Chicago College of Medicine have uncovered how changes in metabolism of human embryonic stem cells help coax them to mature into specific cell types — and may improve their function in engineered organs or tissues.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,200+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,600+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!