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scieNce oN the cUttiNg edge

The Scripps Research Institute News

Scientists Look To Nature at its disposal to generate them,” Steele says. “We found

To Discover Method For nature has provided us with a solution to tackle this
problem.”
Installing Sulfur Into Complex engineer sulfur-containing compounds and paves the way
The current discovery enriches the toolbox needed to
Molecules for synthetic biologists to develop entirely new classes of
molecules to impact chemistry, biology, and medicine, they
Advance provides new tools for synthetic chemists say.
and biologists looking to probe and modify sulfur-based “I tell my students, if you want to discover something,
biochemistry. find how nature does it, that can present a solution,” Shen
A group of highly reactive compounds called persulfides says.
have provoked great curiosity among biochemists, because Chemistry professor and Department Chair Ben Shen, Ph.D., In addition to Shen, Meng, Steele and Kalkreuter,
of their role in nature, and how they interact with proteins to has discovered a new group of enzymes that install sulfur the other authors of the study, “Thiocysteine lyases as
change their structure and function, affecting health, aging into protein molecules. polyketide synthase domains installing hydropersulfide into
and disease processes. natural products and a hydropersulfide methyltransferase,”
Studying persulfides and their effects has proven Soon after, they discovered the thiocysteine lyases, a include Wei Yan, Guohui Pan, Yu-Chen Liu and Zhengren
challenging, however, due to the chemical’s instability. As family of previously unknown enzymes that nature uses to Xu, all of Scripps Research in Jupiter, Fla.
soon as persulfides are generated, they want to react with make persulfides as key intermediates to build the entire Funding for the study was provided by the National
nearby molecules before they can be fully investigated. leinamycin family of natural products. Institutes of Health, (GM134954). A.D.S. and E.K.
A new study from the Florida campus of Scripps The natural products collection has been the key to their are supported in part by NIH Postdoctoral fellowships
Research, published in Nature Communications, Sept. 28, success, adds Edward Kalkreuter, Ph.D., a co-author on the (GM133114 and GM134688). W.Y. is supported in part by
reveals a previously unrecognized way that nature solves paper. the Nanjing Agricultural University, Nanjing, China, and a
this problem and makes use of persulfides, through the “While traditionally only one biosynthetic pathway scholarship from the Chinese Scholarship Council.
generation of helpful enzymes that play a role in sulfur could be studied at a time, our strain collection now allows
placement. The discovery provides researchers with a new us to discover evolutionarily-related families, thereby Wiring The Brain To Learn
method for generating potentially important sulfur-based comparing and evaluating many similar pathways at once,”
molecules in the lab, and offers an answer to one of nature’s he adds. Requires Autism-Linked Gene
fascinating biological mysteries: How does sulfur become The enzymes enabling the persulfide formation are likely
integrated into complex molecules in the first place? to have a broad range of potential applications in the future, Study finds imbalance between active and inactive
Sulfur is the fifth most common element of life, yet they add. neurons if Syngap1 diminishes, resulting in reduced
nature uses a relatively small number of mechanisms to “Persulfides have been found in numerous fundamental connections and learning impairment.
install it into small molecules, says Ben Shen, professor and disease-related biochemical systems, but the field of
and chair of the Scripps Research Department of Chemistry synthetic chemistry has only a few specialized methods The Scripps Research Institute News on page 17
in Jupiter, Fla., and senior author of the study.
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sequencing and analyzing – their genetic material for telltale
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“We have now discovered a new mechanism by which
nature installs two sulfur atoms into a small molecule at the
same time, overcoming the long-lasting challenge in their
instability,” Shen says. “This particular finding illustrates
how powerful our natural product strain collection is, and
how it enables us to do things that are innovative.”
The natural product collection at Scripps Research in
Florida includes more than 125,000 strains of bacteria,
which were collected by research groups worldwide during
the decades after streptomycin was discovered.
Bacteria from soil must evolve diverse, biologically
active natural products to survive in a hostile and
competitive world. Those natural products have enormous
potential to act as medicines or serve other purposes, if they
can be discovered, studied and understood, Shen says.
Constructing these molecules requires the bacteria to
act as chemists themselves, devising sometimes innovative
processes like new catalytic enzymes, says Song Meng,
Ph.D., a lead author of the publication.
“The study of natural products allows us to explore how
nature uses simple building blocks to build up the most
complex structures humanity has ever seen, which provides
opportunities for enzyme discovery and potential impact
throughout the entire field of organic chemistry,” Meng
says.
By learning how nature builds natural products, the
researchers in Shen’s lab aim to inspire future efforts in
diverse fields such as microbiology, biotechnology, organic
chemistry, and medicinal chemistry.
Study coauthors Meng and Andrew Steele, Ph.D.,
recalled the moment they knew they would achieve their
goal.
“We had been working tirelessly to make unstable
persulfides. They degrade into smelly hydrogen sulfide, so
the first time that we smelled rotten eggs we knew that we
had made a breakthrough,” Steele says.