Molecular 'GPS' Helps Researchers Probe Processes Important in Aging and Disease

Newswise — With all the hype about beneficial antioxidants in everything from face cream to cereal bars, you'd think their targets---oxygen radicals---must be up to no good. It's true, the buildup of oxygen radicals and other reactive oxygen species (ROS) in cells contributes to aging and possibly to diseases such as cancer and Alzheimer's.

But in moderate amounts, ROS also help keep cells healthy by controlling cell division, movement and other normal biological processes.

To better understand the role of ROS in disease, scientists first need to explore how ROS function in healthy cells, and research by a University of Michigan team led by chemical biologist Kate Carroll provides an important new tool for doing that. The research is described in a paper scheduled to be published Sept. 18 in the journal ACS Chemical Biology.

The tool, a small molecule called DAz-2, functions something like a subcellular GPS, helping researchers home in on the specific proteins that ROS affect.

The cells of all organisms, from bacteria and yeast to humans, sense ROS through a chemical modification process, known as oxidation, which influences how proteins interact with each other.

"While this overall phenomenon is widely accepted, scientists are still working to identify exactly which proteins are affected by ROS in living cells," said Carroll, assistant professor of chemistry and a research assistant professor in the Life Sciences Institute. Teasing out which proteins are modified and exactly how and where the modification takes place has been hindered by a lack of tools, but Carroll's group has developed a series of chemical probes for that purpose, of which DAz-2 is the latest.

"The new probes allow us to easily sort the proteins we want to analyze and study from other proteins that aren't modified by ROS." Carroll said.

Specifically, DAz-2 observes the oxidation of the protein building block cysteine to sulfenic acid, which can control how proteins behave and associate with other proteins. Because the modification of cysteine to sulfenic acid is so transient, it has been difficult to observe, and until recently scientists had identified only a few proteins undergoing this type of oxidation. But using DAz-2, which directly detects sulfenic acid in living cells, Carroll's group has identified more than 190 proteins, involved in diverse biological processes, that undergo this modification.

"This tool will allow the investigation of the oxidation of proteins in cellular signaling and many disease states, leading to greater understanding of how these processes operate," Carroll said. "These findings should pave the way for new therapeutic strategies to combat diseases that involve chronic oxidative stress and should lead to a better overall understanding of how cells work."

Carroll's coauthors on the paper are graduate student Stephen Leonard and postdoctoral fellow Khalilah Reddie. The researchers received funding from the Life Sciences Institute, the Leukemia & Lymphoma Society and the American Heart Association.

For more information:

Kate Carroll: http://www.lsi.umich.edu/faculty/research/labs/carroll

ACS Chemical Biology: http://pubs.acs.org/journal/acbcct

A paper published earlier this year in the journal Chemistry & Biology by Carroll and graduate student Candice Paulsen demonstrated the utility of this class of probes. The paper is available at: http://www.cell.com/chemistry-biology/abstract/S1074-5521(09)00027-1.