Revealing how a soil bacterium carries out surprising chemistry
18 Apr 2012 by Evoluted New Media
An international team of researchers have discovered how soil bacteria utilising surprising chemistry defies a longstanding set of chemical rules and could pave the way for a new synthesis of polyether drugs.
Streptomyces lasaliensis is able to convert an epoxide into a six-membered cyclic ether during synthesis of lasalocid, a natural antibiotic. However, this type of chemical transformation is known to be kinetically unfavourable – according to Baldwin’s Rules for Ring Closure, the lasalocid should form a five-membered ring.
“Our study has broad implications because six-membered cyclic ether is a common structural feature found in hundreds of drug molecules produced by nature,” said principal investigator Chu-Young Kim from the National University of Singapore.
“We have analysed the genes of six other organisms that produce similar polyether drugs and we are now confident that the biosynthetic strategy we have uncovered is also used by those organisms.”
[caption id="attachment_27676" align="alignright" width="200" caption="The crystal structure of Lsd19 determined at 1.59 Å resolution (PDB ID: 3RGA). The X-ray diffraction data was collected at beam line 7-1 of Stanford Synchrotron Radiation Lightsource Credit: Dr. Kinya Hotta"]
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In order to understand why the bacteria formed six-membered rings, researchers from Singapore, Japan, the UK and USA needed to understand the unique structure of the enzyme Lsd19 – which catalyses the formation of two cyclic ether moieties that are part of the lasalocid structure. They bombarded frozen crystals of Lsd19 with x-rays, and analysed how the crystals diffracted the x-rays.
“The bugs have taught us a valuable chemistry lesson,” Kim said. “With a new understanding of how nature synthesises the six-membered ring, chemists may be able to develop new methods to produce polyether drugs with ease in the laboratory.”
“Alternatively, protein engineers may be able to use our results to develop a biofactory, where polyether drugs are mass produced using fermentation. Either method will make more effective and more affordable drugs available to the public.”
The group will now investigate how nature synthesises echinomycin, an anti-cancer compound produced by soil bacteria.
