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NUS scientists unravel 30-year-old chemical mystery

15 March 2012

Asst Prof Kim working in the X-ray Crystallography Laboratory of NUS Department of Biological Sciences

A group of scientists from NUS Department of Biological Sciences and other countries have solved a decades-old chemical mystery. Their paper titled "Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis", appeared in today's issue of Nature. The research was also featured in Chemical and Engineering News on 5 March.

The team, led by principal investigator Asst Prof Kim Chu-Young from NUS, included members from Oxford University, Hokkaido University, University of Shizuoka and University of California at Los Angeles.

The researchers made use of powerful X-rays to decipher how an antibiotic-producing soil bacterium, Streptomyces lasaliensis, is able to convert an epoxide into a six-membered cyclic ether during synthesis of lasalocid, a natural polyether antibiotic.

According to "Baldwin's Rules for Ring Closure" which predicts the way these rings form, lasalocid should contain a five-membered ring instead of the observed six-membered ring. How the bacterium achieves this kinetically unfavourable chemical transformation has remained an enigma for decades.

The team used X-ray diffraction to analyse the atomic structure of a bacterial enzyme capable of catalysing the ring closure reaction, and confirmed their finding.

Said Asst Prof Kim: "Our study has broad implications because the six-membered cyclic ether is a common structural feature found in hundreds of drug molecules produced by nature. 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."

He believes that the new understanding can lead to more effective and affordable drugs. Chemists may be able to develop new methods to produce polyether drugs with ease in the laboratory, and protein engineers may use the results to develop a biofactory where polyether drugs are mass-produced using fermentation.

Moving forward, the group is investigating how nature synthesises echinomycin, an antitumour compound produced by the same soil bacteria.

The study was supported by the Royal Commission for the Exhibition of 1851 Research Fellowship; Fulbright-AstraZeneca Research Scholarship; the Japan Society for the Promotion of Science; the US National Institutes of Health; the Ministry of Education, Culture, Sports, Science and Technology in Japan; and the NUS Life Sciences Institute Young Investigator Award.