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Princeton chemists reveal the first path for introducing selenium into natural products

Princeton Chemistry researchers have discovered a biosynthetic pathway that incorporates selenium into small microbial molecules, marking the first time such atoms have been discovered in natural products and opening new avenues in selenobiology.

Research also strongly suggests that selenium, an essential trace element in all realms of life, may play a more important biological role in bacteria than scientists initially hypothesized.

Chase Kayrouz, Mo Lab fourth year student and lead author of the paper published this week in Nature. Photo by C. Todd Reichart

The lab article, “Biosynthesis of Selenium-Containing Small Molecules in Different Microorganisms,” was written by Chase Kayrouz, a fourth-year graduate student in the lab; postdoc Jonathan Huang and Nicole Hauser; and Mohammad Seyedsayamdost, professor in the Department of Chemistry.

“It was a kind of closed field. No one had found a new pathway in selenium metabolism in 20 years, “Kayrouz said.” The biosynthesis of selenoproteins and selenonucleic acids was elucidated in the 1980s and 1990s. And since then, people have thought that these were the only things microbes do with selenium. We simply wondered if they could incorporate selenium into other small molecules? It turns out they do. “

Seyedsayamdost said: “Our work shows that nature has indeed developed pathways to incorporate this element into small molecules, sugars and secondary metabolites. Selenium has remarkable properties that are distinct from those of any other element present in biomolecules. The incorporation of selenium into selenonein, for example, makes it a much better antioxidant than the sulfur version of the molecule. But while sulfur is ubiquitous in biomolecules, the presence of selenium is much rarer and was thought to be limited to biopolymers.

“Nature has developed specific mechanisms to incorporate sulfur or selenium into natural products, thus exploiting the unique properties of both elements through specific pathways for each.”


The lab began its investigation on the assumption that selenium atoms should exist in natural products due to their ubiquity of use elsewhere. They asked, what would such a signature look like in microbial genomes?

“How do you see where a new drug, a natural product or a selenium metabolite is, how do you find it?” Kayrouz said. “We usually look for clusters of biosynthetic genes, groups of genes on the chromosome that code for the biosynthesis of those molecules. So if we have a path to making a compound containing selenium, it has to be encoded by the genes. “

They implemented a genome extraction strategy looking for genes lying next to selD, which encodes the first step in all known selenium processes within the cell.

Quite quickly, they found a gene that was co-localized with selD, called senB, which caught their attention, particularly because it had not previously been implicated in selenium metabolism.

Further tests found a third co-localized gene, called SenA. Kayrouz hypothesized that these three genes may be involved in a novel selenium biosynthetic pathway.

“First, we defined what a biosynthetic gene cluster that incorporates selenium would look like,” Seyedsayamdost said. ‘We then used bioinformatics to look for such genes and identified what we now call’ sen clusters ‘in different microbial genomes.’

They were able to express each of these new genes in Escherichia coli, thus assembling the entire pathway in a test tube. This revealed the production of two small selenium-containing molecules: a selenosugar and a molecule called selenonein. It also revealed two enzymes that form carbon-selenium bonds, the first such enzymes to act on small biological molecules.

“Microbes are putting selenium into these compounds for a reason, so there must be an interesting bioactivity associated with them,” Kayrouz said. “We don’t know what it is yet, but it’s extremely exciting. As biological chemists, discoveries like this are what we wake up to every day. “

Read the Nature paper here: https://www.nature.com/articles/s41586-022-05174-2

“Biosynthesis of small selenium-containing molecules in different microorganisms” was written by Chase Kayrouz, Jonathan Huang, Nicole Hauser and Mohammad Seyedsayamdost. This research is supported by a CAREER Award from the National Science Foundation (# 1847932 for MRS) and the National Institutes of Health (GM129496), as well as Edward C. Taylor’s 3rd Year Chemistry Scholarship, Scholarship postdoctoral study of the Life Sciences Research Foundation, and the postdoctoral fellowship of the Swiss National Science Foundation.

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