Researchers at the University of Buffalo have identified for the first time an enzyme in the foxglove plant that is responsible for producing the compounds needed to make the heart failure drug digoxin.
The breakthrough discovery, described in a paper published July 8 at Communication in Nature, established knowledge of compounds, known as cardiac glycosides. It will also help speed up the production of plant-based medicine, which is one of the oldest medicines used in the field of cariology, and help researchers develop less toxic alternatives.
The work was led by Zhen Wang, assistant professor in the Department of Biological Sciences, along with his lab’s Ph.D. student Emily Carroll and postdoctoral associate Baradwaj Ravi Gopal, who are both co-first authors.
“The enzyme has been speculated for more than half a century, but no one had found it until Emily’s work. We were the first to discover the enzyme,” Wang said.
“I was surprised that, as a young lab without a lot of experience in this field, we were able to pull it off in a relatively short time and do it. discover this enzyme, and we’re going to discover other enzymes,” Wang said. “It’s like a dream come true.”
Education exposed professor of herbal medicine
Wang, who joined the UB faculty in 2017, says his upbringing influenced his decision to focus on natural plant products.
“I grew up in China, where I had exposure to traditional Chinese herbal medicines, so it was definitely a cultural connection for me. There are a lot of resources, and a lot of unknowns in terms of chemical diversity. of plants that will undoubtedly benefit modern medicine.” said Wang.
Wang started his lab with the mission of bringing medicinal plants and natural products back into the human medicine cabinet.
He targeted foxglove because it produces digoxin, which is an accepted plant-based medicine that the World Health Organization says is an essential medicine for human health.
Researchers have mapped foxglove mRNA
Digoxin is produced in foxglove leaves, but not in any other tissues. This led Ravi Gopal to map the mRNA producing enzymes—a process called transcriptome analysis—to compare the enzymes present in the leaves and other tissues of foxglove.
Carroll then tried to activate these enzymes using tobacco and yeast, work that led to the discovery of the key enzyme.
Ravi Gopal says his motivation to discover new ways to produce digoxin is also based on the future nature of climate change. The production of digoxin through agricultural means will soon become impractical, he said. “We cannot continue with this level of land and water resources used for production, so this is the real alternative and more viable way to do it,” he said.
Digoxin takes two years to produce because the foxglove plant must fully mature before the leaves can be harvested. “Then the leaves are dried for a year,” Wang explained, and after that, “the active ingredient—the drug—is extracted from the dried leaves. The yield is extremely low, only 0.06% of the dry weight -to the plant.”
Carroll says these types of compounds are complex and often difficult to synthesize through organic chemistry. This makes finding an alternative way to make them important. Plants and other organisms naturally produce these compounds, and he hopes to use this knowledge to make medicine more efficient.
Ravi Gopal hopes that advances in the lab will allow them to produce this compound in a shorter period of time, and more sustainably. “We want to see if we can do it overnight, or maybe for a week instead,” he said.
What does the future hold?
Wang hopes that the progress made in his lab can lead to faster and more widespread production of digoxin and other cardiac glycosides, by triggering yeast-microscopic fungi-to produce digoxin.
“We’re looking at expanding the use of this class of compounds because digoxin can have serious side effects in patients, so it’s no longer a frontline drug for heart failure or atrial fibrillation, but it’s a “It’s still a life-saving drug when patients don’t respond to front-line drugs,” Wang said. “We hope that, by changing the structure of digoxin, we will be able to create a new drug with high efficacy and less toxicity.”
Making these compounds with the help of yeast will lead to future advances in producing other cardiac glycosides that Wang hopes will be used to treat neurodegenerative diseases, cancers and inflammatory diseases such as arthritis.
“The discovery of this enzyme is like adding a new tool to an existing toolbox that we can use to make new molecules,” Carroll said.
Ravi Gopal says that this process and its implications for the future of medicine is similar to the development of antibiotics from penicillin. Similarly, he thinks they will pave the way for future compounds very similar to digoxin, with different applications.
“It looks like 10 to 20 years from now,” Wang said. “However, instead of using organic chemistry to synthesize these compounds, we hope to engineer microbes to produce a new class of cardiac glycosides with expanding medical applications.”
Emily Carroll et al, A cytochrome P450 CYP87A4 mediates sterol side-chain cleavage in digoxin biosynthesis, Communication in Nature (2023). DOI: 10.1038/s41467-023-39719-4
Provided by the University at Buffalo
Citation: Researchers identify key enzyme for heart failure drug digoxin (2023, July 17) retrieved on 17 July 2023 from https://phys.org/news/2023-07-key-enzyme- heart-failure-drug.html
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