Genetically engineered yeast may help revolutionise painkillers' research

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London, August 11 : A team of researchers at the California Institute of Technology in Pasadena has moved a step closer to commercially producing previously unobtainable and potentially valuable alkaloids - naturally occurring chemical compounds such as morphine that often have useful pharmaceutical properties.

Chemist Christina Smolke and her colleague Kristy Hawkins claim that they have successfully reconstructed, within a yeast cell, many of the key elements of the elaborate pathways for synthesising alkaloids.

The researchers focused on the benzylisoquinoline alkaloids (BIAs) that include the painkillers morphine and codeine, and inserted into yeast cells genes from three plants-the opium poppy, Papaver somniferum, the common meadow rue, Thalictrum flavum and thale cress, Arabidopsis thaliana.

They also added the gene for a human enzyme called P450, which is known to act on a range of alkaloid molecules.

By mixing and matching different enzyme combinations, the researchers were able to create substantial amounts of seven different BIAs.

"Now that we have access to intermediates that were not previously available, people will want to do careful studies on their pharmacological activity. And we were getting yields of 100 to 200 milligrams per litre, which is respectable for potentially valuable molecules. With relatively simple optimisation of the fermentation you could obtain 10 or 100 times more than this," Nature magazine quoted Smolke as saying.

The researchers also developed a method to tune the system so that the yeast produced the optimum amount of each enzyme to synthesise whichever alkaloid they wanted, and did not waste energy making an excess of any given enzyme. This work has been hailed by Sarah O'Connor, an expert on the biosynthesis of natural products at the Massachusetts Institute of Technology, Cambridge.

"It's very exciting that plant alkaloid pathways are starting to be reconstituted in microbes. Very importantly, Smolke has also shown how this strain can be used to discover new enzymes that catalyse biosynthetic transformations," O'Connor said.

Smolke says: "We are now hoping to extend the pathway both ways - to get a broader range of intermediates downstream, including the end products, and to be able to start with simpler substrates upstream."

The researcher adds: "The system will also allow us to start producing non-natural alkaloids by using enzymes from different sources and in combinations that do not occur in nature."

A report on the study has been published in the journal Nature Chemical Biology.

ANI

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