Even the smallest molecule can change the course of a cell's future, an apropos modification of J.R.R. Tolkien’s writing from the “The Fellowship of the Ring” with respect to a recent discovery by investigators at Case Western Reserve University (CWRU). These researchers have uncovered previously unknown enzymes in the body that convert nitric oxide (NO) into “stopgap” molecules (SNOs) that then modulate proteins. Clinicians have long treated heart attacks, improved asthma symptoms, and cured impotence by increasing levels of NO in the body. These newly discovered enzymes help NO have diverse roles in cells, and they may also be prime therapeutic targets to treat a range of diseases. Findings from the new study were released today in Molecular Cell.
“NO has been implicated in virtually all cellular functions, and too much or too little is widely implicated in disease, including Alzheimer's, heart failure, cancer, asthma, and infection,” explained lead study investigator Jonathan Stamler, M.D., professor of medicine at CWRU School of Medicine and president of University Hospitals Harrington Discovery Institute. “The prevailing view in the field is that too much or too little NO is due to the activity of enzymes that make NO, called NO synthases. However, the new findings suggest that NO synthases operate in concert with two new classes of enzymes that attach NO to target proteins, and raise the possibility of literally hundreds of enzymes mediating NO-based signaling.”
The research team found that the enzymes work together to control proteins through a process called S-nitrosylation. Dr. Stamler and his colleagues described a chain reaction. First, NO synthases generate NO. Then, the new class of enzymes—SNO synthases—convert NO into SNOs, which attach to proteins and modulate their function. A third class transfers the SNOs to additional proteins that control numerous additional cellular functions, including growth, movement, and metabolism, and also protect cells from injury. Without SNO synthases, cells can't use NO. And there are potentially hundreds of different SNO-generating enzymes that make thousands of different SNOs.
“This opens the field to new understanding and opportunity, as hundreds of enzymes likely carry out signaling inside cells through this process,” Dr. Stamler noted. “Each of these enzymes could potentially be targeted specifically in disease.”
With so many enzymes in the new model, it now makes sense why drugs that increase NO levels are not interchangeable. “The assumption is that they all work the same way to increase NO,” Dr. Stamler added. “But our findings suggest that NO itself is just the first step. It's all in what the cell does with NO and which SNO it's converted into. Administration of NO cannot replicate the function of SNOs carried out by these new enzymes.”
Amazingly, this new study finally explains how NO can have so many distinct functions in cells. By converting NO into different SNOs, cells can achieve different results.
The ensuing step for researchers will be to identify individual SNO synthases in different tissues and their specific roles in disease. These new enzymes could serve as therapeutic targets for drug developers. For instance, excessive S-nitrosylation is strongly associated with Alzheimer's and Parkinson's diseases, but NO is also needed for normal brain function, including memory.
“The assumption has been that one has to block NO production to stop this from happening. But the treatments don't work,” Dr. Stamler remarked. “Since NO has such sweeping effects inside cells, blocking it has major side effects. Under the new model, researchers could target disease-specific SNO synthases working downstream of NO.
“Now we know that we can block S-nitrosylation without altering NO production,” he concluded. “This provides a new horizon of therapeutic opportunities and changes perspective in the field.”