A ribbon diagram of the protein Lsd19, which catalyzes the formation of six-membered rings in lasalocid. Image: Kinya Hotta |
Researchers working at the United States
Department of Energy’s (DOE) SLAC National Accelerator Laboratory have used
powerful X-rays to help decipher how certain natural antibiotics defy a longstanding
set of chemical rules—a mechanism that has baffled organic chemists for
decades.
Their result, reported in Nature, details how five carbon atoms
and one oxygen atom in the structure of lasalocid, a natural antibiotic
produced by bacteria in soil, can link into a six-membered ring through an
energetically unfavorable chemical reaction. Unlocking this chemical pathway
could enable scientists to synthesize many important chemicals currently found
only in nature.
“Our study has a broad implication because
the six-membered ring is a common structural feature found in hundreds of drug
molecules produced by nature,” said the study’s principal investigator,
Chu-Young Kim of the National University of Singapore. “We have actually
analyzed the genes of six other organisms that produce similar drugs and we are
now confident that the chemical mechanism we have uncovered applies to these
other organisms as well.”
According to “Baldwin’s
Rules for Ring Closure,” which govern the way these rings form, this
compound should contain a five-membered ring instead of the observed
six-membered ring.
The solution to the molecular mystery
depended in large part on a deeper understanding of the unique protein Lsd19,
the catalyst that enables the formation of lasalocid’s rings. To determine the
protein’s atomic structure, the researchers hit frozen crystals of Lsd19 with
X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource and observed how
the crystals diffracted the X-rays passing through. “You need atomic-level
detail of the crystal’s structure to understand what’s really happening,”
said co-author Irimpan Mathews, a staff scientist at SLAC.
“The bugs have taught us a valuable
chemistry lesson,” Kim said. “With a new understanding of how nature
synthesizes the six-membered rings, chemists may be able to develop novel
methods that will enable us to produce these drugs with ease in the chemical
laboratory. Alternatively, protein engineers may be able to use our results to
develop a biofactory where these drugs are mass produced using a fermentation
method. Either method will make more effective and more affordable drugs
available to the public.”
Kim’s
group has moved on to their next challenge: investigating how nature
synthesizes the anti-cancer drug echinomycin. In the meantime, “The knowledge
we have generated will help researchers in academia and industry to develop new
methods for biological production of important polyether drugs,” he said. “We
are not talking about the distant future.”
