Scientists at the universities of Bristol and Newcastle have uncovered the secret of an elusive chemical reaction in a bacterium that lives at the bottom of the Pacific Ocean.
The research team hopes that the discovery could lead to the development of new antibiotics and other medical treatments. The Diels-Alder reaction, originally discovered by Nobel Prize-wining chemists Otto Diels and Kurt Alder, is one of the most powerful chemical reactions known, and is used extensively by synthetic chemists to produce molecules, including antibiotics, anti-cancer drugs and agrochemicals.
However, there has been much debate about whether or not nature uses the reaction to produce its own useful molecules and the identity of the biological catalysts, in the form of enzymes, responsible for performing this reaction have remained a mystery. Some natural ‘Diels-Alderases’ have been identified but have either been shown not to perform the reaction or the evidence is ambiguous. Now, researchers at BrisSynBio, a BBSRC/EPSRC Synthetic Biology Research Centre at the University of Bristol and the School of Biology at Newcastle University have shown that a true ‘Diels-Alderase’, a Diels-Alder enzyme, exists and have established in atomic detail how it catalyses the reaction.
Dr Paul Race, from BrisSynBio, said they found the enzyme, called AbyU, in a bacterium called Verrucosispora maris which lives on the Pacific seabed. V. maris uses the AbyU enzyme to biosynthesise a molecule called abyssomicin C, which has potent antibiotic properties. The team first had to solve the atomic structure of AbyU, and then simulate the enzyme reaction using quantum mechanics methods.
Dr Race said: “Once we had figured out how AbyU was able to make natural antibiotic, we were able to show that it could also perform the Diels-Alder reaction on other molecules that are difficult to transform using synthetic chemistry.” The team are now investigating ways of using the enzyme to make molecules similar to abyssomisin C, in the hope that antibiotics are found that are even more effective than the natural molecule.
Dr Race said: “What is particularly exciting about our work is that not only have we resolved the riddle of the natural Diels-Alderase, but we have also shown that the enzyme can perform Diels-Alder reactions that are challenging to perform using synthetic chemistry. “The work opens up a raft of possibilities for making new useful molecules that could, for example, form the basis of new medicines, materials, or commodity chemicals.”
Dr Jem Stach, from Newcastle University, a co-author of the paper, said: “Nature, not only in the compounds it produces, but also the means by which it does so, is the best chemist. This has never been clearer to me than it was during this collaboration between biologists and chemists. “Starting with genome gazing, and ending with new chemistry, on a journey that took in structural biology, synthetic chemistry and computational chemistry, was utterly rewarding, educational and fascinating.”
‘Unity needed after Brexit vote’
The organisation representing the UK chemical industry says that the UK Government must work with its members to protect the sector after the Brexit vote in June.
Steve Elliott, Chief Executive of the Chemical Industries Association which represents chemical and pharmaceutical businesses across the UK, said “It is not the decision that our sector wanted, but we fully respect the wish of the people for change.
“Whilst business craves certainty, it is also used to operating in challenging and changing circumstances; this is what companies and their representative bodies do wherever they operate. We now have to look to the future and I am confident that an important and resilient industry such as ours can prosper in this new situation. “I am calling on the Government to work hard on securing the best exit plan for the UK and then establishing the new trading arrangements. Whilst we need to progress both these negotiations as soon as we can to limit uncertainty, we also need an immediate period of calm reflection to minimise instability.
“As an Association we will do everything we can to help our members through any period of uncertainty and to be influential in the Government’s negotiations, both here in the UK and with our partners in Brussels. “Our sector looks forward to playing its part in helping to carve out a new role for our country, maximising UK chemical and pharmaceutical competitiveness and jobs in the global economy.”