Nav: Home

Researchers discover new enzymes central to cell function

January 18, 2018

Doctors have long treated heart attacks, improved asthma symptoms, and cured impotence by increasing levels of a single molecule in the body: nitric oxide.

The tiny molecule can change how proteins function. But new research featured in Molecular Cell suggests supplementing nitric oxide--NO--is only the first step. Researchers have discovered previously unknown enzymes in the body that convert NO into "stopgap" molecules--SNOs--that then modulate proteins. The newly discovered enzymes help NO have diverse roles in cells. They may also be prime therapeutic targets to treat a range of diseases.

The discovery represents a paradigm shift for biologists in the field, says study lead Jonathan Stamler, MD, professor of medicine at Case Western Reserve University School of Medicine and President, University Hospitals Harrington Discovery Institute.

"Nitric oxide 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," he explained. "The prevailing view in the field is that too much or too little NO is due to 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 enzymes work together to control proteins through a process called S-nitrosylation. Stamler and colleagues describe a chain reaction. First, NO synthases make NO. Then, a new class of enzymes--SNO synthases--convert NO into SNOs, that 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.

NO signaling in cells is essentially designed to make SNOs--lots of them.

"This opens the field to new understanding and opportunity, as hundreds of enzymes likely carry out signaling inside cells through this process. Each of these enzymes could potentially be targeted specifically in disease," Stamler said.

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. 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," Stamler said. "Administration of NO cannot replicate the function of SNOs carried out by these new enzymes."

The groundbreaking study finally explains how NO can have so many different functions in cells. By converting NO into different SNOs, cells can achieve different results.

The next step for researchers will be to identify individual SNO synthases in different tissues and their specific roles in disease, says Stamler. The new enzymes could serve as therapeutic targets for drug developers. For example, 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," he said. 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," Stamler said. "This provides a new horizon of therapeutic opportunities, and changes perspective in the field."
-end-
Seth, et al. "A Multiplex Enzymatic Machinery for Cellular Protein S-nitrosylation." Molecular Cell.

This work was supported by National Institutes of Health grant R01-GM099921.

For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.

About University Hospitals / Cleveland, Ohio

Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 18 hospitals, more than 40 outpatient health centers and 200 physician offices in 15 counties throughout northern Ohio. The system's flagship academic medical center, University Hospitals Cleveland Medical Center, located on a 35-acre campus in Cleveland's University Circle, is affiliated with Case Western Reserve University School of Medicine. The main campus also includes University Hospitals Rainbow Babies & Children's Hospital, ranked among the top children's hospitals in the nation; University Hospitals MacDonald Women's Hospital, Ohio's only hospital for women; and University Hospitals Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, including cancer, pediatrics, women's health, orthopedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and urology. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including "America's Best Hospitals" from U.S. News & World Report. UH is also home to Harrington Discovery Institute at University Hospitals - part of The Harrington Project for Discovery & Development. UH is one of the largest employers in Northeast Ohio with 27,000 employees. Follow UH on Facebook @UniversityHospitals and Twitter @UHhospitals. For more information, go to UHhospitals.org.

Case Western Reserve University

Related Proteins Articles:

Discovering, counting, cataloguing proteins
Scientists describe a well-defined mitochondrial proteome in baker's yeast.
Interrogating proteins
Scientists from the University of Bristol have designed a new protein structure, and are using it to understand how protein structures are stabilized.
Ancient proteins studied in detail
How did protein interactions arise and how have they developed?
What can we learn from dinosaur proteins?
Researchers recently confirmed it is possible to extract proteins from 80-million-year-old dinosaur bones.
Relocation of proteins with a new nanobody tool
Researchers at the Biozentrum of the University of Basel have developed a new method by which proteins can be transported to a new location in a cell.
Proteins that can take the heat
Ancient proteins may offer clues on how to engineer proteins that can withstand the high temperatures required in industrial applications, according to new research published in the Proceedings of the National Academy of Sciences.
Designer proteins fold DNA
Florian Praetorius and Professor Hendrik Dietz of the Technical University of Munich have developed a new method that can be used to construct custom hybrid structures using DNA and proteins.
The proteins that domesticated our genomes
EPFL scientists have carried out a genomic and evolutionary study of a large and enigmatic family of human proteins, to demonstrate that it is responsible for harnessing the millions of transposable elements in the human genome.
Rare proteins collapse earlier
Some organisms are able to survive in hot springs, while others can only live at mild temperatures because their proteins aren't able to withstand such extreme heat.
How proteins reshape cell membranes
Small 'bubbles' frequently form on membranes of cells and are taken up into their interior.

Related Proteins Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#529 Do You Really Want to Find Out Who's Your Daddy?
At least some of you by now have probably spit into a tube and mailed it off to find out who your closest relatives are, where you might be from, and what terrible diseases might await you. But what exactly did you find out? And what did you give away? In this live panel at Awesome Con we bring in science writer Tina Saey to talk about all her DNA testing, and bioethicist Debra Mathews, to determine whether Tina should have done it at all. Related links: What FamilyTreeDNA sharing genetic data with police means for you Crime solvers embraced...